literature review example biomedical science

Biomedical Science: Literature Review

Searching & reviewing the literature.

• Literature Review
• Search Strategy
• Database search tips

A literature review is an evaluation of relevant literature on a topic and is usually the starting point for any undergraduate essay or postgraduate thesis. The focus for a literature review is on scholarly published materials such as books, journal articles and reports.

A search and review of relevant sources may be extensive and form part of a thesis or research project. Postgraduate researchers will normally focus on primary sources such as research studies in journals.

A literature review also provides evidence for an undergraduate assignment. Students new to a discipline may find that starting with an overview or review of relevant research in books and journals, the easiest way to begin researching a topic and obtaining the necessary background information.

Source materials can be categorised as:

Primary source : Original research from journals articles or conference papers, original materials such as historical documents, or creative works.

Secondary source : Evaluations, reviews or syntheses of original work. e.g. review articles in journals.

Tertiary source : Broadly scoped material put together usually from secondary sources to provide an overview, e.g. a book.

The Literature Review Structure : Like a standard academic essay, a literature review is made up of three key components: an introduction, a body and a conclusion. Most literature reviews can follow the following format: • Introduction: Introduce the topic/problem and the context within which it is found. • Body: Examine past research in the area highlighting methodological and/or theoretical developments, areas of agreement, contentious areas, important studies and so forth. Keep the focus on your area of interest and identify gaps in the research that your research/investigation will attempt to fill. State clearly how your work builds on or responds to earlier work. • Conclusion: Summarise what has emerged from the review of literature and reiterate conclusions.

This information has been adapted from the Edith Cowan University Literature review: Academic tip sheet .

Steps in searching and reviewing the literature:

• Define the topic and scope of the assignment. Ensure you understand the question and expectations of the assignment. It's useful to develop a plan and outline, headings, etc.  
• Check terminology. e.g. dictionaries, encyclopedias, thesauruses  
• Identify keywords for searching (include English and American spelling and terminology)  
• Identify types of publications. e.g. books, journal articles, reports.  
• Search relevant databases (refer to the relevant subject guide for key databases and sources)  
• Select and evaluate relevant sources  
• Synthesise the information  
• Write the review following the structure outlined.  
• Save references used. e.g. from the databases save, email, print or download references to EndNote.  
• Reference sources (APA 7th) (see Referencing Library Guide )

When you are writing for an academic purpose such as an essay for an assignment, you need to find evidence to support your ideas. The library is a good place to begin your search for the evidence, as it acquires books and journals to support the disciplines within the University. The following outlines a list of steps to follow when starting to write an academic assignment:

Define your topic and scope of the search

• This will provide the search terms when gathering evidence from the literature to support your arguments.
• Sometimes it is a good idea to concept map key themes.

The scope will advise you:

• How much information is required, often identified by the number of words ie 500 or 3000 words
• What sort of writing you are to do eg essay, report, annotated bibliography
• How many marks are assigned. This may indicate the amount of time to allocate to the task.

Gather the information - Before writing about your topic, you will need to find evidence to support your ideas. 

Books provide a useful starting point for an introduction to the subject. Books also provide an in-depth coverage of a topic.

Journal Articles: For current research or information on a very specific topic, journal articles may be the most useful, as they are published on a regular basis. It is normally expected that you will use some journal articles in your assignment. When using journal articles, check whether they are from a magazine or scholalry publication. Scholarly publications are often peer reviewed, which means that the articles are reviewed by expert/s before being accepted for publication.

Reports : useful information can also be found in free web publications from government or research organizations (e.g. reports). Any web publications should be carefully evaluated. You are also required to view the whole publication, not just the abstract, if using the information in your assignment.

Remember to ensure that you note the citation details for references that you collect, at the time of locating the items. It is often time consuming and impossible to track the required data later.

Analyse the information collected

• Have I collected enough information on the topic?

Synthesise your information

Write the report or essay

• Check the ECU Academic tip sheet: the Academic Essay for some useful pointers
• Remember, in most cases you will need an introduction, body and conclusion
• Record details of references used for referencing. Information on referencing can be located on the ECU Referencing Guide.

Database search tips:

1. Identify main concepts and keywords . Search the main concepts first, then limit further as necessary.

2. Find Synonyms (Boolean  OR broadens the search to include alternative keywords or subject thesaurus terms):

• pediatrics  OR children
• teenagers  OR adolescents

3. AND (Boolean AND  joins concepts and narrows the                search):

• occupational therapy  AND children
• stress  AND (occupation OR job)

4. Be aware of differences in American and English spelling and terminology. Most databases use American spelling and terminology as preferred subject terms.

5. Use Truncation (putting * at the end of a word stem will search all forms of the word):

• disab * (disability, disabilities, disabled)
• child * (child, children, childhood, children's)

6. "...." (inverted commas) use for a phrase

• "mental health"
• "occupational therapy"

7. Wildcard ? will search for any single letter in the space. e.g. wom?n will search women, woman, organi?ation will search organisation, organization.

8. Wildcard * can also be used where alternate spelling may contain an extra character. e.g. p*ediatric, will search paediatric or pediatric, behavio*r, will search behaviour or behavior.

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7 Writing a Literature Review

Hundreds of original investigation research articles on health science topics are published each year. It is becoming harder and harder to keep on top of all new findings in a topic area and – more importantly – to work out how they all fit together to determine our current understanding of a topic. This is where literature reviews come in.

In this chapter, we explain what a literature review is and outline the stages involved in writing one. We also provide practical tips on how to communicate the results of a review of current literature on a topic in the format of a literature review.

7.1 What is a literature review?

Literature reviews provide a synthesis and evaluation  of the existing literature on a particular topic with the aim of gaining a new, deeper understanding of the topic.

Published literature reviews are typically written by scientists who are experts in that particular area of science. Usually, they will be widely published as authors of their own original work, making them highly qualified to author a literature review.

However, literature reviews are still subject to peer review before being published. Literature reviews provide an important bridge between the expert scientific community and many other communities, such as science journalists, teachers, and medical and allied health professionals. When the most up-to-date knowledge reaches such audiences, it is more likely that this information will find its way to the general public. When this happens, – the ultimate good of science can be realised.

A literature review is structured differently from an original research article. It is developed based on themes, rather than stages of the scientific method.

In the article Ten simple rules for writing a literature review , Marco Pautasso explains the importance of literature reviews:

Literature reviews are in great demand in most scientific fields. Their need stems from the ever-increasing output of scientific publications. For example, compared to 1991, in 2008 three, eight, and forty times more papers were indexed in Web of Science on malaria, obesity, and biodiversity, respectively. Given such mountains of papers, scientists cannot be expected to examine in detail every single new paper relevant to their interests. Thus, it is both advantageous and necessary to rely on regular summaries of the recent literature. Although recognition for scientists mainly comes from primary research, timely literature reviews can lead to new synthetic insights and are often widely read. For such summaries to be useful, however, they need to be compiled in a professional way (Pautasso, 2013, para. 1).

An example of a literature review is shown in Figure 7.1.

Video 7.1: What is a literature review? [2 mins, 11 secs]

Watch this video created by Steely Library at Northern Kentucky Library called ‘ What is a literature review? Note: Closed captions are available by clicking on the CC button below.

Examples of published literature reviews

• Strength training alone, exercise therapy alone, and exercise therapy with passive manual mobilisation each reduce pain and disability in people with knee osteoarthritis: a systematic review
• Traveler’s diarrhea: a clinical review
• Cultural concepts of distress and psychiatric disorders: literature review and research recommendations for global mental health epidemiology

7.2 Steps of writing a literature review

Writing a literature review is a very challenging task. Figure 7.2 summarises the steps of writing a literature review. Depending on why you are writing your literature review, you may be given a topic area, or may choose a topic that particularly interests you or is related to a research project that you wish to undertake.

Chapter 6 provides instructions on finding scientific literature that would form the basis for your literature review.

Once you have your topic and have accessed the literature, the next stages (analysis, synthesis and evaluation) are challenging. Next, we look at these important cognitive skills student scientists will need to develop and employ to successfully write a literature review, and provide some guidance for navigating these stages.

Analysis, synthesis and evaluation

Analysis, synthesis and evaluation are three essential skills required by scientists  and you will need to develop these skills if you are to write a good literature review ( Figure 7.3 ). These important cognitive skills are discussed in more detail in Chapter 9.

The first step in writing a literature review is to analyse the original investigation research papers that you have gathered related to your topic.

Analysis requires examining the papers methodically and in detail, so you can understand and interpret aspects of the study described in each research article.

An analysis grid is a simple tool you can use to help with the careful examination and breakdown of each paper. This tool will allow you to create a concise summary of each research paper; see Table 7.1 for an example of  an analysis grid. When filling in the grid, the aim is to draw out key aspects of each research paper. Use a different row for each paper, and a different column for each aspect of the paper ( Tables 7.2 and 7.3 show how completed analysis grid may look).

Before completing your own grid, look at these examples and note the types of information that have been included, as well as the level of detail. Completing an analysis grid with a sufficient level of detail will help you to complete the synthesis and evaluation stages effectively. This grid will allow you to more easily observe similarities and differences across the findings of the research papers and to identify possible explanations (e.g., differences in methodologies employed) for observed differences between the findings of different research papers.

Table 7.1: Example of an analysis grid

Table 7.3: Sample filled-in analysis grid for research article by Ping and colleagues

Source: Ping, WC, Keong, CC & Bandyopadhyay, A 2010, ‘Effects of acute supplementation of caffeine on cardiorespiratory responses during endurance running in a hot and humid climate’, Indian Journal of Medical Research, vol. 132, pp. 36–41. Used under a CC-BY-NC-SA licence.

Step two of writing a literature review is synthesis.

Synthesis describes combining separate components or elements to form a connected whole.

You will use the results of your analysis to find themes to build your literature review around. Each of the themes identified will become a subheading within the body of your literature review.

A good place to start when identifying themes is with the dependent variables (results/findings) that were investigated in the research studies.

Because all of the research articles you are incorporating into your literature review are related to your topic, it is likely that they have similar study designs and have measured similar dependent variables. Review the ‘Results’ column of your analysis grid. You may like to collate the common themes in a synthesis grid (see, for example Table 7.4 ).

Step three of writing a literature review is evaluation, which can only be done after carefully analysing your research papers and synthesising the common themes (findings).

During the evaluation stage, you are making judgements on the themes presented in the research articles that you have read. This includes providing physiological explanations for the findings. It may be useful to refer to the discussion section of published original investigation research papers, or another literature review, where the authors may mention tested or hypothetical physiological mechanisms that may explain their findings.

When the findings of the investigations related to a particular theme are inconsistent (e.g., one study shows that caffeine effects performance and another study shows that caffeine had no effect on performance) you should attempt to provide explanations of why the results differ, including physiological explanations. A good place to start is by comparing the methodologies to determine if there are any differences that may explain the differences in the findings (see the ‘Experimental design’ column of your analysis grid). An example of evaluation is shown in the examples that follow in this section, under ‘Running performance’ and ‘RPE ratings’.

When the findings of the papers related to a particular theme are consistent (e.g., caffeine had no effect on oxygen uptake in both studies) an evaluation should include an explanation of why the results are similar. Once again, include physiological explanations. It is still a good idea to compare methodologies as a background to the evaluation. An example of evaluation is shown in the following under ‘Oxygen consumption’.

7.3 Writing your literature review

Once you have completed the analysis, and synthesis grids and written your evaluation of the research papers , you can combine synthesis and evaluation information to create a paragraph for a literature review ( Figure 7.4 ).

The following paragraphs are an example of combining the outcome of the synthesis and evaluation stages to produce a paragraph for a literature review.

Note that this is an example using only two papers – most literature reviews would be presenting information on many more papers than this ( (e.g., 106 papers in the review article by Bain and colleagues discussed later in this chapter). However, the same principle applies regardless of the number of papers reviewed.

The next part of this chapter looks at the each section of a literature review and explains how to write them by referring to a review article that was published in Frontiers in Physiology and shown in Figure 7.1. Each section from the published article is annotated to highlight important features of the format of the review article, and identifies the synthesis and evaluation information.

In the examination of each review article section we will point out examples of how the authors have presented certain information and where they display application of important cognitive processes; we will use the colour code shown below:

This should be one paragraph that accurately reflects the contents of the review article.

Introduction

The introduction should establish the context and importance of the review

Body of literature review

The reference section provides a list of the references that you cited in the body of your review article. The format will depend on the journal of publication as each journal has their own specific referencing format.

It is important to accurately cite references in research papers to acknowledge your sources and ensure credit is appropriately given to authors of work you have referred to. An accurate and comprehensive reference list also shows your readers that you are well-read in your topic area and are aware of the key papers that provide the context to your research.

It is important to keep track of your resources and to reference them consistently in the format required by the publication in which your work will appear. Most scientists will use reference management software to store details of all of the journal articles (and other sources) they use while writing their review article. This software also automates the process of adding in-text references and creating a reference list. In the review article by Bain et al. (2014) used as an example in this chapter, the reference list contains 106 items, so you can imagine how much help referencing software would be. Chapter 5 shows you how to use EndNote, one example of reference management software.

Click the drop down below to review the terms learned from this chapter.

Copyright note:

• The quotation from Pautasso, M 2013, ‘Ten simple rules for writing a literature review’, PLoS Computational Biology is use under a CC-BY licence. 
• Content from the annotated article and tables are based on Schubert, MM, Astorino, TA & Azevedo, JJL 2013, ‘The effects of caffeinated ‘energy shots’ on time trial performance’, Nutrients, vol. 5, no. 6, pp. 2062–2075 (used under a CC-BY 3.0 licence ) and P ing, WC, Keong , CC & Bandyopadhyay, A 2010, ‘Effects of acute supplementation of caffeine on cardiorespiratory responses during endurance running in a hot and humid climate’, Indian Journal of Medical Research, vol. 132, pp. 36–41 (used under a CC-BY-NC-SA 4.0 licence ). 

Bain, A.R., Morrison, S.A., & Ainslie, P.N. (2014). Cerebral oxygenation and hyperthermia. Frontiers in Physiology, 5 , 92.

Pautasso, M. (2013). Ten simple rules for writing a literature review. PLoS Computational Biology, 9 (7), e1003149.

How To Do Science Copyright © 2022 by University of Southern Queensland is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License , except where otherwise noted.

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What is a Literature Review?

A literature review is a body of text that aims to review the critical points of current knowledge on a particular topic. Most often associated with science-oriented literature, such as a thesis, the literature review usually proceeds a research proposal, methodology and results section. Its ultimate goals is to bring the reader up to date with current literature on a topic and forms that basis for another goal, such as the justification for future research in the area. (retrieved from  http://en.wikipedia.org/wiki/Literature_review )

Writing a Literature Review

The literature review is the section of your paper in which you cite and briefly review the related research studies that have been conducted. In this space, you will describe the foundation on which  your  research will be/is built. You will:

• discuss the work of others
• evaluate their methods and findings
• identify any gaps in their research
• state how  your  research is different

The literature review should be selective and should group the cited studies in some logical fashion.

If you need some additional assistance writing your literature review, the Knight Institute for Writing in the Disciplines offers a  Graduate Writing Service .

Demystifying the Literature Review

For more information, visit our guide devoted to " Demystifying the Literature Review " which includes:

• guide to conducting a literature review,
• a recorded 1.5 hour workshop covering the steps of a literature review, a checklist for drafting your topic and search terms, citation management software for organizing your results, and database searching.

Online Resources

• A Guide to Library Research at Cornell University
• Literature Reviews: An Overview for Graduate Students North Carolina State University 
• The Literature Review: A Few Tips on Conducting Written by Dena Taylor, Director, Health Sciences Writing Centre, and Margaret Procter, Coordinator, Writing Support, University of Toronto
• How to Write a Literature Review University Library, University of California, Santa Cruz
• Review of Literature The Writing Center, University of Wisconsin-Madison

Print Resources

• << Previous: Writing
• Next: Evidence Synthesis and Systematic Reviews >>
• Last Updated: Oct 25, 2023 11:28 AM
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• 04 December 2020
• Correction 09 December 2020

How to write a superb literature review

Andy Tay is a freelance writer based in Singapore.

You can also search for this author in PubMed   Google Scholar

Literature reviews are important resources for scientists. They provide historical context for a field while offering opinions on its future trajectory. Creating them can provide inspiration for one’s own research, as well as some practice in writing. But few scientists are trained in how to write a review — or in what constitutes an excellent one. Even picking the appropriate software to use can be an involved decision (see ‘Tools and techniques’). So Nature asked editors and working scientists with well-cited reviews for their tips.

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doi: https://doi.org/10.1038/d41586-020-03422-x

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Updates & Corrections

Correction 09 December 2020 : An earlier version of the tables in this article included some incorrect details about the programs Zotero, Endnote and Manubot. These have now been corrected.

Hsing, I.-M., Xu, Y. & Zhao, W. Electroanalysis 19 , 755–768 (2007).

Article   Google Scholar  

Ledesma, H. A. et al. Nature Nanotechnol. 14 , 645–657 (2019).

Article   PubMed   Google Scholar  

Brahlek, M., Koirala, N., Bansal, N. & Oh, S. Solid State Commun. 215–216 , 54–62 (2015).

Choi, Y. & Lee, S. Y. Nature Rev. Chem . https://doi.org/10.1038/s41570-020-00221-w (2020).

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What are the types of reviews?

Literature review examples, systematic review examples, meta-analysis examples.

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As you begin searching through the literature for evidence, you will come across different types of publications. Below are examples of the most common types and explanations of what they are. Although systematic reviews and meta-analysis are considered the highest quality of evidence, not every topic will have an SR or MA.

Remember, a literature review provides an overview of a topic. There may or may not be a method for how studies are collected or interpreted. Lit reviews aren't always obviously labeled "literature review"; they may be embedded within sections such as the introduction or background. You can figure this out by reading the article. 

• Can the "Appropriate" Footwear Prevent Injury in Leisure-Time Running? Evidence Versus Beliefs. Full Citation: Malisoux, L., & Theisen, D. (2020). Can the “Appropriate” Footwear Prevent Injury in Leisure-Time Running? Evidence Versus Beliefs. Journal of Athletic Training (Allen Press), 55(12), 1215–1223.
• Weightlifting Overhead Pressing Derivatives: A Review of the Literature Full Citation: Soriano, M. A., Suchomel, T. J., & Comfort, P. (2019). Weightlifting overhead pressing derivatives: A review of the literature. Sports Medicine, 49(6), 867-885. doi:10.1007/s40279-019-01096-8

Systematic reviews address a clinical question.  Reviews are gathered using a specific, defined set of criteria.

• Selection criteria is defined
• The words "Systematic Review" may appear int he title or abstract
• BTW -> Cochrane Reviews aka Systematic Reviews
• Additional reviews can be found by using a systematic review limit 
• First aid cooling techniques for heat stroke and exertional hyperthermia: A systematic review and meta-analysis Full Citation: Douma, M. J., Aves, T., Allan, K. S., Bendall, J. C., Berry, D. C., Chang, W. T., ... & Lin, S. (2020). First Aid Task Force of the International Liaison Committee on Resuscitation. First aid cooling techniques for heat stroke and exertional hyperthermia: A systematic review and meta-analysis. Resuscitation, 148, 173-190.
• Treatment of exertional rhabdomyolysis in athletes Full Citation: Manspeaker, Sarah; Henderson, Kelley; Riddle, Dru Treatment of exertional rhabdomyolysis in athletes, JBI Database of Systematic Reviews and Implementation Reports: June 2016 - Volume 14 - Issue 6 - p 117-147 doi: 10.11124/JBISRIR-2016-001879
• Cochrane Library (Wiley) This link opens in a new window Over 5000 reviews of research on medical treatments, practices, and diagnostic tests are provided in this database. Cochrane Reviews is the premier resource for Evidence Based Practice.
• PubMed (NLM) This link opens in a new window PubMed comprises more than 22 million citations for biomedical literature from MEDLINE, life science journals, and online books.

Meta-analysis is a study that combines data from OTHER studies. All the studies are combined to argue whether a clinical intervention is statistically significant by combining the results from the other studies.  For example, you want to examine a specific headache intervention without running a clinical trial.  You can look at other articles that discuss your clinical intervention, combine all the participants from those articles, and run a statistical analysis to test if your results are significant. Guess what? There's a lot of math. 

• Include the words "meta-analysis" or "meta analysis" in your keywords
• Meta-analyses will always be accompanied by a systematic review, but a systematic review may not have a meta-analysis
• See if the abstract or results section mention a meta-analysis
• Use databases like Cochrane or PubMed
• A Meta-Analysis to Determine if Lower Extremity Muscle Strengthening Should Be Included in Military Knee Overuse Injury-Prevention Programs Full Citation: Roger O. Kollock, Corey Andrews, Ashlyn Johnston, Teresa Elliott, Alan E. Wilson, Kenneth E. Games, JoEllen M. Sefton; A Meta-Analysis to Determine if Lower Extremity Muscle Strengthening Should Be Included in Military Knee Overuse Injury-Prevention Programs. J Athl Train 1 November 2016; 51 (11): 919–926. doi: https://doi.org/10.4085/1062-6050-51.4.09
• Effects of training and competition on the sleep of elite athletes: a systematic review and meta-analysis Full Citation: Roberts SSH, Teo W, Warmington SAEffects of training and competition on the sleep of elite athletes: a systematic review and meta-analysisBritish Journal of Sports Medicine 2019;53:513-522.
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A necessary skill for any doctor

What causes disease, which drug is best, does this patient need surgery, and what is the prognosis? Although experience helps in answering these questions, ultimately they are best answered by evidence based medicine. But how do you assess the evidence? As a medical student, and throughout your career as a doctor, critical appraisal of published literature is an important skill to develop and refine. At medical school you will repeatedly appraise published literature and write literature reviews. These activities are commonly part of a special study module, research project for an intercalated degree, or another type of essay based assignment.

Formulating a question

Literature reviews are most commonly performed to help answer a particular question. While you are at medical school, there will usually be some choice regarding the area you are going to review.

Once you have identified a subject area for review, the next step is to formulate a specific research question. This is arguably the most important step because a clear question needs to be defined from the outset, which you aim to answer by doing the review. The clearer the question, the more likely it is that the answer will be clear too. It is important to have discussions with your supervisor when formulating a research question as his or her input will be invaluable. The research question must be objective and concise because it is easier to search through the evidence with a clear question. The question also needs to be feasible. What is the point in having a question for which no published evidence exists? Your supervisor’s input will ensure you are not trying to answer an unrealistic question. Finally, is the research question clinically important? There are many research questions that may be answered, but not all of them will …

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What is a Literature Review?

A literature review is a comprehensive and up-to-date overview of the principal research about the topic being studied.

The aim of a literature review is to show "that the writer has studied existing work in the field with insight" (Haywood and Wragg, 1982). It is not enough merely to show what others in your field have discovered. You need to view the work of others with insight to review critically. An effective review analyses and synthesizes material, and it should meet the following requirements: (Caulley, 1992)

• Compare and contrast different authors' views on an issue
• Group authors who draw similar conclusions,
• Criticise aspects of methodology,
• Note areas in which authors are in disagreement,
• Highlight exemplary studies,
• Identify patterns or trends in the literature
• Highlight gaps in and omissions in previous research or questions left unanswered
• Show how your study relates to previous studies,
• Show how your study relates to the literature in general,
• Conclude by summarising what the literature says.

A literature review has a number of purposes. It enables you to:

• Set the background on what has been researched on a topic.
• Show why a topic is significant to a subject area.
• Discover relationships between ideas.
• Identify major themes & concepts.
• Identify critical gaps & points of disagreement.
• Help the researcher turn a network of articles into a coherent view of the literature.

Source: University of Melbourne's Literature Review Libguide

Organizing the Review

Categorizing the Literature

When categorizing the writings in the review, the researcher might consider

• the methodology employed;
• the quality of the findings or conclusions;
• the document’s major strengths and weaknesses;
• any other pivotal information.

He/She might consider such questions as:

• what beliefs are expressed?
• Is there an ideological stance?
• What is being described? Is it comprehensive or narrow?
• Are the results generalizable?

Remember that you are relating other studies to your study. How do the studies in your lit. review relate to your thesis? How are the other studies related to each other?

From http://libguides.redlands.edu/content.php?pid=32380&sid=239161

Literature Review Samples

• Otterbein's Institutional Repository You can browse by collection and then department and student scholarship. Look up samples of literature reviews in theses and dissertations.
• OhioLink's ETD Browse by institution and look up samples of literature review in the students' theses and dissertations

Planning your Literature Review

While planning your review, in addition to finding and analyzing the reviews in dissertations, you might ask yourself questions such as the following:

What is my central question or issue that the literature can help define?

What is already known about the topic?

Is the scope of the literature being reviewed wide or narrow enough?

Is there a conflict or debate in the literature?

What connections can be made between the texts being reviewed?

What sort of literature should be reviewed? Historical? Theoretical? Methodological? Quantitative? Qualitative?

What criteria should be used to evaluate the literature being reviewed?

How will reviewing the literature justify the topic I plan to investigate?

From: Writing the successful thesis and dissertation: entering the conversation, by Irene L. Clark

source: Kent State University's Literature Reviews Libguide

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Writing in the Health Sciences: Research and Lit Reviews

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What Is a Literature Review?

In simple terms, a literature review investigates the available information on a certain topic. It may be only a knowledge survey with an intentional focus. However, it is often a well-organized examination of the existing research which evaluates each resource in a systematic way. Often a lit review will involve a series of inclusion/exclusion criteria or an assessment rubric which examines the research in-depth. Below are some interesting sources to consider.

The Writing Center's Literature Reviews - UNC-Chapel Hill's writing center explains some of the key criteria involved in doing a literature review.

Literature Review vs. Systematic Review - This recent article details the difference between a literature review and a systematic review. Though the two share similar attributes, key differences are identified here.

Literature Review Steps

1. Identify a research question. For example: "Does the use of warfarin in elderly patients recovering from myocardial infarction help prevent stroke?"

2. Consider which databases might provide information for your topic. Often PubMed or CINAHL will cover a wide spectrum of biomedical issues. However, other databases and grey literature sources may specialize in certain disciplines. Embase is generally comprehensive but also specializes in pharmacological interventions.

3. Select the major subjects or ideas from your question.  Focus in on the particular concepts involved in your research. Then brainstorm synonyms and related terminology for these topics.

4. Look for the  preferred indexing terms for each concept in your question. This is especially important with databases such as PubMed, CINAHL, or Scopus where headings within the MeSH database or under the Emtree umbrella are present.  For example, the above question's keywords such as " warfarin " or "myocardial infarction" can involve related terminology or subject headings such as "anti-coagulants" or "cardiovascular disease."

5. Build your search using boolean operators. Combine the synonyms in your database using boolean operators such as AND or OR. Sometimes it is necessary to research parts of a question rather than the whole. So you might link searches for things like the preventive effects of anti-coagulants with stroke or embolism, then AND these results with the therapy for patients with cardiovascular disease.

6. Filter and save your search results from the first database (do this for all databases). This may be a short list because of your topic's limitations, but it should be no longer than 15 articles for an initial search. Make sure your list is saved or archived and presents you with what's needed to access the full text.

7. Use the same process with the next databases on your list. But pay attention to how certain major headings may alter the terminology. "Stroke" may have a suggested term of "embolism" or even "cerebrovascular incident" depending on the database.

8. Read through the material for inclusion/exclusion . Based on your project's criteria and objective, consider which studies or reviews deserve to be included and which should be discarded. Make sure the information you have permits you to go forward. 

9. Write the literature review. Begin by summarizing why your research is important and explain why your approach will help fill gaps in current knowledge. Then incorporate how the information you've selected will help you to do this. You do not need to write about all of the included research you've chosen, only the most pe rtinent.

10. Select the most relevant literature for inclusion in the body of your report. Choose the articles and data sets that are most particularly relevant to your experimental approach. Consider how you might arrange these sources in the body of your draft. 

Library Books

Call #: WZ 345 G192h 2011

ISBN #: 9780763771867

This book details a practical, step-by-step method for conducting a literature review in the health sciences. Aiming to  synthesize the information while also analyzing it, the Matrix Indexing System enables users to establish a  structured process for tracking, organizing and integrating the knowledge within a collection.

Key Research Databases

PubMed -  The premier medical database for review articles in medicine, nursing, healthcare, other related biomedical disciplines. PubMed contains over 20 million citations and can be navigated through multiple database capabilities and searching strategies.

CINAHL Ultimate - Offers comprehensive coverage of health science literature. CINAHL is particularly useful for those researching the allied disciplines of nursing, medicine, and pharmaceutical sciences.

Scopus - Database with over 12 million abstracts and citations which include peer-reviewed titles from international and Open Access journals. Also includes interactive bibliometrics and researcher profiling.

Embase - Elsevier's fully interoperable database of both Medline and Emtree-indexed articles. Embase also specializes in pharmacologic interventions.

Cochrane - Selected evidence-based medicine resources from the Cochrane Collaboration that includes peer-reviewed systematic reviews and randomized controlled trials. Access this database through OVID with TTUHSC Libraries.

DARE - Literally the Datatase of Abstracts of Reviews of Effectiveness, this collection of systematic reviews and other evidence-based research contains critical assessments from a wide variety of medical journals.

TRIP - This TRIP database is structured according to the level of evidence for its EBM content. It allows users to quickly and easily locate high-quality, accredited medical literature for clinical and research purposes.

Web of Science - Contains bibliographic articles and data from a wide variety of publications in the life sciences and other fields. Also, see this link for conducting a lit review exclusively within Web of Science.

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How to write a good scientific review article

Affiliation.

• 1 The FEBS Journal Editorial Office, Cambridge, UK.
• PMID: 35792782
• DOI: 10.1111/febs.16565

Literature reviews are valuable resources for the scientific community. With research accelerating at an unprecedented speed in recent years and more and more original papers being published, review articles have become increasingly important as a means to keep up to date with developments in a particular area of research. A good review article provides readers with an in-depth understanding of a field and highlights key gaps and challenges to address with future research. Writing a review article also helps to expand the writer's knowledge of their specialist area and to develop their analytical and communication skills, amongst other benefits. Thus, the importance of building review-writing into a scientific career cannot be overstated. In this instalment of The FEBS Journal's Words of Advice series, I provide detailed guidance on planning and writing an informative and engaging literature review.

© 2022 Federation of European Biochemical Societies.

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• Tawfik GM, Dila KAS, Mohamed MYF, Tam DNH, Kien ND, Ahmed AM, et al. A step by step guide for conducting a systematic review and meta-analysis with simulation data. Trop Med Health. 2019;47:46. https://doi.org/10.1186/s41182-019-0165-6
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What is a Literature Review?

Steps involved in taking a literature review, different types of reviews.

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Steps to writing a review

• Steps to writing a literature review This handy Infographic from Emerald publishing provides an overview to the various steps involved in writing a literature review.

Writing a literature review

Systematic Review Overview

The steps of a systematic review.

Wondering how to conduct a systematic review? This explainer video from The Evidence Synthesis Academy at Brown University walks you through the basic steps.

Evidence Synthesis

Wondering what evidence synthesis is? This explainer video from Cochrane Ireland  walks you through what it is and why we need it, particularly in healthcase.

Management and Software Tools

Systematic review management software tools are specifically tailored to the needs of systematic review teams. These tools can help with data extraction, performing a meta-analysis, tracking team progress, and facilitating communication between members. As indicated below, some of these suggestions are fee-based while others are free. You should also keep in mind that not every tool is appropriate for every kind of synthesis or review.

Note: The University of Victoria holds an institutional license for the web-based software, Covidence , and encourages its researchers to use the platform. Contact UVic science librarian, Monique Grenier at [email protected] , for a consultation. 

• COLANDR Free, but requires registration and login. Includes review planning and project management tools as well as collaborative screening.
• Covidence Covidence is a web-based platform that streamlines the process of conducting a comprehensive literature review. Subscription to unlimited reviews provided by UVic Libraries. Tiered fee structure for those not affiliated to an institutional account. Recommended by Cochrane.
• DistillerSR DistillerSR is an online application designed specifically for the screening and data extraction phases of a systematic review. Fee-based; offers special pricing for students (free for 4 months; $15USD/mo after that) and Cochrane Review Groups.
• EPPI-Reviewer 4 Fee-based; offers one-month free trial. Features include data extraction, coding, and meta-analysis.
• Rayyan Rayyan is a openly accessible (free) web application to help systematic review authors and has a mobile app (works offline and then syncs back to servers when online).
• Systematic Review Data Repository (SRDR) Free, but requires users to create a login. This systematic review repository also acts as a data extraction tool.
• Systematic Review Toolbox Database of tools and software to assist with a variety of evidence synthesis projects.

A literature review is a study of existing published information on a specific topic. Literature reviews:

• identify key information relevant to a topic
• assess the status or quality of existing research
• critically examine support for alternative theories or arguments
• evaluate research methods used in previous studies.

A good literature review will consist of a summary of key sources, and is analytical and synthesizes information. Usually a literature review is organized, not however a chronological description of discoveries in your field, and explains how your research will address gaps in existing literature on a particular topic.

Doing a literature review. (2010). In Thomas, D. R., & Hodges, I. D. Designing and managing your research project: Core skills for social and health research (pp. 105-130). London: SAGE Publications Ltd. doi: 10.4135/9781446289044

Machi, L. A., & McEvoy, B. T. (2012). The literature review: Six steps to success (2nd ed.). Thousand Oaks, Calif: Corwin Press.

Reproduced from: Grant, M. J., & Booth, A. (2009). A typology of reviews: an analysis of 14 review types and associated methodologies. Health Information & Libraries Journal , 26 (2), 91-108. Retried from

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Literature Reviews

• Organizing/Synthesizing
• Peer Review
• Ulrich's -- One More Way To Find Peer-reviewed Papers

"Literature review," "systematic literature review," "integrative literature review" -- these are terms used in different disciplines for basically the same thing -- a rigorous examination of the scholarly literature about a topic (at different levels of rigor, and with some different emphases).  

1. Our library's guide to Writing a Literature Review

2. Other helpful sites

• Writing Center at UNC (Chapel Hill) -- A very good guide about lit reviews and how to write them
• Literature Review: Synthesizing Multiple Sources (LSU, June 2011 but good; PDF) -- Planning, writing, and tips for revising your paper

3. Welch Library's list of the types of expert reviews

Doing a good job of organizing your information makes writing about it a lot easier.

You can organize your sources using a citation manager, such as refworks , or use a matrix (if you only have a few references):.

• Use Google Sheets, Word, Excel, or whatever you prefer to create a table
• The column headings should include the citation information, and the main points that you want to track, as shown

Synthesizing your information is not just summarizing it. Here are processes and examples about how to combine your sources into a good piece of writing:

• Purdue OWL's Synthesizing Sources
• Synthesizing Sources (California State University, Northridge)

Annotated Bibliography  

An "annotation" is a note or comment. An "annotated bibliography" is a "list of citations to books, articles, and [other items]. Each citation is followed by a brief...descriptive and evaluative paragraph, [whose purpose is] to inform the reader of the relevance, accuracy, and quality of the sources cited."*

• Sage Research Methods (database) --> Empirical Research and Writing (ebook) -- Chapter 3: Doing Pre-research  
• Purdue's OWL (Online Writing Lab) includes definitions and samples of annotations  
• Cornell's guide * to writing annotated bibliographies  

* Thank you to Olin Library Reference, Research & Learning Services, Cornell University Library, Ithaca, NY, USA https://guides.library.cornell.edu/annotatedbibliography

What does "peer-reviewed" mean?

• If an article has been peer-reviewed before being published, it means that the article has been read by other people in the same field of study ("peers").
• The author's reviewers have commented on the article, not only noting typos and possible errors, but also giving a judgment about whether or not the article should be published by the journal to which it was submitted.

How do I find "peer-reviewed" materials?

• Most of the the research articles in scholarly journals are peer-reviewed.
• Many databases allow you to check a box that says "peer-reviewed," or to see which results in your list of results are from peer-reviewed sources. Some of the databases that provide this are Academic Search Ultimate, CINAHL, PsycINFO, and Sociological Abstracts.

What kinds of materials are *not* peer-reviewed?

• open web pages
• most newspapers, newsletters, and news items in journals
• letters to the editor
• press releases
• columns and blogs
• book reviews
• anything in a popular magazine (e.g., Time, Newsweek, Glamour, Men's Health)

If a piece of information wasn't peer-reviewed, does that mean that I can't trust it at all?

No; sometimes you can. For example, the preprints submitted to well-known sites such as  arXiv  (mainly covering physics) and  CiteSeerX (mainly covering computer science) are probably trustworthy, as are the databases and web pages produced by entities such as the National Library of Medicine, the Smithsonian Institution, and the American Cancer Society.

Is this paper peer-reviewed? Ulrichsweb will tell you.

1) On the library home page , choose "Articles and Databases" --> "Databases" --> Ulrichsweb

2) Put in the title of the JOURNAL (not the article), in quotation marks so all the words are next to each other

3) Mouse over the black icon, and you'll see that it means "refereed" (which means peer-reviewed, because it's been looked at by referees or reviewers). This journal is not peer-reviewed, because none of the formats have a black icon next to it:

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Literature Review Biomedical Sciences

Description.

A review is an academic paper that provides an overview and critique of relevant literature published on your topic of investigation. You are experienced in reading and writing research papers that make an academic contribution through their own unique data set (scientific articles). Although a review uses no new or original data, it still provides an academic contribution through the interpretations it makes and the conclusions it draws. A good review provides a comprehensive summary of that field (comprehensive but not exhaustive- you are not writing a textbook). It should demonstrate that you have knowledge of the relevant research done in the field. The review should describe relevant pathologies/ mechanisms and interactions relevant to your subject. As well as describing and summarizing research done, the review also provides a critique. The review should highlight relevant debates, contradictory results, and disputed theoretical approaches. The review should identify innovative research and, where relevant, weaknesses in studies. The review provided an interpretation through the way the information is organized (argument) and the conclusions that are drawn.

The literature review should be in narrative (essay) form. It should include a summary, introduction, main body and conclusion sections. Use sub-headings within your sections. You are not writing a systematic review. You do not need to list the search terms you used in your literature search, nor do you need to give inclusion, exclusion criteria for articles chosen. You do not need to include a methodology and you do need to perform a meta-analysis or other statistical calculations.

Length max 3000 words.

Course objectives

The student has:

demonstrated understanding of the subject area

identified key contributors to the field

recognized the current state of research in (frontier of science)

identified major debates e.g. conflicting theories/ contradictory findings

critical engagement with the subject – through own conclusions/ interpretations

produced a well-argued paper (scope/direction/coherence/categorization)

Supervision and evaluation A scientist active in the field chosen; this may be a teacher from a BW subject. If you need help finding a supervisor, contact the course coordinator.

Proposal Send a short description of the subject, and the name of the supervisor, to the coordinator for approval. Supervision will also be given by one of the CIS teachers. If there is sufficient interest a workshop can be organized.

Timing The review is to be written during the first semester of the third year.

Assessment method

The final grade is determined by the course coordinator, based on the grade of the content supervisor (70%) and CIS (30%).

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The eskind biomedical library reference librarians can assist the vanderbilt community by assisting with literature searches, consulting on literature searches, and training on biomedical information resources and citation management programs. contact us by calling the information desk at (615) 936-1410 or using one of our contact forms:, ask biomedical, literature review search request.

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Data Management & Sharing

• Final NIH Policy for Data Management and Sharing
• VU - Research Integrity and Compliance - NIH Data Management and Sharing Plans

Writing & Citation Styles 

• Authors and Contributors ICJME guidelines on defining authorship and contributors.
• AMA Manual of Style Guidance on writing with the American Medical Association citation style.
• APA Style Guidance on writing with the American Medical Association citation style.
• Citation Management Information EndNote, EndNote Web, Mendeley, Zotero
• Keeping Current with the Literature How to setup email alerts for notification when articles are published on your topics of interest.
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• Embase This link opens in a new window
• ERIC (ProQuest version) This link opens in a new window more... less... Coverage: 1966 to present.
• OVID MEDLINE
• PsycINFO This link opens in a new window more... less... Coverage: 1800s to present.
• PubMed This link opens in a new window
• Scopus This link opens in a new window
• Web of Science: Science Citation Index Expanded This link opens in a new window

Registration Databases for Protocols

• PROSPERO accepts registrations for systematic reviews, rapid reviews and umbrella reviews

Visualization Tools

• Robvis Create publication quality risk-of-bias assessment figures
• AHRQ Methods Guide for Effectiveness and Comparative Effective Reviews
• Cochrane Collaboration Cochrane Handbook for Systematic Reviews of Interventions
• EQUATOR Network

Guidelines & Standards

• CONSORT Statement Standards for reporting clinical trials.
• MOOSE Guidelines Meta-analysis of observational studies in epidemiology : Reference: PMID 10789670
• National Academies Press Standards for Systematic Reviews
• PRISMA Statement Standards for reporting of systematic reviews and meta-analyses.
• SQUIRE Guidelines Standards for quality improvement reporting excellence in healthcare
• STROBE Statement Standards for reporting of observational studies in epidemiology.

Protocol Templates

• How to write a scoping review protocol: Guidance and template
• Evidence synthesis protocol template

Screening Software

• Covidence This link opens in a new window systematic reviews production tool for title/abstract screening, full-text screening, data abstraction, and quality assessment.
• Join Vanderbilt's Covidence Institutional License
• Abstrackr used to screen and organize abstracts
• Rayyan used to screen and organize abstracts

Author & Article Impact

• ORCiD -unique author id number -useful for manuscript & grant submissions
• Scopus This link opens in a new window -abstract and citation information for peer-reviewed journals
• Web of Science This link opens in a new window -generate citation reports by author -create citation maps for articles

Risk of Bias Assessment

• RoB 2 revised tool for Risk of Bias in randomized trials
• ROBINS-E Risk Of Bias in non-randomized Studies - of Exposures
• ROB ME Risk Of Bias due to Missing Evidence in a synthesis
• ROBINS-I Risk Of Bias in Non-randomized Studies - of Interventions

What's the difference between a literature review and a systematic literature review?

According to the cochrane collaboration, a systematic review summarises the results of available carefully designed healthcare studies (controlled trials) and provides a high level of evidence on the effectiveness of healthcare interventions. judgments may be made about the evidence and inform recommendations for healthcare., these reviews are complicated and depend largely on what clinical trials are available, how they were carried out (the quality of the trials) and the health outcomes that were measured. review authors pool numerical data about effects of the treatment through a process called meta-analyses. then authors assess the evidence for any benefits or harms from those treatments. in this way, systematic reviews are able to summarise the existing clinical research on a topic. , http://consumers.cochrane.org/what-systematic-review, for more information and to better understand the differences between a traditional narrative review and a systematic review, see: systematic reviews: synthesis of best evidence for clinical decisions . .

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• Open access
• Published: 10 November 2020

A brief guide to the science and art of writing manuscripts in biomedicine

• Diego A. Forero 1 , 2 ,
• Sandra Lopez-Leon   ORCID: orcid.org/0000-0001-7504-3441 3 &
• George Perry 4  

Journal of Translational Medicine volume  18 , Article number:  425 ( 2020 ) Cite this article

18k Accesses

22 Citations

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Metrics details

Publishing articles in international scientific journals is the primary method for the communication of validated research findings and ideas. Journal articles are commonly used as a major input for evaluations of researchers and institutions. Few articles have been published previously about the different aspects needed for writing high-quality articles. In this manuscript, we provide an updated and brief guide for the multiple dimensions needed for writing manuscripts in the health and biological sciences, from current, international and interdisciplinary perspectives and from our expertise as authors, peer reviewers and editors. We provide key suggestions for writing major sections of the manuscript (e.g. title, abstract, introduction, methods, results and discussion), for submitting the manuscript and bring an overview of the peer review process and  of the post-publication impact of the articles.

Introduction

Publishing articles in international scientific journals is the current primary approach for the communication of validated research findings and ideas. Scientific papers are commonly used as a major input for evaluations of researchers and institutions [ 1 , 2 ]. However, taking into account the evolving and multidimensional landscape of the publishing process, there is a need for additional updated training in the science and art of writing manuscripts for scientific journals.

Few articles have been published previously about the different aspects needed for writing high-quality articles [ 3 , 4 , 5 , 6 ]. In this article, we provide an updated and brief guide for the multiple dimensions needed for writing manuscripts in the health and biological sciences, from current, international and interdisciplinary perspectives and from our expertise as authors, peer reviewers and editors, extending and complementing previous publications about this topic. The writing of manuscripts in biomedicine has its own standards, including the availability of multiple guidelines for reporting different types of studies, which are discussed in this article.

General recommendations

One of the first steps before starting to write an article should be to read the main papers that have been previously published on the subject. The first search might be focused on the available literature reviews and meta-analyses, and key for a scientist, the technique of performing a proper literature review [ 7 ]. Science advances by building on what it is known and there is no point in re-inventing the wheel [ 8 ].

It has been suggested, when writing scientific papers, to keep it short, compact and simple, avoiding the excessive use of adjectives and adverbs [ 9 ]. If you read a word or sentence and it does not add anything, delete it.

The success of an article depends on the quality of primary data and their analyses, on the way it is written and on the clearness of the tables and figures. It is fundamental to follow the current standards of research integrity (such as avoiding plagiarism and data manipulation) [ 10 ]. Both negative and positive results should be published, to avoid publication bias [ 11 ].

Authors should keep in mind that scientific writing is a process that involves multiple steps, takes time, dedication and inspiration, and involves patience, motivation, analytical thinking and adherence to high-quality standards [ 86 ]. Table 1 provides an important number of online resources that facilitate the writing of scientific manuscripts.

Following international recommendations for the authorship of articles in the biomedical sciences, such as the ones from the International Committee of Medical Journal Editors (ICMJE), is a fundamental topic in scientific publications, in order to avoid ghost and gift authorship practices [ 12 , 13 ]. In general, authors should have a significant involvement in these 4 points: (1) study concept/design, data collection or data analysis/interpretation (2) drafting/revising the manuscript, (3) approving the final version and (4) holding responsibility for accuracy and integrity of all aspects of the reported research [ 14 ].

There is a trend for the increase of the number of authors over the years [ 15 ], which is a reflection of globalization and the increasing complexity of medical research [ 16 ]. In the last two decades, there has been an increased use of consortia authorship with very long lists of authors, usually derived from international mega-collaborations. Authors from non-English speaking countries might have to take into account the current standards for names (two first names and one last name), to avoid confusion in the indexing processes in databases. Authors with two last names can hyphen their two last names to avoid confusing their first last name with a middle name, although the use of ORCID identifiers facilitates the disambiguation of author profiles.

The meaning of the order of the listed authors varies between fields. In many disciplines, the author order indicates the magnitude of the contribution, with the last author usually representing the principal investigator [ 17 ]. It is possible to have an equal co-authorship, either for the first or corresponding authors [ 18 ].

Title and abstract

The Title [ 19 ] and the Abstract [ 20 ] are the two most visible items of the article [ 21 ], as they are the main sections indexed in bibliographic databases. These two elements compete for the reader’s attention; therefore both should be informative, accurate, attractive, concise, clear and specific [ 19 , 20 ]. It is advisable that the title of the manuscript reflects the actual findings of the work and be concise.

The Abstract section should provide a brief description of the main sections of the manuscript, describing key methods, findings and conclusions. It is recommended that the abstract be specific, clear, unbiased, honest, concise, precise, stand-alone, complete, and scholarly [ 22 ]. An important number of medical journals ask for structured abstracts. Usually, keywords are provided at the end of the Abstract section and the use of Medical Subject Headings (MeSH) as keywords is quite helpful.

Introduction section

Although the standards of the length of the Introduction vary between scientific fields (for example, they are longer in psychology journals), it is recommended that the introduction section should be concise, avoiding long reviews about the topics of the article. It has been proposed that the introduction section be designed as a cone or funnel, starting with the main points of the general topic, followed by a highlight of the existing knowledge gap, the hypothesis or main question of the article and ending with a brief overview of the approach of the current work [ 23 ].

Another recommendation is to keep it simple, including three main paragraphs: the first paragraph explaining what is known, the second what is not known and the third what the objective of the study is and explain what it will add to the scientific knowledge. When stating what is known, it should not be a full review of the literature, but it should be the essential information needed to understand the background. Information from the introduction should not overlap with the discussion. The paragraph explaining what is unknown should be focused on helping the reader understand why the research is being performed. The last paragraph should state the research question or hypothesis [ 24 ]. It is important to cite key articles (both recent reviews and related primary works) and to highlight the novelty of the current work.

Methods section

This section is essential and should be written to facilitate other researchers enabling them to replicate the study. This section has been compared to a recipe, which includes all the ingredients and how they need to be combined [ 25 ].

Key details of methods employed, such as overall design of the study, inclusion and exclusion criteria, sample sizes and statistical power, should be described [ 26 ]. Another way to subdivide it is with subheadings that might include: study design, setting, subjects, data collection and data analysis [ 25 ]. The incorporation of data about the origins of samples and validated criteria for diagnoses is indispensable, including key references to validated instruments and methodologies. Description of approval by institutional ethics committees and use of informed consent, when needed, is fundamental. In the case of the use of equipment and reagents, details of the respective manufacturers are needed. Statistical and bioinformatic analyses should be described clearly, including the details of statistical tests and the software used [ 27 , 28 , 29 , 30 ]. It is fundamental that all the results described in the Results section correlate with the procedures described in the Methods section.

Results section

The Results section should provide an adequate and complete description of the main findings of the work carried out. It is suggested to avoid the repetition of the same exact content of the Tables or Figures and to leave the interpretation of the results of the findings to the Discussion section [ 31 ]. The main messages and details of the Results section should be provided in the Figures and Tables. No interpretation should be provided in this section.

The results section should be seen as a mirror of the methods: for every method provided, there should be a corresponding result. Subheadings can be included and some suggestions might be: recruitment/response, characteristics of the sample, findings from primary analyses, secondary analyses and additional findings [ 32 ]. Exact p values should be presented and must always be shown together with the estimates and confidence intervals. There should be a consistency with the number of decimal places presented in the results section and in the tables. It is common to present one or two decimals places. Always present the absolute number of cases, in addition to relative measures (e.g. percentage was 22% -33/150-) [ 32 ].

Tables and figures

Tables facilitate the detailed presentation of the results and they should be constructed adequately. Abbreviations are useful for avoiding repetitions of phrases and should be explained in the footnotes [ 33 ]. Each table or figure should be self-explanatory, and there should be no need to read the text to be able to understand it. They have to be presented in the same chronological order, following how they are presented in the text [ 34 ].

For tables where a lot of information is presented, the p values that are statistically significant can be presented in bold. In case of long or complex tables, it is helpful to provide them as supplementary files, leaving the key data in the tables of the main text. It is important to provide details of statistical significance in the table, in order to avoid going back and forth between the tables and the text to read key data.

The creation of figures for scientific articles involves data visualization. A major element in the creation of figures is their focus on the representation of key findings without biases, avoiding the generation of overly complex figures. In addition, it is important to remove the repetition of the same data that is also presented as tables in the main manuscript. Description of key conventions should be provided in detail in the figure legends and it is important to avoid the misrepresentation of data [ 35 ], particularly digital enhancement. As the large majority of journals are published and distributed in digital formats, there are no actual restrictions for the adequate use of colors in scientific images. In case of photographs, it is important to follow the guidelines of the journals regarding image size and resolution. In addition, other recommendations are related to the use of adequate tools and parameters for the generation of figures [ 36 ].

Discussion section

It has been proposed that the general outline of the discussion can be seen as an inverted funnel. Thus, it has been suggested that the configurations of the introduction and discussion sections can have, together, the form of an hourglass [ 37 ] (Fig.  1 ). The first paragraph is usually a summary of the important results, focused on answering the research question. The next paragraphs should focus on integrating the findings with what is known in the literature. If there are different findings, each should have a separate paragraph. The discussion of each result should follow the same order of the methods and results. A balanced contextualization of findings of the current study should be provided by citing the key previous original articles and related reviews that put the results in perspective [ 38 ]. If there are differences between the findings and previously published studies, the differences and similarities of the results and studies should be stated.

A graphical overview of the general structure of research articles

It is important to list the strengths and the limitations of the study. An explanation of the implications of those limitations should be included. An essential point is to include the needs and the perspectives for future studies. It can be stated that the results need replication or to highlight new questions that appeared after the analyses. This point can be of great guidance for future studies and can help the advance of science. It is highly advisable to avoid very long discussion sections and overstatements about the actual findings. The discussion section should not have results that were not described in the Results section. The last paragraph should include a conclusion that clearly states what the study adds to the knowledge.

References section

Although each journal usually has its own citation style, the Vancouver style is quite common in medical journals. There are several freely and commercially available programs (such as EndNote, Zotero or Mendeley) that facilitate the citations process and the generation of the bibliography, including the details for multiple citation styles. They can help to organize, store, download -and most importantly- format the references to the style requirements of the journal you want to submit to. By having the references in these programs, it is easy to reformat the style for any other journal in a matter of seconds.

Always try to cite the original source behind a key statement, making sure that the reference you mention is not only mentioning another source. If you need to choose among several references, take into consideration the level of evidence, the year of publication and the quality of the work [ 39 ].

It is important to verify that the bibliography includes all the publications cited and to check issues with names of authors or journals. Several journals have limitations in the number of citations for certain types of publications.

Acknowledgments and other sections

Usually, the authors thank their funding agencies for their economical support for the studies carried out. In addition, it is possible to include acknowledgements to people who helped with the development of the work (technical support, for example) or in the writing of the manuscript (such as corrections of use of the English language) [ 40 ]. In several cases, the journals ask for declarations about ethical considerations and declarations of the roles of individual authors (such as the design of the study and/or the collection or analysis of the data) [ 41 ]. Declarations of potential conflicts of interest is fundamental for the transparency of scientific activities [ 12 , 42 ].

Supplementary data

With modern high-throughput methods, the size of the analyzed datasets is becoming larger and larger. This means that there is a growing need to provide access to the large datasets as supplementary files (such as spreadsheets or pdf files) or to include them in publicly available repositories (such as OSF or figshare) [ 43 ]. In addition, certain fields have specific guidelines asking authors to submit their data to specific online repositories (such as the NCBI GEO database for whole genome expression data) [ 44 ].

Review articles and other types of publications

There are two main types of review articles: systematic reviews and narrative reviews. In the case of systematic reviews and meta-analyses there are important standards to follow, including the need for well-defined search strategies [ 45 ]. For the writing of narrative reviews [ 46 , 47 ], it is essential to define its scope and current needs and it is highly advisable to construct tables and figures to consolidate and visualize the key information. Articles for case reports follow a different structure and there are recommendations about their development [ 48 ].

Reporting guidelines

It is important to follow published guidelines for the reporting of studies in clinical research, such as STROBE for observational studies [ 49 ], STROBE-ME for molecular epidemiology studies [ 50 ], STREGA for genetic association studies [ 51 ], PRISMA for systematic reviews and meta-analyses [ 52 ], TRIPOD for prediction models of diagnosis or prognosis [ 53 ], CONSORT for clinical trials [ 54 ], CARE for case reports [ 55 ] and AGREE II for practice guidelines [ 56 ], in addition to ARRIVE 2.0 for animal research [ 57 ]. For molecular and cellular analyses, there are several important guidelines, such as MIQE for qPCR [ 58 , 59 ], flow cytometry [ 60 ], cell death [ 61 ], mutational analyses [ 62 ], simulation experiments [ 63 ] and gene nomenclatures [ 64 , 65 ].

Find the best candidate journals

There are several aspects that the authors should take into account in the selection of a journal, such as local standards of publications, the visibility or impact of the journals and their affinities with the topics of the manuscripts. It is highly advisable to verify the indexing of the journals in key databases, such as PubMed, Scopus/Scimago (quartiles) and Journal Citation Reports (impact factor) [ 66 , 67 ]. Finally, authors should be careful with the growing number of predatory journals [ 68 ], which commonly mention spurious impact factors [ 69 ]. Another way to determine which journal is suitable is to see the list of the references in your study. Before selecting the journal, read all the instructions and make sure the scope of the journal and editor preference fits your manuscript. Make a list of 3 to 5 journals, and rank them [ 70 ]. In several cases, sending a pre-submission enquiry to the editor of the journal is helpful [ 71 ]. There is a growing trend for the initial divulgation of manuscripts as preprints, in repositories such as bioRxiv and medRxiv [ 72 ].

Submission and peer review

It is fundamental to follow the guidelines for authors of the selected journal. In addition to manuscript files, tables, figures and supplementary data, it is common that the authors provide a cover letter (highlighting the main contributions of the work) in their submissions. In the cover letter it is recommended to include: (1) Your request to submit your work (mentioning the title). (2) 2–3 sentences summarizing the significance of the work (importance, main finding, message) (3) A statement of the relevance to the journal audience (eg. A related work published in the journal) (4) Any statement required from the journal, such as that the material has not been submitted/published elsewhere [ 73 ].

There are differences in peer review practices between journals. In many cases, there are two or more peer reviewers in a single-blind approach (the authors do not know the identities of the reviewers). In other cases, there is an approach based in double-blind, in which the reviewers also do not know the identities of the authors. In recent years, there has been an increase in the implementation of open peer review, in which the identities and concepts of the reviewers are publicly available.

Answer to peer reviewers

When addressing the comments and questions of the peer reviewers do it in a new document. Copy/paste all comments and number them. For each comment briefly respond and indicate where the change was made in the manuscript. The response should be in present tense or past present (e.g. We now present; we have added to the first paragraph).

Make the changes in the paper with “track changes” or highlighting the change in another color. Be thankful and respectful to each reviewer and editor and take each comment very seriously. If you disagree with the comment, add solid evidence, adding references or key data [ 74 ].

The process of providing adequate answers to peer reviewers and editors and of the incorporation of their suggestions into the revised manuscript is an important challenge [ 75 ] in the publishing of an article.

Open science

Interest in Open Science practices has been growing in recent years, considering their advantages to facilitate the access to information and their potential to increase the reproducibility and the quality of research findings [ 76 , 77 , 78 , 79 , 80 ]. It has been shown that open access articles [ 81 ] have advantages in terms of the amount of citations [ 82 ] and that articles that provide links to repositories with primary data have also have a higher citation count [ 43 ]. Open Science, in addition to open peer review, also involves open protocols, materials [ 8 , 83 ] and data (Fig.  2 ).

An overview of the different dimensions and components of Open Science

Post-publication impact

Citation counts are one of the main ways to measure the scientific impact of publications, allowing the development of multiple metrics, such as the H index [ 84 ], to measure the influence and visibility of scientists and research groups [ 1 ]. Recently, there is a growing use of alternative metrics [ 85 ], which measure other types of article mentions (such as social networks, blogs and news, recorded by Altmetric) or downloads. There are platforms (such as PubPeer and Retraction Watch) that allow comments on published articles, facilitating divulgation of possible issues on reported findings (among others) and to visualize information about retracted articles.

Conclusions

The quality of scientific publications is directly related to the careful revision by peer reviewers of the manuscript, in order to improve the submitted manuscript. This process means that receiving feedback is a constant process and that authors should have the resilience to receive rejections and recommendations for major changes [ 2 ]. In addition, authors can have feedback from collaborators before submitting the manuscript (including revision of the use of the English language) and they can benefit themselves from the experience of being peer reviewers [ 86 ]. In the current scientific environment, publishing an article is not the end of a process; it is the beginning: the article is beginning its journey of being read and analyzed by people around the world.

The writing of a scientific article is a work of art that is honed with experience. The more publications you have, the easier it is to write a manuscript. The collaboration between authors can be very enriching and give rise to new projects and new learnings. The contribution to science and to following generations comes with every single article one publishes. Therefore, one should always strive for the best.

Availability of data and materials

Not applicable.

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Acknowledgements

DAF has been previously supported by research grants from MinCiencias. GP is supported by the NIH and the Alzheimer´s Association. The authors thank Leon Ruiter Lopez for his help in the creation of Fig.  1 .

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Diego A. Forero

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Global Drug Development, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

Sandra Lopez-Leon

Department of Biology and Neurosciences Institute, The University of Texas at San Antonio, San Antonio, TX, USA

George Perry

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DAF wrote an initial draft of the manuscript; DAF, SLL and GP contributed to different sections of the manuscript. All authors read and approved the final manuscript.

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Forero, D.A., Lopez-Leon, S. & Perry, G. A brief guide to the science and art of writing manuscripts in biomedicine. J Transl Med 18 , 425 (2020). https://doi.org/10.1186/s12967-020-02596-2

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• Doing a lit review

What do your professors want in a literature review?

Whether you are doing a topic summary for a term paper, a state-of-the-art survey, or a full literature review for a thesis or article, there are some common expectations that your professors have for graduate student work. They are not looking for you to simply describe some papers that you have read on the topic, one after the other. What they do expect is:

• That you have found and thoroughly read enough papers to have a solid grasp of the particular topic. This is where it's very important to properly define your topic so you can do a good job, and do a structured database search! You should start to encounter some of the same authors and papers repeatedly as you read, indicating that you are finding the major works in this topic. For searching advice, see the Find Articles tab. You should use at least two search tools (Scopus, Web of Science, Google Scholar, etc).
• That you have understood them enough to identify major trends, methods, approaches, and differences . This takes work! You do not want to just re-phrase the abstract. See below for some tips on doing this.
• That you can communicate your own perspective and informed opinion on what is truly important - including where the current research is lacking (where there is a gap). If you are doing your own research, this is a very important part of the literature review as it justifies the rest of your project.

The process of doing a literature review

Source: North Carolina State University. (n.d.). Literature Reviews: An Overview for Graduate Students . https://www.lib.ncsu.edu/tutorials/litreview/

Reading and note-taking efficiently

Getting started.

You want to be organized from the start when doing a literature review, especially for a project that will take a long time. 

• In a Word or Excel file, keep track of your searching - which search databases and tools you use, and paste in all the search queries you run that are useful, with parameters. In Scopus, for example, this might be ' TITLE-ABS-KEY   (   anaerobic   AND  digestion   AND  feedstock   )   AND   PUBYEAR   >   2013'. This will help you avoid duplicating work later.
• Use a citation manager program like Zotero or Mendeley, to keep track of your papers as you find them, and format citations later. See this guide for details on the programs. Save the PDFs to your computer, and attach them to the entries in your citation manager if it isn't added automatically.

Reading and Note-taking on Individual papers

When you actually read the papers that you find, most people take a staged approach to save time:

• Read the abstract fully to determine if it's actually on topic.
• If so, read the discussion and conclusion, and the figures and graphs, to figure out if the results were significant or produced interesting results.
• If so, make sure it is saved. Then read the full article, and annotate the article right away.

What does annotating mean? Take very short notes (on paper or digital) of the most important findings and/or highlight important lines in the paper. You can highlight and annotate the PDF file if you want, or in your citation manager. You don't usually need to summarize the whole article - instead focus on what is important for your research or review, and write it in your own words. This could be the

• whether the study was theoretical, experimental, numerical simulation, etc
• main theoretical approach, model, algorithms, etc
• number of test specimens or subjects
• key assumptions made that might impact its general validity
• key outcome measured, statistical significance of it, etc
• Your own comments - for example, strengths and weaknesses

Synthesizing the papers and structuring your review

Concept mapping.

One technique is to create a concept map or 'mind map' showing the relationships or groupings of the key papers on your topic, with short labels. This way, you can try out different options for how to structure your paper and see which one makes the most sense. You can do this on paper:

You can also do this digitally, using a mind-mapping website. There are some easy-to-use, free tools that are available now. Two that I have used are Coggle and Miro. You can also just sketch on paper.

Created using  Coggle.it, based on a chart in Huang, H. (2018). Methods for Rolling Element Bearing Fault Diagnosis under Constant and Time-varying Rotational Speed Conditions (Ph.D. Thesis, University of Ottawa). http://dx.doi.org/10.20381/ruor-21835

Image: Pacheco-Vega, R. (2016, June 15). How to do a literature review: Citation tracing, concept saturation and results’ mind-mapping. Retrieved from http://www.raulpacheco.org/2016/06/how-to-do-a-literature-review-citation-tracing-concept-saturation-and-results-mind-mapping/

After you have taken notes on individual articles, it can be very helpful to create a chart with key variables that seem important. Not every article will cover the same material. But there should be some common factors, and some differences between them. This chart is called a synthesis matrix.

Example of a 'synthesis matrix'

Source: University of Western Ontario Library (n.d.). “Writing your literature review”. https://guides.lib.uwo.ca/mme9642/litreview

See this blog post by researcher Raul Pacheco-Vega for another example of how he does this.

This chart can help you decide how to organize your review. If it's a very short review, some people write it chronologically - they describe how the topic evolved, one paper at a time. But if you have more than 10 papers, this is not a good approach. Instead, it is best to organize your review thematically . In this approach, you group the papers into several groups or themes, and discuss each theme in a separate section. Usually the groups are major methods of tackling the problem, or concepts, or techniques.

In each section of your paper, you introduce the theme, and then discuss and compare the papers in the group. Using this approach lets you show that you have not just read the papers, but have understood the topic as a whole, and can synthesize the literature.

For example, this paper co-authored by Ping Li , a Civil Engineering PhD graduate of uOttawa, organizes the papers into three categories: ones that used a 'traditional' approach; ones based on characterization of the soil microstructure, and ones that also incorporate soil mechanics. The strengths and weaknesses of category are discussed, and in the conclusion, the authors recommend approaches for future studies. 

You can often include a form of a synthesis chart in your paper or thesis, as a visual summary of your lit review. This is part of a chart included in a Masters' thesis in Computer Science from uOttawa.

From Le Page, S. (2019). Understanding the Phishing Ecosystem (M.Sc. Thesis, University of Ottawa). http://dx.doi.org/10.20381/ruor-23629

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20 Topics For A Biology Literature Review

Advanced Stem Cell And Developmental Biology – Experimental Design

Finding Articles And Books Using Database For Your Discipline

• The literature review writing service helps the researchers to complte their medical researches. In most research areas literature reviews are in high demand. A need stems from the ever-increasing output of scientific publications .
• Although recognition for scientists mainly comes from primary research, timely literature reviews and the topic selected can lead to new synthetic insights and are often widely read.

The building block of all academic research activities , regardless of discipline, is to base the work on existing knowledge and link it up. Hence, doing so correctly should be a priority for all academics. However, the task has got more and more complicated. Development of knowledge within the field of business research is growing at a tremendous pace while remaining fragmented and interdisciplinary at the same time. This makes it difficult to keep up with state of the art studies and be at the forefront, as well as analyse the accumulated evidence in a specific area of research. Therefore, the literature review as a method of research is more relevant than ever. A review of literature can be generally defined as a more or less systematic way of collecting and synthesizing prior research.

A successful and well-done analysis as a research method provides a firm foundation for the advancement of knowledge and the growth of theory. Scientific research support service offer the medical analysis data that are related to research work. Through combining observations and insights from many scientific studies, a review of the literature will answer research questions with a strength that no single study has (Boyd & Solarino , 2016).

Literature Search, Topics, Journals, Coronavirus, Biology

The Process of Conducting a Literature Review

There are a number of steps that need to be taken and decisions are taken to produce a study that satisfies the publication criteria.  The basic steps and essential choices involved in conducting a literature review will be suggested and addressed in four phases; (1) Planning of the review, (2) Conducting of the review, (3) Analyses and (4) Writing the review (Palmatier et al., 2018).

Interesting topics to Choose in Biology

Here we have discussed 20 topics to choose in biology, which can be quite interesting. The first 10 topics are explained to the point where we can work and the remaining 10 articles are stated on general themes.

1.Obesity related to Genetic Phenomenon

Obesity is a heterogeneous disease whose biological causes are complex. The increasing frequency of obesity over the last few decades is attributed to environmental factors such as sedentary lifestyles and overnutrition, but that is obese at an individual level is determined by genetic susceptibility (Venkatesan & Mohan, 2016).

2.Is Paleo diet the healthiest choice

Paleolithic diet has been gaining worldwide popularity due to its putative health benefits. “Paleo” was Google’s most wanted diet word in 2014. Nonetheless, a 2015 US News and World Report ranking of 35 diets with feedback from a panel of health experts ranked the Paleolithic diet dead last, citing a lack of evidence of clinical benefits from research (Manheimer et al., 2015).

3.Resistant to Antibiotics

Antibiotics are the’ wonder medicines’ used for battling microbes. Numerous types of antibiotics have been not only used for therapeutic purposes for decades but have been used prophylactically across other fields such as livestock and animal husbandry. Uncertainty has emerged as microbes have become immune to specific antibiotics while the host remains unaware of the development of antibiotic resistance (Zaman et al., 2017).

4.The Need of the Hour – Coronavirus

A cluster of identified-cause pneumonia patients was related to a wholesale market for seafood in Wuhan, China, in December 2019. A previously unknown betacoronavirus was discovered from patients with pneumonia by using objective sequencing in the samples .

5.Impact of Tobacco Use

Cigarettes smoked in the form of either smoke or smokeless is dangerous for the human body. Globally, the death toll from cigarettes has risen to around 6.4 million annually and is on a steady rise (Shah et al., 2018).

6.The need to review HIV

Human Immunodeficiency Virus / Acquired Immunodeficiency Syndrome (HIV / AIDS) is a global health problem: more than 70 million people were diagnosed with HIV, 35 million died, and 36.7 million people are currently living with the disease (Fajardo-Ortiz et al., 2017).

7.The Unsolved Leprosy

Leprosy, a chronic mycobacterial infection caused by Mycobacterium leprae, is an infectious disease that has destroyed human societies for thousands of years. This ancestral pathogen causes cutaneous lesions to disfigure, peripheral nerve damage, ostearticular deformity, loss of limbs and weakness, blindness and stigma (Franco-Paredes & Rodriguez-Morales, 2016).

8.Tuberculosis – The Disease without Boundaries

An airborne disease of Tuberculosis (TB) is caused by Mycobacterium tuberculosis (MTB), which usually affects the lungs causing severe coughing, fever, and chest pain. While current research has provided valuable insight into the transmission, diagnosis, and treatment of TB over the past four years, much remains to be learned to effectively decrease the occurrence of and ultimately eliminate TB (Levine et al., 2015).

9.The Epidemic of the Century – Diabetes

It studies the epidemic essence of diabetes mellitus in various regions. The North Africa and the Middle East region has the lowest prevalence of diabetes in adults (10.9 percent), while the Western Pacific region has the highest number of diabetes-diagnosed adults and countries with the highest incidence of diabetes (37.5 per cent) (Kharroubi, 2015).

10.Parkinson’s Disease

The disease of Parkinson is a progressive neurodegenerative disease characterized by tremor and bradykinesia and is a common neurological disorder. Male sex and advancing age are independent risk factors, and rising productivity and medical resources are taking on increasing toll as the population ages (Hayes, 2019).

General Topics to Focus

• Challenges faced in Research of Herbal Medicines.
• The Global Burden of Periodontitis.
• The new Addiction of the Era – Gaming.
• The prevalence of Road Traffic Accidents among Food Delivery Workers.
• Diet and Nutrition assessment among School Children
• The Boon and Ban of self-medication in India.
• Zombie – A Psychological concept of old tales.
• Backpain among weavers and farmers in India.
• Trends of Oral Cancer in India.
• Self-examination for Breast Cancer among women

Future Scopes

A review of the literature may be thorough or limited, but it should discuss landmark or principal works and works that have been important in the field. The complexity of a review of the literature can vary according to assignment and discipline. The analysis of literature may be part of a larger piece of work or a stand-alone post, meaning it’s a paper entirely. Moreover, literature reviews can pave a way to numerous research questions and research ideas.

References:

• Boyd, B. K., & Solarino, A. M. (2016). Ownership of Corporations. Journal of Management, 42(5), 1282–1314. https://doi.org/10.1177/0149206316633746
• Fajardo-Ortiz, D., Lopez-Cervantes, M., Duran, L., Dumontier, M., Lara, M., Ochoa, H., & Castano, V. M. (2017). The emergence and evolution of the research fronts in HIV/AIDS research. PLOS ONE, 12(5), e0178293. https://doi.org/10.1371/journal.pone.0178293
• Franco-Paredes, C., & Rodriguez-Morales, A. J. (2016). Unsolved matters in leprosy: a descriptive review and call for further research. Annals of Clinical Microbiology and Antimicrobials, 15(1), 33. https://doi.org/10.1186/s12941-016-0149-x
• Hayes, M. T. (2019). Parkinson’s Disease and Parkinsonism. The American Journal of Medicine, 132(7), 802–807. https://doi.org/10.1016/j.amjmed.2019.03.001
• Kharroubi, A. T. (2015). Diabetes mellitus: The epidemic of the century. World Journal of Diabetes, 6(6), 850. https://doi.org/10.4239/wjd.v6.i6.850
• Levine, D. M., Dutta, N. K., Eckels, J., Scanga, C., Stein, C., Mehra, S., Kaushal, D., Karakousis, P. C., & Salamon, H. (2015). A tuberculosis ontology for host systems biology. Tuberculosis, 95(5), 570–574. https://www.sciencedirect.com/science/article/pii/S1472979214205890
• Manheimer, E. W., van Zuuren, E. J., Fedorowicz, Z., & Pijl, H. (2015). Paleolithic nutrition for metabolic syndrome: systematic review and meta-analysis. The American Journal of Clinical Nutrition, 102(4), 922–932. https://doi.org/10.3945/ajcn.115.113613
• Palmatier, R. W., Houston, M. B., & Hulland, J. (2018). Review articles: purpose, process, and structure. Journal of the Academy of Marketing Science, 46(1), 1–5. https://doi.org/10.1007/s11747-017-0563-4
• Shah, S., Dave, B., Shah, R., Mehta, T., & Dave, R. (2018). Socioeconomic and cultural impact of tobacco in India. Journal of Family Medicine and Primary Care, 7(6), 1173. https://doi.org/10.4103/jfmpc.jfmpc_36_18
• Venkatesan, R., & Mohan, V. (2016). Obesity – Are we continuing to play the genetic “blame game”? Advances in Genomics and Genetics, Volume 6, 11–23. https://doi.org/10.2147/AGG.S52018
• Zaman, S. Bin, Hussain, M. A., Nye, R., Mehta, V., Mamun, K. T., & Hossain, N. (2017). A Review on Antibiotic Resistance: Alarm Bells are Ringing. Cureus. https://doi.org/10.7759/cureus.1403

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Accessing Biomedical Literature in the Current Information Landscape

National Center for Biotechnology Information, U.S. National Library of Medicine, NIH, Blg 38 A, Rm 1003B, 8600 Rockville Pike, Bethesda, MD 20894

Robert Leaman

National Center for Biotechnology Information, U.S. National Library of Medicine, NIH, Blg 38 A, Rm 1003E, 8600 Rockville Pike, Bethesda, MD 20894

National Center for Biotechnology Information, U.S. National Library of Medicine, NIH, Blg 38 A, Rm 1003A, 8600 Rockville Pike, Bethesda, MD 20894

Biomedical and life sciences literature is unique because of its exponentially increasing volume and interdisciplinary nature. Biomedical literature access is essential for several types of users including biomedical researchers, clinicians, database curators, and bibliometricians. In the past few decades, several online search tools and literature archives, generic as well as biomedicine-specific, have been developed. We present this chapter in the light of three consecutive steps of literature access: searching for citations, retrieving full-text, and viewing the article. The first section presents the current state of practice of biomedical literature access, including an analysis of the search tools most frequently used by the users, including PubMed, Google Scholar, Web of Science, Scopus, and Embase, and a study on biomedical literature archives such as PubMed Central. The next section describes current research and the state-of-the-art systems motivated by the challenges a user faces during query formulation and interpretation of search results. The research solutions are classified into five key areas related to text and data mining, text similarity search, semantic search, query support, relevance ranking, and clustering results. Finally, the last section describes some predicted future trends for improving biomedical literature access, such as searching and reading articles on portable devices, and adoption of the open access policy.

1. Introduction

Literature search is the task of finding relevant information from the literature, e.g. finding the most influential articles on a topic, finding the answer to a specific question, or finding other (bibliographic or non-bibliographic) information on citations. Literature search is a fundamental step for every biomedical researcher in their scientific discovery process. Its roles range from reviewing past works at the beginning of a scientific study to the final step of results interpretation and discussion. Literature search is also important for clinicians seeking established and new findings for making important clinical decisions. Furthermore, since current biomedical research is heavily dependent on access to various kinds of online biological databases, literature search is also a key component of transforming knowledge encoded in nature language data, such as journal publications, into structured database records by dedicated database curators. In addition, literature search has other uses such as biomedical citation analysis for academic needs, and data collection for biomedical text mining research.

To meet the diverse needs of literature access by the scientific community worldwide, a number of Web-based search tools, e.g. PubMed [ 1 ] and Google Scholar [ 2 ], and online bibliographic archives, e.g. PubMed Central [ 3 ], have been developed over the last decades. As a result, the literature access process typically includes the following consecutive steps, searching for citations on a search tool, retrieving full-text on a bibliographic archive, and reading the article. Despite advances in information technologies, the ease of searching the biomedical literature has not kept pace for two main reasons. First, the size of the biomedical literature is large (dozens of millions) and it continues to grow rapidly (over a million per year), thus making the selection of proper search keywords and reviewing results a daunting task [ 4 , 5 ]. Second, biomedical research is becoming increasingly multi-disciplinary. As a result, the information most relevant to an individual researcher may appear in journals that are not usually considered relevant to his or her own research. For example, a 2006 study [ 6 ] found that half of the renal information is published in non-renal journals.

In response to the aforementioned challenges, there has been a recent surge in improving the literature access through the use of advanced information technologies in information retrieval (IR), data mining, and natural language processing (NLP). For instance, recent IR research includes relevance-ranking algorithms aimed at improving user retrieval effectiveness. Data mining algorithms can group similar results into clusters, thus providing users with a quick overview of the search results before focusing on individual papers. Text mining and NLP techniques can be used to automatically recognize named entities (e.g. genes) and their relations (e.g. protein-protein interaction) in the biomedical text, thus enabling novel entity-specific semantic searches as opposed to the traditional keyword based searches.

A number of literature search assistants using aforementioned information techniques have been developed over the years, some of which have been shown to be effective in real-world uses. For instance, by comparing words from the title and abstract of each citation, and the indexed MeSH terms using a weighted IR algorithm, related papers can be grouped together into clusters [ 7 ]. When used in most search tools, such a technique is known as “related articles” where users can easily find all papers relevant to a search result through a simple mouse click. The “related article” application has been frequently used [ 8 ] since its appearance in PubMed. Because of its success in PubMed, this feature has been adopted by many journal websites as well as commercial search tools.

Retrieving full-text of bibliographic archives poses another challenge for literature access. While most article abstracts are freely accessible, their full texts are still locked by the publishers: in order to read the full text, one would need either an institutional subscription or pay-per-view. Such an access model is inconvenient to the researchers and the global scholarly community [ 9 ]. In recognition of such a problem, a number of initiatives began to promote open access to the scientific literature. For instance, the Budapest Open Access Initiative reaffirmed in its 10 th anniversary in 2012 that its goal is to make open access the default method for distributing new peer-reviewed research in every field and country. Agreed with such initiatives, a number of publishers and journals are adopting the open access paradigm for publishing articles. For instance, two major open access publishers include the BioMed Central (BMC) and Public Library of Science (PLoS). To accelerate open access, the U.S. National Library of Medicine started PubMed Central (PMC), a free digital repository of full-text articles in biomedical and life sciences in early 2000. With a little over 10 years development, PMC currently contains approximately three million items, and continues to grow at least 7% per year [ 10 ] despite some criticisms from professional societies and commercial publishers [ 11 ].

This chapter describes all of the above-mentioned issues in more depth. It first introduces some existing literature search tools, and bibliographic archives, that are commonly used to access the biomedical literature, in three consecutive steps: searching, retrieving, and reading articles. Next, it presents a selection of five key categories of text mining and IR applications that address challenges in searching literature. Finally, there is a discussion on the future trends of biomedical literature access, with a focus on the open access activities in the biomedical domain and recent transition to reading articles on portable devices.

2. Current Access to Biomedical Literature

Open access availability of biomedical literature has led an increasing number of users to resort to online methods of literature access. Journals and online databases are currently the most frequently accessed resources among biomedical information seekers, followed by books, proceedings, newsletters, technical reports, author web pages, etc. [ 12 , 13 ]. Given the rising quality, volume, and diversity of biomedical literature [ 14 ], the information seeking trend has advanced to multiple layers of information access. Current framework comprises a search tool that provides unified access to multiple literature archives; these archives store the full text of articles and offer multiple viewing media to read those articles. Current practice begins with the user crafting a keyword or faceted (structured) query, and submitting on the search tool. In response, the tool presents a ranked list of citations relevant to the user query. The user has the option to go to a specific citation, access the full-text on the linked literature archive, and view the article using a particular medium. Figure 1 demonstrates the three-step process of literature access.

The Three Steps of Biomedical Literature Access (a) Searching the literature and reviewing results using a search tool (e.g. PubMed), (b) Retrieving the full-text on a literature archive (e.g., PubMed Central), (c) Consuming the article on a viewing media (e.g. PubTator)

2.1 Literature Search Tools

A search tool provides a single access point to multiple literature archives. At the core, the tool contains a citation database developed by indexing articles (abstract or full-text) from different sources. The tool interface serves two purposes: (i) provides search functionality supporting queries ranging from the standard keyword search to the comprehensive faceted search (e.g. search by author, journal, title, etc.), (ii) presents ranked list of citations relevant to the query, with several options to filter and re-sort the results; in addition to bibliographic information, each citation contains a link to retrieve the full-text of the article on a literature archive.

PubMed [ 1 ] is the most widely used search tool dedicated to biomedical and life sciences literature. Launched in 1996, PubMed is a publicly available citation database developed and maintained by the U.S. National Library of Medicine. To date, PubMed contains more than 22.9 million citations for biomedical literature belonging to MEDLINE indexed journals, manuscripts deposited in PubMed Central, and the NCBI Bookshelf. PubMed articles are indexed by the controlled vocabulary thesaurus, Medical Subject Headings (MeSH ® ). The search algorithm is based on PubMed’s automatic term mapping algorithm [ 15 ]. The PubMed citation database is updated daily. PubMed citations date back to the early 1950s, and approximately half a million also date back to 1809. The PubMed interface offers the keyword search, and allows the advanced queries by various fields such as author name, publication date, PubMed entering date, editor, grant number, status of MeSH indexing for MEDLINE citations, etc. A noteworthy feature of PubMed is the related citations algorithm [ 8 ] based on document similarity.

Embase [ 16 ] is a subscription-based biomedical citation database developed by Elsevier in 2000. This search service was developed primarily for biomedical and clinical practice with particular focus on drug discovery and development, drug safety, and pharmacovigilance research. Embase contains 25 million indexed records and indexes full-text articles from 8,306 journals, out of which 7,203 publish English language articles. Embase is often compared with MEDLINE, and contains 5 million records and covers 2,000 journals not included by MEDLINE. The Embase database is updated every day and nearly one million records are added per year. Embase has digitally scanned the articles from 1947 to 1973. While the official reported temporal coverage of Embase dates backs to 1947, some articles also date back to 1880s. The records are indexed by Emtree thesaurus for drug and chemical information. This allows for deep indexing of articles and flexible keyword searching using term mapping [ 17 ]. The search capability is enhanced using auto complete and synonym suggestion features. The results can be filtered by drug and disease mentions in the article.

While several other state of the art biomedical-specific search tools [ 14 , 18 – 20 ] have been designed since the inception of PubMed, these are not widely used as yet. Instead, other than PubMed, biomedical information seekers prefer rather generic tools that index articles from several disciplines in addition to biomedical and life sciences. Based on the popularity and discussion in previous studies [ 21 – 23 ], we describe one publicly available (Google Scholar [ 2 ]) and two subscription-based (Web of Science and Scopus [ 24 , 25 ]) tools, and describe their unique features.

Google Scholar [ 2 ], launched in 2004, is a Web search engine owned by Google Inc. Google Scholar indexes full-text articles from multiple disciplines from most peer-reviewed online journals of European and American publishers, scholarly books, and other non-peer reviewed journals. The size and coverage of biomedical articles in Google Scholar are not revealed; theoretically it consists of all biomedical articles available electronically. In addition to the keyword search, the tool offers searching by various fields such as author, publication date, journal, words occurring in title and body, with different methods of term matching. The results are sorted by relevance as determined by full text of each article, author, journal, and number of citations received.

Web of Science [ 24 ], developed by Thompson Reuters in 2004, is a citation database that covers over 12,000 top-tier international and regional journals, as per their selection process[ 26 ], in every area of the natural sciences, social sciences, and arts and humanities. The science citation database of Web of Science, which is likely to contain biomedical specific articles, covers more than 8,500 notable journals from 150 disciplines and is updated weekly. The temporal coverage is dated back to 1900 to the present day. The total number of biomedical citations cannot be approximated. The citations can be searched by various bibliographic fields, and the results display the total number of citations, comprehensive backward and forward citation maps, and additional keyword suggestions to improve the query. The result is ranked based on the overlap between the search terms and the terms in the articles. Also, the results can be filtered by Web of Science subject areas that are pre-assigned to journals.

Scopus [ 25 ], launched in 2004 by Elsevier, is a citation database for peer-reviewed literature from life sciences, health sciences, physical sciences, social sciences and humanities. Scopus, as of November 2012, includes citations from 19,500 peer-reviewed journals, 400 trade publications, 360 book series, and is updated one-to-two times weekly. Temporally, citations date back to 1823. Scopus contains more than 18,300 citations from the life, health, and physical science subject areas. The faceted search is comprehensive and includes fields such as publication date, document type, subject area, author, title, keywords, affiliation, etc. For each result citation, the number of incoming citations, Emtree drug terms, and Emtree medical terms are displayed. For a given citation, Scopus also displays the related articles computed based on shared references. The relevance rank of results is calculated based on relative frequency and location of the search terms in the article.

Table 1 summarizes various search tools based on some key features. The biomedical coverage and size of the generic search tools, Google Scholar, Web of Science, and Scopus, could not be accurately computed, as they do not provide a breakdown for biomedical and life science specific journals or articles. To get some insight on the coverage, we conducted a small experiment and submitted the query “type 2 diabetes mellitus” on various search tools. The results are shown in Table 2 . Google Scholar returns the highest number of results. This is expected given the crawling nature of the search engine and the liberal inclusion criteria. Embase returns more citations than PubMed. While Web of Science returns the least number of results, it is discussed in higher number (10,356) of PubMed articles as compared to Scopus and Google Scholar which are discussed in 3,231 and 1,621 articles, respectively. The most recent and the oldest articles differ for each tool. With PubMed as reference point, Google Scholar shows the most up-to-date result. Also, the number of incoming citations for a 2001 article [ 27 ] is 7092, 3655, and 4722, on Google Scholar, Web of Science, and Scopus (and Embase), respectively. This highlights the differences in coverage of various tools.

Summary of various popular biomedical literature search tools

Comparison of search results for “type 2 diabetes mellitus” on July 15 2013

Out of the above-mentioned tools, PubMed and Embase stand out in that they are the foremost developments, biomedical-specific, and the most frequently updated search tools. In addition, their inbuilt search algorithms utilize controlled vocabularies. The other three generic tools differ from PubMed and Embase in that they perform citation analysis and provide indications of scholarly impact of articles; Google scholar and Scopus provide the number of incoming citations for each article, and Web of Science offer thorough analysis including visual summaries of citation distributions. Also, all tools but PubMed employ a ranking algorithm that computes the relevance score of a given article with respect to search terms, incoming citations, journal, etc.

PubMed, Embase, and Scopus are similar in terms of their use of controlled vocabularies such as MeSH and Emtree in curating the articles. PubMed and Scopus are similar in their employment of the related citations algorithm, though internally quite different from each other. Web of Science is unique in that it has the keyword recommendation feature, and a strict criterion for journal selection. The selling point of Embase is that it covers significant number of biomedical articles and journals that are not covered by PubMed. Google Scholar is unique in the comprehensiveness of its ranking algorithm. Another advantage of Google Scholar is that it links to free full-text articles more than the other search tools that might point to a locked journal [ 22 ]. Google Scholar, however, unlike others, does not support bibliography management, such as integration with bibtex, RefWorks, EndNote, EndNote Web, etc. In sum, currently, there is no one-stop shop available for biomedical literature search as each tool has its own strengths and weaknesses. The choice of tool depends would thus depend on the subject matter, publication year, and the usage context, and a wise search strategy would use multiple tools instead of relying on one [ 21 ].

2.2 Full-text Literature Archives and Viewing Media

A literature search tool is integrated with multiple literature archives where full-text articles can be retrieved for further consumption. As of June 18 2013, out of the 22.9 million citations in PubMed, 4 million citations are linked to their free full text archives. Out of the citations linked to free full text archives, 2.3 million are archived in the PubMed Central [ 3 ] literature archive, and the remaining either contain direct links to journal’s website (e.g., Journal of Cell Biology, Oncotarget, Anticancer Research, BMJ Journals), or to comprehensive literature archives developed by major publishing companies.

PubMed Central (PMC) [ 3 ], launched in 2000, is a free federal digital archive of full-text biomedical and life sciences articles maintained by the U.S. National Library of Medicine. Currently, the PMC archives approximately 2.7 million articles provided by about 3,700 journals including full participation, NIH portfolio, and selective deposit journals. PMC also contains supplemental items optionally accompanying each article. Another domain-specific archive, EBSCO’s Cumulative Index to Nursing & Allied Health Literature (CINAHL) Plus with full text [ 28 ] is a subscription-based full-text literature archive designed for nurses, allied health professionals, researchers, nurse educators and students. The content is dated back to 1937 and includes full-text from 768 journals and 275 books from nursing and allied health disciplines. CINAHL is also a widely used search tool among nursing professionals.

Springer’s SpringerLink [ 29 ] was launched in 1996 and archives full-text content available from 1996. SpringerLink covers approximately 7.7 million full-text articles from electronic books and journals from all disciplines, out of which 6.4 million could be classified under the categories of biomedical, chemical, life, public health, and medical sciences. Supplementary material is also archived with each article.

ScienceDirect [ 30 ] is a subscription-based literature archive launched by Elsevier in 2000. ScienceDirect contains more than 11 million peer reviewed journal articles and book chapters from more than 2,500 peer-reviewed journals and more than 11,000 books, including 8,077 journals and book chapters from life and health sciences. ScienceDirect’s coverage goes back to 1823. Elsevier, which is also the host of Scopus search tool, has digitalized most of the pre-1996 content. Some additional content such as audio, video, datasets, and supplemental items are also archived. Since its launch, more than 700 million articles have been downloaded from the ScienceDirect website [ 31 ]. Recently, Elsevier has integrated its search tool, Scopus, and the literature archive, ScienceDirect into a new platform, SciVerse.

Wiley online library is a subscription-based full-text archive, developed in 2010 by Wiley-Blackwell publishing company. Wiley online library contains multidisciplinary collection of four million full-text articles from 1,500 journals, over 13,000 online books, and hundreds of reference works. The subject areas include chemistry, life sciences, medicine, nursing, dentistry and healthcare, veterinary medicine, physical sciences, and non-biomedical subjects [ 32 ]. The coverage of biomedical subject areas is not known.

Table 3 summarizes the above-discussed literature archives by their provider, launch year, temporal coverage, content coverage, and supported viewing media. Similar to the generic search tools, the total number of biomedical articles in the generic archives such as SpringerLink and ScienceDirect, could not be precisely computed. SpringerLink does provide a subject-wise breakdown, and archives the most number of full-text articles from biomedical and related areas. In PubMed, CINAHL is discussed in the highest number of articles (8595), followed by ScienceDirect (298), SpringerLink (116), and Wiley Online Library (38). These articles are related to information seeking and retrieval studies focused on biomedical articles. It should be noted that these numbers might not give a complete picture on the coverage of various archives, as there might be other studies published in journals not indexed by PubMed.

Comparison of biomedical full-text literature archives

Each literature archive offers one or more media or formats where the retrieved literature can be consumed (read) by the user. Currently, the aforementioned literature archives offer at least four types of viewing media. The first view is the classic view wherein the article can be viewed on the archive website itself. This view does not have any page breaks and needs to be read by scrolling vertically through a single long page. This is the default HTML format view offered by most literature sources for quick reference. The second viewing media is the PDF format (.pdf extension) wherein the article can be downloaded onto a device. All literature sources archive full-text in the PDF format that can be used to read on laptops, desktops, and Kindle, and can be printed into a hard copy. PDF format appears exactly as it would appear on a piece of paper; it allows paging, zooming, annotation, and commenting. The third viewing media is the open e-book standard EPUB (.epub extension) offered by PMC and ScienceDirect. This format offers a downloadable file that can be displayed on several devices and readers such as Calibre, iBooks, Google Books, Mobipocket, on various platforms such as Android, Windows, Mac OS X, iOS, Web, Google Chrome Extensions, etc. Finally, PMC offers a new view, PubReader [ 33 ], a user-friendly modification to the classic view that emulates the ease of reading the printed version of an article. PubReader was launched by the National Center for Biotechnology Information (NCBI) in 2012 and is coded in CSS and JavaScript. The PubReader display allows an article to be read on a Web browser through laptops, desktops, and tablet computers. PubReader offers ease of navigation and readability by organizing the article into columns and pages to fit into the target screen. In addition, ScienceDirect also offers mobile applications to be used on iPad, phones, and Tablet computers.

3. Text Mining Solutions to address Search Challenges

Given the exponential growth and increasing diversity of biomedical literature, the default querying mechanism (keyword or faceted search) would no longer be enough to meet the user needs. There is a need to provide alternative methods of writing queries and interactive support in query formulation [ 34 – 36 ]. Existing biomedical search tools have made a few efforts in this direction, such as keyword recommendation feature by Web of Science, and flexible keyword searching by Embase. Even when the user finds the right query to input, identifying the few most relevant articles among thousands of citations is not getting any easier. While most search tools employ a ranking algorithm to compute the relevance score of a given article, relevance remains an important topic in IR research [ 37 , 38 ]. Existing tools also provide filters to narrow down the results by different fields. Their ability to present the results in a summarized manner however remains largely unexplored.

In response to the shortcomings of the existing tools, the literature describes many alternative or experimental search interfaces. In this section, we discuss advanced NLP and IR techniques, primarily by discussing alternative interfaces implementing methods not yet available in the major literature search tools. We categorize these techniques into five sections: text similarity search, semantic search, query support, relevance ranking, and clustering; the former three primarily address the search challenges, and latter two address the result presentation issues.

3.1 Text Similarity Search

It can be difficult for users to make their exact information need explicit and then translate it into a query. Several alternative search interfaces have implemented another type of search where the query consists of one or more documents known to be relevant. The relevance of the documents to be retrieved is then calculated based on their similarity to the relevant documents.

eTBLAST is a tool for searching the literature for documents similar to a given passage of text, such as an abstract [ 39 ]. The tool extracts a set of keywords from the text and uses these to gather a subset of the literature. A final similarity score is computed for each document in the set by aligning the sentences in the input passage with the document retrieved. MedlineRanker allows the user to input a set of documents, and then finds the set of words most discriminative of the documents within the set [ 40 ]. These are then used as features in a classifier (Naïve Bayes), which is applied to unlabeled documents to return the most relevant results. While effective, this approach requires a sufficiently large training set, between 100 and 1000 abstracts.

Recent work by Ortuno et al. [ 41 ] partially alleviates the need for a large training set by allowing the user to enter a single abstract as query. The articles cited by the input article are then used to enrich the input set. This approach significantly improves the quality of the results over using only the input article and also typically returns significantly better results than pseudo relevance feedback. Tbahriti et al. [ 42 ] significantly improved the ability to determine whether two articles were related by classifying each sentence according to its purpose in the argumentative structure of the abstract (Purpose, Methods, Results, Conclusion). They found that the best results were obtained by increasing the weight of Purpose and Conclusion sentences relative to sentences classified as Methods or Results.

MScanner is similar to the other textual similarity tools in that it learns a classifier (Naïve Bayes) from a set of relevant documents input by the user [ 43 ]. In the case of MScanner, however, the only features are the set of MeSH terms associated with each article and the name of the journal where the article appears, resulting in a very high speed retrieval system. Other systems have experimented with using inputs other than text. Caipirini, for example, allows the user to specify a set of genes that are of interest and a set of genes that are not of interest [ 44 ]. The system locates abstracts mentioning the genes specified, and the system extracts keywords that appear more frequently than chance in these abstracts. These keywords are then used as features for a classifier (SVM), which provides a score representing the similarity of a text to the abstracts that mention the genes of interest versus the background set. This classifier is then applied to all of Medline and the top results are returned.

3.2 Semantic Search

A large part of the meaning of biomedical texts is captured by the entities they mention and the relationships discussed. This observation can be exploited to support semantic search in both the queries and in the way the results are displayed to the user. Systems supporting semantic search also differ in the types of entities and relationships extracted and the methodology employed.

MedEvi is a semantic search tool intended for finding evidence of specific relationships [ 45 ]. The tool recognizes 10 keywords representing entity types, such as “[gene]” and “[disease].” In addition, the tool orders results by preferring results containing the terms in the same order as they appear in the query and within close proximity. Kleio supports keyword searches of multiple prespecified fields [ 46 ], including both semantic types (including Protein, Metabolite, Disease, Organ, Acronyms, and Natural phenomenon) and article metadata (e.g. author). A specialized tool for specifically querying authors is Authority [ 47 ]. Authority uses a clustering approach over article metadata to determine whether ambiguous author names represent the same person or not. When the users queries for an author, the system displays the matching author clusters.

MEDIE allows queries to specify any combination of subject, verb and object [ 48 ]. For example, the query representing “What causes cancer?” would be verb =“cause” and object =“cancer.” This query returns a list of text fragments where the verb matches “cause” and its object is “cancer” or any of its hyponyms, such as “leukemia.” The results highlight genes and diseases in different colors. PubNet extracts entities and relationships from the articles returned by a standard PubMed query, then visualizes the results as a graph [ 49 ]. Entities supported include genes and proteins, MeSH terms and authors.

The EBIMed service uses keyword queries as input and provides a listing of the entities most common in documents matching the query [ 50 ]. EBIMed supports a fixed set of entity types (protein, cellular component, biological process, molecular function, drug and species) and locates both entities and relationships between two entities. All results are linked to the biological database that defines the entity. Quertle locates articles that describe relationships between the entities provided in a query, results are grouped by the relationship described [ 51 , 52 ]. Users may also switch to a keyword search with a single click. Quertle also supports a list of predefined query keywords that refer to entity types of varying granularity.

A Web-based text mining application named PubTator[ 53 , 54 ] was recently developed to support manual biocuration [ 55 – 58 ]. Because finding articles relevant to specific biological entities (such as gene/protein) is often the first step in biocuration, PubTator supports entity-specific semantic searches based on the use of several challenging-winning named entity recognition tools [ 59 – 64 ].

3.3 Query Support

An important aspect of improving the relevance of query results is to help the user translate their information need into a query. While text similarity, as discussed in Section 3.1, is a useful method for reducing this barrier, another method is to directly support the creation and revision of both keyword and faceted queries [ 34 ].

The iPubMed tool allows searching MEDLINE records to be more interactive through the search-as-you-type paradigm. Query results are dynamically updated after every keypress. iPubMed also supports approximate search, allowing users to dynamically correct spelling errors.

PubMed Assistant is a standalone system which includes a visual tool for creating Boolean queries and a query refinement tool that gathers useful keywords from results marked relevant by the user [ 65 ]. PubMed Assistant also supports integration with a citation manager.

Schardt et al. [ 66 ] demonstrated that search interfaces supporting the PICO system for focusing clinical queries improved the precision of the results. PICO is a framework for supporting evidence based medicine and is an acronym for P atient problem, I ntervention, C omparison and O utcome [ 67 , 68 ]. SLIM is a tool emphasizing clinical queries which uses slider bars to quickly customize query results. Modifiable parameters include the age of the article, the journal subset, and both the age group and the study design of the clinical trial reported. askMEDLINE is a system which accepts clinical queries in the form of natural language questions. The system is particularly designed to support users who are not medical experts.

3.4 Relevance Ranking

Ranking results in order of their relevance to the query is a well-supported technique for reducing the workload of the user, and is supported in most existing tools for searching the literature except PubMed itself. While straightforward measurements such as TF-IDF are known to work well [ 37 ], there are still aspects that can be improved.

A common ranking technique in web search is to incorporate a measurement of the importance of the document into the score. The scientific record contains many types of bibliometric information that can be used to infer the quality or importance of an article. The PubFocus system, for example, ranks relevant documents according to an importance score that includes the impact factor of the journal and the volume of citations [ 69 ].

Bernstam et al. [ 70 ] demonstrated that algorithms that use citation data to determine document importance – including both simple citation counts and PageRank – significantly improve over algorithms that do not use citation data. Unfortunately, however, citation data suffers from “citation lag” – the period of time between when an article is published and when it is cited by another article. Tanaka et al. [ 71 ] partially overcome this limitation by using the data available at publication to learn which articles are likely to eventually be highly cited.

Lin [ 72 ] takes a different approach and instead uses the PubMed Related Articles tool to create a graph by linking similar document pairs. PageRank is then applied, producing a score for each document where higher scores imply the document contains more of the content from its neighbors in the graph. Scores are thus independent of any query but documents with higher scores will naturally be relevant for a wider range of queries.

Yeganova et al. [ 73 ] examined PubMed query logs and found that users frequently enter phrases such as “sudden death syndrome” without the quotes to indicate that the query contains a phrase. While PubMed interprets such queries as the conjunction of the individual terms, the authors demonstrate a qualitative difference between results that contain all terms and results that contain the terms as a phrase. They conclude that it would be beneficial to attempt to interpret such queries as containing a phrase, and in particular suggest that documents containing the terms in close proximity are more relevant than results that merely contain all terms.

The RefMed system employs relevance feedback to explicitly model the relevance of query results [ 74 ]. In relevance feedback, the system returns an initial set of results, allows the user to indicate whether each result is useful, and then uses the input as feedback to improve the next round of results. While relevance has traditionally been considered to be binary, RefMed uses a learning to rank algorithm (rankSVM) to allow the user to specify varying degrees of relevance along a scale.

The MiSearch tool uses an implicit form of relevance feedback to model the relevance of articles to the user [ 75 ]. The system automatically collects relevant documents by recording which documents are opened while browsing. This data is used to create a model of the likelihood that the user will open a document that can be used to rank the results of any query. Features for the model include authors, journal and PubMed indexing information.

3.5 Clustering Results

Clustering the results of the user query into topics helps in several ways. First, clustering the results helps to differentiate between the different meanings of ambiguous query terms. Second, in large sets of search results it can help the user focus on the subset of documents that interest them. Third, the clusters themselves can serve as an overview of the topic. This method has been considered in several PubMed derivatives that vary in their method of determining the clustering methodology. Popular variations include MeSH terms, other semantic content (such as UMLS concepts and GO terms), keywords, and document metadata (such as journal, authors, and date).

Anne O’Tate provides additional structure and a summary of the query results by clustering the content of the documents retrieved and also by extracting important words, the publication date, authors and their institutions [ 76 ]. Users are allowed to extend the query by any of the summarized information simply by clicking on it, and any query returning less than 50 results can be expanded to include the articles most closely related.

The McSyBi tool clusters query results both hierarchically and non-hierarchically [ 77 ]. Whereas the non-hierarchical clustering is primarily useful for focusing the query on particular subsets, the hierarchical clustering provides a brief summary of the query results. McSyBi also provides the ability for the user to adjust or reformulate the clustering by introducing a MeSH term, which is interpreted as a new binary feature for each document, depending on whether the document has been assigned the specified MeSH term. Users can also introduce a UMLS Semantic Type, which is considered present if the document is assigned at least one MeSH term with the specified type.

GoPubMed originally used the Gene Ontology (GO) [ 78 ] to organize the search results [ 79 ]. It currently groups search results according to categories “what” (biomedical concepts), “where” (affiliations and journals), “who” (author names), and “when” (date of publication). The “what” category is further subdivided into concepts from Gene Ontology, MeSH and UniProt. GO terms are located in the abstracts retrieved, even if they do not appear directly, and are highlighted when the abstract is displayed.

XplorMed is a tool for multifactored analysis of query results [ 80 , 81 ]. Results are displayed grouped both by coarse MeSH categories and important words that are shown both in summary and in context. Users may then explore the important words in more depth or display results ranked by inclusion of the important words.

Boyack et al. [ 7 ] sought to determine which clustering approach would produce the most coherent clusters over a large subset of MEDLINE. The analysis considered five analytical techniques: a vector space approach with TF-IDF vectors and cosine similarity, latent semantic analysis, topic modeling, the Poisson-based language model BM25 and PubMed Related Articles. The analysis also considered two data sources, MeSH subject headings and words from titles and abstracts. The article concluded that PubMed Related Articles created the most coherent clusters, closely followed by BM25, and also concluded that the clusters based on titles and abstracts are significantly better than those based only on MeSH headings.

SEACOIN (Search Explore Analyze COnnect INspire) is a system that merges important word analysis with clustering and a graphical visualization to achieve a simple interface suitable for novice users [ 82 ]. The SEACOIN visualization combines a word cloud that allows the user to add additional terms to the query, a multi-level tree-like graphic that allows users to see the relative number of documents containing different terms and term combinations, and a table listing the documents returned.

SimMed presents users with clusters of documents ranked by their degree of relevance to the query [ 83 ]. The interface emphasizes the clusters found to provide a summary of the query topic, thereby explicitly supporting exploratory searches. The clusters used are computed offline, allowing high retrieval performance.

4. Future Trends to Improve Biomedical Literature Access

In terms of the search tools, in addition to the research directions highlighted in Section 3, we can expect to see more reader-friendly and smart applications based on advanced IR and NLP techniques in order to help readers find and digest articles more effectively and efficiently. Furthermore, with the use of social media such as blogging and tweeting, new ways of sharing and recommending papers will gain more importance in the future, in addition to the traditional search-based mechanism. For instance, using social media makes it easier to make and share comments on papers, thus providing alternative views with respect to the impact of individual papers. In the future, biomedical literature search could also be personalized. That is, search results are tailored towards the interests of individual researchers based on their own work and/or past searches. In other words, the same query by two different users may return different search results. This is desirable in certain cases. For instance, a bench scientist and medical doctor are likely to search for different information (biological vs. clinical, respectively) even though they both search for the same drug and disease pair. In the general Web search domain, personalized search has been shown useful [ 84 ]. Therefore, such a feature could also be helpful to users when it comes to the biomedical literature search.

With regard to open access papers, we believe its size will continue to grow rapidly over the next 5 to 10 years. This is evidenced by the increasing number of publishers and journals interested in adopting the open access policy, as well as by the ever-growing interests from the scientific community. That is, more and more authors are considering open-access journals as their preferred choice for publishing their work. As this happens and together with Web and computer technology advances, we can imagine free access to most research articles anywhere, anytime on any devices.

Finally, with increased use of portable devices such as smartphones and computer tablets to access the Internet, there are growing needs and interests in searching and reading literature on those devices. Portable devices provide a great deal of benefits such as convenience, but also present new challenges. First, it is less likely to print out the papers with portable devices – a common way for reading papers. As a result, reading directly on those devices becomes necessary. But compared to desktop or laptop computers, the screen size of portable devices is usually much smaller. As such, readability becomes a real issue on those small-screen devices, especially when it comes to reading papers. This is because unlike reading emails or news articles, people do not generally read straight through an article. Instead, they often need to go back and forth when reading a journal article in order to understand and digest its content. Scrolling up and down on a modern computer screen is hard but still viable; this kind of operation becomes almost impossible on small-screen devices. As mentioned in Section 2.2, there has already been work on supporting convenient reading on small-screen devices from new reading apps to reader-friendly Web interfaces. Although these tools already provide better readability than the traditional Web browsers, further improvement is needed in order to make users to read and digest articles comfortably on those devices. We also expect advances in Web technology to help facilitate such a transition.

Acknowledgments

This research was supported by the Intramural Research Program at the National Institutes of Health, National Library of Medicine.

Contributor Information

Ritu Khare, National Center for Biotechnology Information, U.S. National Library of Medicine, NIH, Blg 38 A, Rm 1003B, 8600 Rockville Pike, Bethesda, MD 20894.

Robert Leaman, National Center for Biotechnology Information, U.S. National Library of Medicine, NIH, Blg 38 A, Rm 1003E, 8600 Rockville Pike, Bethesda, MD 20894.

Zhiyong Lu, National Center for Biotechnology Information, U.S. National Library of Medicine, NIH, Blg 38 A, Rm 1003A, 8600 Rockville Pike, Bethesda, MD 20894.

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The double whammy of ER-retention and dominant-negative effects in numerous autosomal dominant diseases: significance in disease mechanisms and therapy

• Nesrin Gariballa 1 ,
• Feda Mohamed 1 , 2 ,
• Sally Badawi 1 &
• Bassam R. Ali 1 , 2  

Journal of Biomedical Science volume  31 , Article number:  64 ( 2024 ) Cite this article

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The endoplasmic reticulum (ER) employs stringent quality control mechanisms to ensure the integrity of protein folding, allowing only properly folded, processed and assembled proteins to exit the ER and reach their functional destinations. Mutant proteins unable to attain their correct tertiary conformation or form complexes with their partners are retained in the ER and subsequently degraded through ER-associated protein degradation (ERAD) and associated mechanisms. ER retention contributes to a spectrum of monogenic diseases with diverse modes of inheritance and molecular mechanisms. In autosomal dominant diseases, when mutant proteins get retained in the ER, they can interact with their wild-type counterparts. This interaction may lead to the formation of mixed dimers or aberrant complexes, disrupting their normal trafficking and function in a dominant-negative manner. The combination of ER retention and dominant-negative effects has been frequently documented to cause a significant loss of functional proteins, thereby exacerbating disease severity. This review aims to examine existing literature and provide insights into the impact of dominant-negative effects exerted by mutant proteins retained in the ER in a range of autosomal dominant diseases including skeletal and connective tissue disorders, vascular disorders, neurological disorders, eye disorders and serpinopathies. Most crucially, we aim to emphasize the importance of this area of research, offering substantial potential for understanding the factors influencing phenotypic variability associated with genetic variants. Furthermore, we highlight current and prospective therapeutic approaches targeted at ameliorating the effects of mutations exhibiting dominant-negative effects. These approaches encompass experimental studies exploring treatments and their translation into clinical practice.

The exploration of molecular and cellular mechanisms underlying many genetic diseases typically starts by evaluating the early stages of the protein biogenesis as well as its subsequent processes including trafficking, interactions, the execution of its biological function and even its disposal. A detailed understanding of defects and aberrations in these processes provides key insights into the molecular foundation of the pathogenesis of genetic diseases and the consequent manifestations of the pathological phenotypes. In eukaryotic cells, secretory and endomembrane proteins destined for many cellular organelles typically enter the endoplasmic reticulum (ER) in their unfolded states, where they undergo their initial and crucial processes to acquire their proper tertiary conformations [ 1 , 2 ]. In particular, this is where these ER-targeted proteins undergo essential post-translational modifications including glycosylation, proline isomerization, lipidation and disulfide bond formation, which are often crucial for guiding proper folding, stability and the performance of their biological functions [ 3 , 4 ]. To ensure efficiency and fidelity, cells have adapted extensive ER quality control (ERQC) mechanisms that allow only properly folded proteins to reach their functional destination [ 5 ]. Due to the extensive and rigorous cellular mechanisms dedicated to maintaining protein fidelity and proper conformation, it is estimated that 12–15% of newly synthesized proteins do not successfully attain their intended conformation, leading to their subsequent elimination via one or more of the cellular degradation pathways within the secretory pathway [ 6 , 7 ]. This percentage is significantly increased when proteins harbor mutations that lead to their mis- or mal-folding, and often the removal of the mutant protein quantitatively [ 8 ]. Disease-causing mutations, including point mutations, insertions, deletions and repeat expansions impact protein structure and function in diverse ways, leading to three primary disease cellular mechanisms: loss-of-function, gain-of-function or dominant-negative effects [ 9 ]. Loss-of-function mutations may cause decreased or total loss of protein function that consequently leads to failure or reduction in performing its normal physiological function [ 10 ]. Conversely, gain-of-function mutations occur when the mutant protein acquires a new or abnormal function such as increased or uncontrolled activities leading to dysregulation in the normal cellular activities [ 11 ]. In autosomal dominant diseases where one allele expresses the mutant protein, while the other allele preserves its WT expression, a range of disease mechanisms can be demonstrated including loss-of-function of one allele (haploinsufficiency), gain-of-function, dominant-negative effects or a combination of two mechanisms [ 11 ]. The dominant-negative effects exerted by the mutant protein on the WT protein may exacerbate the haploinsufficiency state in autosomal dominant diseases [ 12 ]. This occurs through interference with the function or trafficking of the normally functioning protein. It is common for proteins to function as homodimers, oligomers or part of multi-subunit complexes. As a consequence, when a mutant protein is expressed from the mutant allele, this can lead to the formation of abnormal dimers, heteromers or multi-subunit complexes that often negatively impact the function or stability of their functioning unit. Numerous studies, including our own, indicate that ER-targeted mutant proteins that are unable to attain their correct conformation, often experience defective trafficking, leading to their entrapment in the ER and subsequent degradation via the ER-associated protein degradation (ERAD) and other associated mechanisms [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. Therefore, exploring whether certain ER-retained mutant proteins exert dominant-negative effects on their WT counterparts, or their complexes has become crucial. Such effects may exacerbate the disease pathological state, potentially explaining some of the broad and variable spectrum of phenotypic expressivity observed for many monogenic diseases [ 12 ]. Despite extensive research efforts directed towards comprehending loss of function and gain of function mutations in dominant conditions, there has been relatively limited exploration into the involvement of dominant-negative effects mechanisms. ERAD is a complex mechanism that plays a crucial role in protein quality control in the secretory pathway, involving the recognition of mutant, orphaned and misfolded proteins then targeting them for re-translocation for degradation by the proteasomal or lysosomal machineries. This mechanism has been implicated in the pathology of numerus human genetic condition and the number is expected to keep rising due to the central importance of this quality control mechanism in the monitoring almost a third of the cellular proteins [ 21 , 22 , 23 ].

In this manuscript, we aim to review the literature and include our perspectives on the impact of various dominant-negative effects implicated in the pathology of a spectrum of autosomal dominant diseases caused by mutations in secretory and membrane proteins (Table  1 ). We will focus on both the currently acknowledged and potential dominant-negative effects displayed by mutant variants retained in the ER as a result of the ER quality control (ERQC) mechanisms. In addition, we will also highlight existing and potential therapeutic interventions aimed at mitigating the impact of mutations exhibiting dominant-negative effects, spanning from experimental research on therapies to their application in patient care.

The dominant-negative effects: Concept and mechanisms

Dominant-negative mutations have been defined in 1987 by Ira Herskovitz as “those leading to mutant polypeptides that disrupt the activity of the WT gene when overexpressed” [ 83 , 84 ]. This current review is focused on the combinational mechanism of ER retention and dominant-negative effects exerted by the mutant proteins on their WT counterpart, resulting in the entrapment and defective trafficking of WT proteins from the ER to their functional destinations. `It is crucial, however, to recognize that dominant-negative mechanisms extend far beyond those caused by ER-retained mutants. Here is an overview of some of these mechanisms:

Altered protein trafficking: Mutant proteins might alter the trafficking of the WT proteins causing their entrapment in cellular compartments, thus preventing their trafficking to their functional destination. For example, some ER-retained endoglin mutants associated with hereditary haemorrhagic telangiectasia type 1(HHT1) form heterodimers with WT endoglin in the ER and thus preventing its trafficking to the plasma membrane [ 47 ]

The formation of inactive protein complexes: Trafficking-competent mutant proteins can form heterodimers with their WT counterpart expressed by the unaffected allele or with other WT partner proteins expressed by different genes, which renders the heterodimeric complex inactive [ 85 ]. This type of dominant-negative effect is best represented in collagen disorders such as Osteogenesis Imperfecta (OI), in which a mutant collagen protein forms inactive complexes with its WT partners negatively impacting the function of the whole collagen matrix [ 39 ].

Competitive binding inhibition: In this case, the mutant proteins compete with the WT counterparts for binding to shared substrates or ligands, thereby limiting proper binding interactions, leading to a potential inhibitory effect. For example, Von Willebrand disease (VWD) is a bleeding disease caused by mutants von Willebrand factor (VWF), a glycoprotein expressed by endothelial cells [ 86 ]. Mutants VWF interfere with the binding of WT protein to platelets and sub-endothelium in a dominant-negative manner, resulting in reduced clotting function and increased risk of bleeding [ 87 ].

Protein destabilizing effect: The dominant-negative effect exerted by the mutant protein results in WT reduced stability or even premature degradation. Certain p53 tumor suppressor mutant proteins adversely affect the stability of WT p53, leading to its reduced function and effectiveness [ 88 ].

Conformational effects: Secreted misfolded mutant proteins with structural defects may give rise to conformational defects in the WT protein complex, impeding its physiological function. For example, mutant fibrillin-1 proteins encoded by FBN1 gene, associated with Marfan disease exhibit a dominant-negative effect on the WT protein via disruption of the normal assembly of the extracellular matrix [ 89 ].

Protein quality control mechanisms in the early secretory pathway: Components and involvement in human diseases

Newly synthesized secretory and membrane proteins are transported to the ER where they undergo various interactions, posttranslational modifications and assembly to generate mature proteins in fully folded three-dimensional states. While protein folding can occur co- or posttranslationally, its accuracy and efficiency are important factors for the protein’s functionality and cellular homeostasis. Protein folding in the ER is mediated via a complex ER-resident chaperoning and folding machineries, consisting of the heat shock protein (Hsp) chaperones and the calnexin/calreticulin (CNX/CRT) lectin-like chaperones [ 90 ]. Among the major molecular chaperones involved in preventing protein aggregations and incorrect folding is the Hsp70 chaperone; BiP (Fig.  1 ) [ 91 , 92 ]. Dysfunction in the chaperoning machinery contributes to various diseases, including Alzheimer's and Parkinson diseases [ 93 ].

Protein synthesis and quality control mechanisms in the ER. Newly synthesized proteins in the ER undergo quality control checks to ensure correct folding. Misfolded proteins form aggregates in the ER lumen and activate the UPR response that leads to transcriptional activation of various ER stress genes and are degraded via the proteasomal ERAD machinery based on their lesioned domain

In addition to the failure of the chaperoning systems, several other factors contribute to defective protein folding in the ER, including transcriptional or translational errors, abnormal chemical protein modifications, oxidative stress, and genetic mutations [ 18 , 94 ]. Consequently, incorrect protein folding results in defective trafficking of the proteins to their destination associated with ER retention and the formation of protein aggregates in the ER lumen. Accumulation of misfolded proteins in the ER triggers an ER stress signaling cascade known as the unfolded protein response (UPR). The UPR employs cytoprotective strategies aimed at preserving ER homeostasis, thereby alleviating ER stress caused by the burden of misfolded proteins. This is accomplished by activating downstream ER quality control activities. The UPR cascade is induced by three established arms: protein kinase RNA like endoplasmic reticulum kinase (PERK), inositol requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6) (Fig.  1 ) [ 20 , 95 ]. The coordinated activation of the three UPR arms collectively targets the attenuation of protein synthesis within the ER, induction of molecular chaperones’ gene expression aiding in protein folding, and ultimately the removal of misfolded proteins via ERAD mechanism [ 96 ]. ER stress and the disruption of the UPR have been linked to the development of various diseases, spanning neurodegenerative conditions like Alzheimer's and Parkinson's diseases [ 97 ], metabolic disorders such as diabetes and obesity [ 98 , 99 , 100 ], inflammatory diseases [ 101 ], cancer [ 102 , 103 ], and rare genetic disorders like cystic fibrosis (CF) [ 104 ], Gaucher disease [ 105 , 106 ], Acromesomelic Dysplasia 1, Maroteaux type [ 18 ] and many others [ 107 , 108 , 109 , 110 ]. Understanding the mechanisms underlying ER stress and the UPR activation is crucial for elucidating disease pathogenesis and developing therapeutic strategies. CF has been recognized as a pioneering disease in the field of ER stress research due to its well-defined genetic basis, thoroughly investigated pathophysiology, and the availability of animal models and cell culture systems for studying disease mechanisms [ 111 ]. CF is an autosomal recessive disorder caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene, which encodes a chloride channel primarily found in the apical membrane of epithelial cells [ 112 ]. Mutations in CFTR result in defective chloride ion transport across cell membranes, leading to sticky mucus production in the lungs and digestive system. Studies have revealed that most CF disease-causing mutations, including the most common CF variant (F508del), result in defective protein folding and trafficking, leading to ER retention and degradation of misfolded CFTR protein [ 113 , 114 , 115 , 116 , 117 ]. This accumulation of misfolded CFTR protein in the ER triggers ER stress and activates the the UPR mechanism aimed at restoring ER homeostasis [ 118 ].

In eukaryotic cells, nascently synthesized proteins are subjected to unique quality control assessments. This step involves the UDP-glucose: glycoprotein glucosyltransferase (UGGT) interaction with partially or misfolded proteins providing a further folding attempt mediated by the CNX/CRT chaperones cycle [ 119 ]. Proteins failing to meet the stringent quality checks are destined for degradation via various pathways including the ERAD machinery. Misfolded proteins are recognized and processed by distinct ERAD sub-pathways: ERAD-L, ERAD-M, and ERAD-C, based on the site of the defective domain within the protein—luminal (ERAD-L), membrane-bound (ERAD-M), or cytosolic (ERAD-C) (Fig.  1 ) [ 120 ]. ERAD substrates are exported and tagged with ubiquitin that serves as a degradation signal. These proteins are retrotranslocated to the cytosol for degradation by the large protein complex, the proteasome or the lysosomes, via a pathway known as the ER-to-lysosome associated degradation (ERLAD) [ 121 ]. Moreover, some ER retained mutants might escape the ERQC mechanism and avoid being degraded. These mutants might form aggregates in the ER lumen or interact in a dominant-negative manner with their WT counterparts and possibly affect their normal physiological function. These mechanisms and indeed defects in their components have been implicated in numerous human conditions, which is the focus of this review.

ER-retained mutant proteins exhibit dominant-negative effects in a range of autosomal dominant disorders

As indicated earlier, the entrapment of secretory proteins may result in a spectrum of monogenic diseases with varied modes of inheritance and molecular mechanisms. These encompass a range from loss of function, gain of function, dominant-negative effects, or combinations thereof. Here, we emphasize the dominant-negative effects demonstrated or predicted to play significant roles in the pathology of numerous autosomal dominant diseases. In these conditions, both the WT and mutant variants are expressed and anticipated to interact during the initial stages of the protein biogenesis and assembly within the ER, particularly in cases where the protein functions as a dimer, oligomer or part of a multi-subunit complex (Fig.  2 ). The broad spectrum of phenotypic severity observed across various autosomal dominant diseases constitutes a significant area of ambiguity and concern in biomedical research. The exploration of mechanisms, or combinations thereof, that cause phenotypic heterogeneity among affected individuals is essential in understanding the complex genotype–phenotype interplay. Extensive literature highlights examples of dominant-negative effects instigated by mutant variants, wherein these mutants impair the function of the WT counterpart at the functional location. In this review, we specifically explore the dominant-negative effects exerted by ER-retained mutants on the WT proteins, thereby initiating a double effect that entails dominant-negative effects on top of haploinsufficiency leading to the entrapment and possibly premature degradation of WT protein. Consequently, this combinatorial mechanism causes an excessive loss of protein function, thereby exacerbating the severity of disease phenotypes for some mutants exhibiting ER retention. It is important to note that our aim in this review is not to exhaustively cover every condition exhibiting dominant-negative effects within the field, but rather to highlight the widespread involvement of these mechanisms in disease pathogenesis in some autosomal dominant conditions.

Dominant-negative effects exerted by ER-retained mutant on the WT protein expressed by the functional allele. Monomeric Plasma membrane proteins or secretory proteins that fail to attain their normal conformation get targeted by the ERAD machinery for proteasomal degradation. In the case of dimeric or oligomeric proteins, ER-retained mutants are likely to interfere with the WT counterpart via a formation of hetero dimers/oligomers complexes. This interreference causes the entrapment of the WT within these complexes impeding its normal trafficking and leading to premature degradation through the ERAD mechanism

Skeletal and connective tissue disorders

Marfan Syndrome (MFS, MIM #154700) is an autosomal dominant genetic disease caused by heterozygous mutations in the FBN1 gene that encodes Fibrillin-1, a crucial protein component in the extracellular matrix (ECM) [ 122 ]. The disease is broadly classified as a connective tissue disorder with clinical manifestations impacting various organs including the heart, the blood vessels and the eyes [ 123 ]. The most distinctives features include a long face, high-arched palate, elongated limbs, tall and slender physique, chest deformities, lens dislocation, aortic root dilation and potential aneurysms [ 122 ]. MFS is characterized by a wide spectrum of phenotypic variabilities among affected individuals, including those carrying different genetic variants or even those with the same variant [ 123 ]. Fibrillin family of proteins encompasses three main types of fibrillin, fibrillin-1, 2 and 3. Fibrillin-2 and 3 are predominantly expressed during development, whereas fbrillin-1 is expressed throughout adulthood, as it provides strength and elasticity to connective tissues in major organs [ 124 ]. Fibrillin-1 is a 250 kDa glycoprotein characterized by multi-modular organization and is considered as the major structural component of the connective tissues microfibrils [ 24 ]. However, the mechanism by which fibrillin-1 assembles into microfibrils, remains to be fully elucidated. The majority of disease-causing variants in FBN-1 involve the substitution of cysteine amino acids, which play a critical role in forming disulphide bridges and maintaining proper protein conformation. For instance, severely misfolded variants like C1117Y and C1129Y, where cysteine is replaced by tyrosine, exhibit defective trafficking and become trapped and accumulate in the ER [ 24 ]. Conversely, the disease-causing variant G1127S is secreted normally, similar to the WT. These conclusions were drawn by examining their glycosylation profiles. Variants C1117Y and C1129Y exhibit a simple N-linked glycosylation pattern characteristic of ER acquisition. On the other hand, they lack the complex N-glycosylation typical of Golgi apparatus processing, resulting in a lower molecular weight presentation on SDS-PAGE, confirming their retention in the ER. In contrast, variant G1127S appears in a mature, fully glycosylated form, mirroring WT fibrillin-1 [ 24 ]. As a result, it was proposed that normally-trafficked fibrillin-1 mutants such as G1127S are likely to exert dominant-negative effects via misincorporation into the normal microfibril, however, no clear evidence was presented. In addition, intracellular dominant-negative was postulated as a probable disease mechanism attributed to the ER-retained variants such as C1117Y and C1129Y in addition to haploinsufficiency. This occurs because ER-retained mutants are prone to interact with WT fibrillin-1, forming heterodimers during the initial stages of protein dimerization within the ER. This interaction hampers the trafficking and secretion of fibrillin-1 to the cell surface [ 24 ]. The concept of a dominant-negative effect was previously proposed by Dietz and colleagues , supported by their demonstration that patients expressing the least amount of the nonsense mutant variants of fibrillin-1 exhibited the mildest disease phenotype. Conversely, patients with fully expressed variants exhibited the usual moderate to severe manifestation of the diseases [ 25 ].

Recent advances in high-throughput genomic analysis have revealed that idiopathic short stature (ISS, MIM # 300582) in children is linked to various genes that regulate growth plate function, including heterozygous mutations in NPR2 [ 29 ]. NPR-B encoded by NPR2 functions as a homodimer that catalyzes the conversion of GTP to cGMP upon binding of its ligand, C-type natriuretic peptide (CNP) [ 30 ]. Recently, co-immunoprecipitation assays have revealed that diseases-causing heterozygous missense NPR-B variants (R110C, R495C and Y598N) identified in ISS subjects exhibit dominant-negative effects on the WT receptor [ 29 , 31 ]. These studies have demonstrated that intracellular cGMP levels significantly increase upon cell transfection with the WT NPR-B. On the other hand, a significant decrease is observed when a mutant variant is co-expressed with the WT receptor. Notably, a prior investigation has also identified variant R110C as an ISS-causing mutation. This study demonstrated that this particular variant displays defective trafficking from the ER to the Golgi apparatus, evidenced by an immature glycosylation profile characteristic of ER-retained mutants [ 28 ]. Conversely, variant Q417E, also identified in the same study, trafficked normally to the plasma membrane. Interestingly, both variants exhibited dominant-negative effects, as evidenced by a decrease in cGMP production capacities. Specifically, R110C showed a negligible cGMP response, while Q417E displayed a significantly reduced response. These findings underscore the importance of further investigating the implications of dominant-negative effects and ER retention across a broader spectrum of variants. This approach will enable researchers to gain a more comprehensive understanding of the molecular pathology associated with variable variants.

Autosomal dominant Limb-girdle Muscular Dystrophy (LGMD-1CI, MIM # 609115) is a specific subtype of LGMD that is associated with mutations in CAV3 gene. The disorder is characterized by progressive muscle weakness primarily affecting the shoulders and hips muscles [ 125 ]. Caveolin-3 encoded by CAV3 is a member of the caveolin integral membrane proteins and a key structural protein of caveolar membrane in muscle cells [ 126 ]. Up to date ten LGMD-1C-disease causing variants of CAV3 have been identified according to the Human Genome Mutation Database (HGMD) ( https://www.hgmd.cf.ac.uk/ac/index.php ). Amongst the most studied variants are P104L, ΔTFT/63–65 (deletion of amino acids 63 to 65) and A45T. Minetti, Sotgia, Lisanti, and colleagues were the first to report the disease causing variants P104L, ΔTFT/63–65 in LGMD-1C patients [ 127 ]. In vitro characterization and immunofluorescence staining experiments have shown that the two variants fail to reach the plasma membrane. Instead, they are retained at the Golgi complex level and subsequently degraded through proteasomal degradation, along with partial degradation of the WT protein [ 128 ]. These findings suggest a dominant-negative effect of these two variants on the WT protein, leading to its entrapment in mixed WT/mutant oligomers, which ultimately results in proteasomal degradation, as evidenced by ER-localization. The same research group later demonstrated that treatment with the proteasomal inhibitor (MG-132) significantly enhanced the trafficking of WT protein entrapped at the Golgi complex to the plasma membrane in cells expressing both the WT and mutant variants [ 34 ]. Similarly Herrmann and colleagues have demonstrated that disease-causing variant A45T exhibit defective trafficking and also prevent the normal localization of WT caveolin-3 in a dominant-negative manner [ 129 ].

Collagen-related mutations in connective tissue disorders

The intricacy of collagen structures and their assembly plays a pivotal role in the diverse phenotypic manifestations observed in individuals with mutant collagen genes. Collagen, being the most abundant protein in the human body and a fundamental component of connective tissues, contributes significantly to the structural integrity of various tissues in the body such as skin, cartilage, and blood vessels [ 130 ]. The variability in collagen types and their interactions within heterotypic fibrils adds a layer of complexity to the assembly process. Mutations in collagen genes can disrupt this intricate network, leading to a spectrum of phenotypes broadly known as collagenopathies or connective tissue disorders [ 131 ].

A collagen molecule is most characterized by its triple-helical α-domain, which constitutes up to 95% of the molecule in some classes of collagen (reviewed in [ 132 , 133 ]. Several collagen-related genetic disorders are caused by a dominant inheritance of glycine substitution to a larger amino acid in the triple helical domain of the protein, which structurally affect collagen folding and assembly [ 131 ].

Mutations in collagen type VII alpha 1 encoded by the gene COL7A1 cause dystrophic epidermolysis bullosa (DEB, MIM # 131750), a genetic disorder characterized by skin blistering in response to minor trauma or friction [ 134 ]. It has long been established that certain disease-causing variants involving glycine substitutions accumulate intracellularly in the endoplasmic reticulum (ER) and fail to undergo proper extracellular secretion [ 135 ]. This failure to secrete results in a haploinsufficiency state, contributing to the manifestation of the disease. The same group has later shown that secreted mutant α1(VII) chains exert a dominant-negative effect by interacting with the WT protein forming heterotrimeric triple helix complex, leading to a destabilizing effect on collagen VII structure [ 131 ].

Heterozygous mutations in collagen VI genes ( COL6A1, COL6A2  and  COL6A3 ) are associated with Bethlem myopathy disorder (BMD, MIM # 158810), which is a milder form of Ullrich congenital muscular dystrophy (UCMD, MIM # 254090) also associated with homozygous mutations in the same genes. Bethlem myopathy is mainly characterized by proximal muscle weakness and joint contracture that progressively affect mobility and flexibility [ 136 ]. However, distinction between the two diseases in terms of their mode of inheritance was revised when patients with heterozygous mutations exhibited a severe form of the disease that is typical of UCMD. This finding has given rise to rigorous protein synthesis studies in order to provide an explanation for the consequences of severe mutations in the extremely complex structure of collagen VI [ 37 , 137 ]. The three alpha chains α1, α2 and α3 that characterize collagen VI fold into triple helical heterotrimeric monomer in the ER, which are then transported to the cell surface via the Golgi apparatus [ 133 ]. When these procollagen monomers reach the cell surface, they align in a staggered fashion to form dimers that are bonded via a disulfide bond, then dimers are aligned laterally to form a tetrameric complex in the extracellular matrix (ECM) [ 138 ]. It has been demonstrated that large amino acid deletion at the N terminal of the triple helical domain resulted in the secretion of mutant heterotetramers. The tetrameric stoichiometry of collagen VI means that mutations in any of the three alpha chains would result in only 1/16 normal tetramer [ 37 , 137 ]. This finding unequivocally illustrates the dominant-negative impact exerted by the mutant chain on the overall structural assembly of collagen VI. As a result, the collective effect resembles the complete loss of collagen VI observed in individuals with the homozygous mutation in UCMD. On the other hand, patients carrying heterozygous, in-frame amino acid deletions downstream of the triple-helical domain, which removes cysteines required for dimerization, exhibit a milder form of the disease. This deletion prevents the formation of WT/mutant dimers and consequently reduces the dominant-negative impact on the WT protein [ 137 ].

Osteogenesis imperfecta (OI) has served as a classic example for dominant-negative effects of structural proteins [ 41 ]. The disease, also known as brittle bone disease, is characterized mainly by bone fragility, short stature, loose joints and other variable skeletal deformities [ 139 ]. Classical OI types I to IV are caused by autosomal inherited mutations in COL1A1  or  COL1A2 genes that encode α1 and α2 subunits of collagen 1, respectively. Type I collagen is a heterotrimeric complex that consists of two α1 and one α2 chains, synthesized in the ER and assembled via a recognition sequence at the C terminal, along with the formation of disulfide bondings, prior to being transported to the Golgi apparatus [ 39 , 140 ]. The variability in the phenotype of this disease, coupled with a limited understanding of its underlying mechanisms, has prompted researchers to identify additional collagen-related genes involved in the regulation of collagen metabolism and assembly. Most of these genes have been linked to autosomal recessive pattern of inheritance. Nonetheless, mutations in Collagen1 genes still account for the majority of OI cases [ 141 ].

Molecular mechanisms attributed to the manifestation of autosomal dominant OI include decreased transcript due to nonsense mutation, decreased collagen secretion due to ER retention, and disrupted pro-collagen chains assembly and processing [ 41 , 142 , 143 , 144 ]. ER retention of glycine-substitution mutant variants of α1 and α2 subunits of collagen 1 was observed through transmission electron microscopy analysis of OI fibroblasts, revealing the presence of an enlarged ER indicative of ER stress [ 145 ]. Apoptotic cellular death was also demonstrated to be triggered despite autophagic activation through the UPR in an attempt to salvage the cells. Severe forms of OI that involve glycine substitution are associated with pathogenic variants that exert a dominant-negative effect, disrupting the assembly of the triple helix and collagen fibril. This disruption results in severe structural damage to the bone matrix [ 41 , 146 , 147 ].

Ehlers-Danlos syndromes (EDS) represent a group of genetically heterogenous conditions that are caused by pathogenic variants in up to 19 genes, mostly encode collagens or collage-related proteins [ 148 ]. Classic EDS (cEDS, MIM # 130000) is mainly associated with mutations in COL5A1 or COL5A2 genes encoding α1 and α2 chains of the collagen 5. Patients of this class of EDS present with joint hypermobility, skin hyper-elasticity and a tendency to develop atrophic scars [ 149 ]. Despite the limited number of clinically well described cEDS associated with mutations in COL5A2,  the majority manifest severe phenotypes and have an impact on the structural integrity of collagen V. These mutations exhibit a dominant-negative effects that disrupt the formation of heterotypic fibrils and the interactions between collagen 5 and other constituents of the extracellular matrix [ 43 , 150 ].

Pathogenic variants of COL2A1 and COL11A1 genes encoding collagen II α1 and collagen XI α2 chains have been associated with Stickler syndrome type 1 and 2, (ST1, MIM # 108300 and STL2, MIM # 604841), respectively. The α1 chain from COL11A1 combines with the α2 chain from COL11A2 and the α1 chain from COL2A1 to create heterotrimeric type XI collagen [ 46 ]. Stickler syndromes are a group of heterogenous connective tissue disorders characterized by distinctive facial feature, ocular abnormalities and joint anomalies. Splice site mutations in COL11A2 are the primary disease-causing mutations reported thus far. However, mutant mRNA does not undergo nonsense-mediated decay (NMD), allowing mutant chains to be expressed and associate with other α chains, leading to the formation of mutant collagen XI trimers in a dominant-negative manner [ 46 , 151 ]. Conversely, patients with mutations that lead to unexpressed protein due to targeting by the NMD mechanism tend to exhibit a milder form of the disease, and this mechanism is considered haploinsufficiency only [ 152 ].

Akawi and colleagues have argued that homozygous misfolding mutations in COL11A are more severe than bi-allelic null mutations as a result of the possible interference of the misfolded COL11A with its other collagen partners, presumably as a result of dominant-negative effects, and hence disrupting the function of the whole complex more severely [ 153 , 154 ]. On the other hand, pathogenic variants of COL2A1 , associated with Stickler syndrome type1, are believed to manifest the disease phenotype through only haploinsufficiency [ 46 ]. Several misfolded variants of both types of collagens were reported to be retained in the ER, followed by proteasomal degradation [ 45 ]. Nonetheless, to our knowledge, whether ER-retained mutants exert dominant-negative effects by interfering with the WT in heterotrimeric complexes remains largely unexplored.

The preceding discussion highlights how the complexity of collagen structure magnifies the dominant-negative effect of mutant subunits by exacerbating the disruption in the intricate network of collagen assembly. Mutant collagen subunits, with their altered structures, not only compromise the functionality of individual molecules but also introduce a destabilizing influence during fibril formation. These effects ultimately contribute to the diverse phenotypic outcomes observed in collagen-related genetic disorders. It’s important to note that there has been limited research dedicated to investigating the dominant-negative effect exerted by mutant collagen subunits when trapped in the ER, potentially affecting their trafficking. The ER serves as a crucial site for proper folding and post-translational modifications of collagen molecules before they are transported to their functional destinations. The presence of mutant subunits in the ER may disrupt these processes, leading to the accumulation of misfolded or improperly modified collagen. This lack of in-depth exploration into the consequences of such entrapment hinders a comprehensive understanding of how trafficking abnormalities contribute to the overall pathogenesis of collagen-related genetic disorders.

Vascular monogenic disorders

Hereditary haemorrhagic telangiectasia (HHT) is a vascular genetic disorder characterized by vascular dysplasia inherited in an autosomal dominant manner. Its spectrum of phenotypes varies from occasional nasal bleeds to internal organ hemorrhages affecting the gastrointestinal tracts (GI), kidneys, liver, and brain [ 155 ].The disease has been classified into four types according to the causative gene: HHT1, HHT2, HHT5 and (JPH) Juvenile polyposis and HHT, associated with mutations in ENG, ACVLR1, GDF2 and SMAD4 genes, respectively [ 156 , 157 , 158 , 159 ]. These genes encode proteins that are components of the transforming growth factor beta (TGFβ) signaling pathway, which regulates various cellular processes [ 109 , 160 , 161 ]. Hereditary haemorrhagic telangiectasia type 1 (HHT1, MIM # 187300) is associated with mutations in the gene ENG that encodes endoglin, a dimeric glycoprotein that functions as a co-receptor on the plasma membrane. It is predominantly expressed in vascular endothelial cells of various tissues and organs throughout the body and it is therefore essential for the normal structure of the blood vessels [ 162 ]. In earlier work, we have utilized glycosylation profiling assays and immunofluorescence microscopy to demonstrate that several disease-causing missense endoglin variants get trapped in the ER by the machinery of the ERQC mechanism and fail to traffic to the plasma membrane, where they function [ 13 ]. Subsequently, we have also demonstrated the implication of ERAD in the degradation of ER-retained missense mutant variants P165L and V105D using HRD1-knockout HEK293 invitro cellular model [ 163 ]. Protein elimination leads to a haploinsufficiency state, ultimately contributing to the manifestation of the disease phenotype. Given that endoglin is a homodimeric protein synthesized in the ER, it was logical to explore whether mutant variants expressed by the affected allele would interact with WT endoglin, potentially leading to a dominant-negative effect. Interestingly, our co-immunoprecipitation assays have clearly demonstrated that ER-retained endoglin variants (L32R, V105D, P165L, I271N and C363Y) heterodimerize with WT endoglin in a dominant-negative manner impairing its trafficking to the plasma membrane [ 47 ]. This mechanism is likely to exacerbates the disease state, resulting in a scenario where 50% of the protein is lost due to the loss of one allele leading to haploinsufficiency, coupled with a possible additional ~ 25% loss attributed to the dominant-negative effects exerted by the mutant ER-retained protein on its WT counterpart. Our findings were consistent with two prior studies that briefly illustrated the formation of mixed dimers of endoglin WT and mutant variants [ 164 , 165 ].

Hereditary haemorrhagic telangiectasia type 2 (HHT2, MIM # 600376) is associated with mutations in ACVRL1 gene, encoding activin receptor-like kinase, also denoted as ALK1, a type 1 receptor in the TGFβ signaling pathway [ 166 ]. Both HHT1 and HHT2 are presented with similar phenotypes, as both endoglin and ALK1 play a crucial role in endothelial cells differentiation during capillary development leading to vascular malformation phenotypes in both disorders [ 167 ]. Similar to endoglin, both our research and other studies have shown that several missense mutant variants located at the intracellular kinase domain of ALK1 receptor become entrapped in the ER and fail to traffic to the plasma membrane where they normally perform their functional role in TGFβ signaling cascade [ 16 , 164 , 168 ]. Currently, haploinsufficiency has been accepted as the primary disease mechanism [ 158 , 169 ]. However, the homodimeric nature of the ALK1 receptor raises a strong possibility that some of these ER-retained mutants may form heterodimeric complexes with the WT, thereby hijacking it and impairing its trafficking to the plasma membrane in a dominant-negative manner. Recently, variants of ALK1 that exhibit a normal trafficking to the plasma membrane were also proposed to exert a dominant-negative effect on the WT via forming dysfunctional heterodimers on the plasma membrane, which further impedes the 50% functionality of WT expressed by the unaffected allele [ 49 ]. These findings further consolidate the prediction that some ER-retained mutants may exhibit a dominant-negative effect on the WT protein through heterodimerization between the mutant and WT alleles.

Pulmonary arterial hypertension (PAH, # 178600) is another hereditary vascular disease associated with heterozygous mutations in BMPR2 gene, encoding yet another type 2 receptor; bone morphogenetic protein receptor 2 [ 170 ]. Considerable research efforts have been carried out to understand the molecular mechanisms that may contribute to the wide spectrum of the disease phenotypes as well as the reduced penetrance rate, (reviewed in [ 171 ]. In an effort to understand the mechanisms by which missense mutant variants lose their functionality, we investigated the trafficking of various disease-causing variants spanning all receptor’s domains. Our findings revealed that some variants that harbor mutations at the ligand binding domain are entirely or partially trapped in the ER, ultimately leading to premature degradation through, most likely, the ERAD mechanism [ 15 ]. Retention of disease-causing missense variants of BMPR2 and the consequential defective trafficking of the receptor to the plasma membrane, which also has also been reported by others, further consolidates the implication of the ERQC mechanism in the pathogenesis of PAH [ 50 , 172 ]. Furthermore, evidence of a dominant-negative effect exerted by BMPR2 missense variants on a type 1 receptor has also been reported [ 50 ]. Remarkably, there has been no exploration into whether those ER-retained mutants would exert a dominant-negative effect on WT BMPR2 expressed from the unaffected allele. Like endoglin and ALK1, BMPR2 is a homodimeric protein. This characteristic raises the possibility that heterodimerization between WT and dominant-negative ER-retained mutants may occur during the early stages of protein biogenesis in the ER, impairing its trafficking to the plasma membrane.

Loeys-Dietz Syndrome (LDS, MIM # 609192) is a rare genetic disorder inherited in an autosomal dominant manner [ 173 ]. It is characterized by multisystemic phenotypic presentations including aortic/arterial aneurysms in addition to craniofacial, osteoarticular, musculoskeletal, and cutaneous malformations [ 173 , 174 ]. Up to date, mutations in six genes (TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2, and TGFB3) that encode TGFβ signaling components have been associated with LDS [ 174 , 175 ]. Functional assays have demonstrated that mutated TGFBR1 interfere with the endogenously expressed WT receptor, reducing its activity in a dominant-negative manner [ 52 ]. These findings open the doors for further investigation into the molecular mechanisms that lead to the loss of function of these major components in the signaling pathway. A possible dominant-negative effect exerted by the mutant allele on the WT may also represent logical contributor to an aggravated haploinsufficiency state in LDS. Furthermore, considering that LDS is associated with several mutant variants of components functioning along the same signaling pathway, it is worthwhile to investigate whether some of these mutant components might interfere with the function of multiple components within the signaling pathway, potentially contributing to the observed heterogeneity in LDS phenotypes.

It is crucial to highlight that the majority of TGFβ signaling pathways involve dimeric proteins, whether secretory or membrane-bound. As illustrated in a prior review, through an extensive literature search, we have shown that these proteins are implicated in around 25 monogenic human diseases [ 109 ]. However, the disease mechanisms of these conditions remain underexplored in terms of possible implication of ERQC mechanism and also the potential existence of dominant-negative effects. Further investigation into these aspects is warranted to enhance our understanding of the pathogenesis associated with TGFβ signaling-related monogenic diseases.

Long QT syndromes (LQTS) are a group of autosomal inherited arrhythmogenic disorders characterized by abnormal cardiac activity presented by prolonged QT intervals, leading to a type of arrhythmia known as torsades de pointes [ 176 ]. Irregularities in the heartbeat have the potential to result in fainting, seizures, or sudden cardiac arrest. LQTS is classified into three primary types based on the causative genes: LQTS1, MIM # 192500, LQST2, MIM # 613688, and LQTS3, MIM # 603830 encoded by the genes ( KCNQ1 ), ( KCNH2 ) and ( SCN5A ), respectively. These genes encode ion channels essential for cardiac repolarization [ 177 ]. Nonetheless, each type has distinct triggers, clinical manifestations, severity and penetrance profile, suggesting variable molecular mechanisms involved, in addition to environmental factors, age and gender [ 178 ]. LQTS2 is associated with KCNH2 , a gene that encodes the voltage-gated K + channel α-subunit (Kv11.1), which function as tetrameric complex that consists of four Kv11.1 α-subunit [ 179 ].

Ficker and colleagues reported through immunoprecipitation analysis that Kv11.1 disease-causing variants R752W and G601S show defective trafficking, evidenced by their strong association with molecular chaperones Hsp90 and Hsp70 in the ER. Defective trafficking results in ER-retention of misfolded Kv11.1variants, followed by premature degradation through the ERAD mechanism. Conversely, the non-functional G628S variant displayed transient associations with the molecular chaperones before being released to the plasma membrane, similar to WT Kv11.1 [ 54 ]. Characterizing the physiological properties of Kv11.1 disease-causing variants harboring the missense mutation (E637K) situated in the pore-S6 loop of the channel, using a Xenopus oocyte heterologous expression system, revealed intriguing findings. Coexpression of WT (WT) and E637K variants resulted in a peak tail current significantly lower than the current peaks anticipated from the WT alone. These findings suggest that this mutation exerts a dominant-negative effect on the WT Kv11.1 channel and highlights the significance of the pore-S6 loop in the channel's function [ 180 , 181 ]. Therefore, if a dominant-negative effect can occur on the plasma membrane through the formation of the WT/mutant tetrameric complexes, then it follows logically that ER-retained mutants may also form similar tetrameric complexes in the ER, that impede the trafficking of the WT ion channel to the plasma membrane, employing a similar dominant-negative mechanism.

Neurological disorders

The spectrum of molecular mechanisms underlying monogenic neurological disorders with autosomal dominant inheritance is diverse, reflecting the wide array of genes and protein variants involved. Nonetheless, protein misfolding and aggregation are recurrent themes, leading to cellular death and permanent neurological dysfunction. Phenotypic traits can be further aggravated by dominant-negative variants that interfere with the remaining 50% functionality of the WT protein.

Heterozygous mutations in the GABAA receptor gamma2 subunit encoded by the gene GABRG2 have been associated with generalized epilepsy with febrile seizures plus (GEFS + , MIM # 607681) [ 59 , 182 ]. The GABAA receptor, a pentameric ligand-gated ion channels serving as a receptor for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), is typically composed of two α subunits, two β subunits, and one γ2 subunit [ 183 ]. The molecular mechanisms associated with disease-causing variants were identified to involve haploinsufficiency attributable to the mutant allele, along with the exertion of a dominant-negative effect by the mutated γ2 subunit. Kang and colleagues have demonstrated, using in vitro cellular models, that the pathogenic variant γ2(Q351X) associated with GEFS exhibits defective trafficking to the plasma membrane, leading to proteasomal degradation through ERAD. Additionally, γ2(Q351X) was shown to exert a dominant-negative effect on WT receptors, reducing their assembly, trafficking, and surface expression ( 59). This effect likely arises from the oligomerization of mutant and other WT subunits that form the full pentameric receptor complex, resulting in ER retention of both WT and mutant subunits followed by premature degradation through ERAD. Pulse-chase experiments revealed that coexpression of the γ2 subunit mutation, Q351X, with other WT subunits reduced GABAA function to a level lower than the predicted 50% level for heterozygous carriers. Therefore, the combined mechanism of ER retention and dominant-negative effect exerted by the mutant γ2 subunit on partnering subunits is predicted to be the most likely mechanism for the manifestation of GEFS + associated with this mutation.

A combination of haploinsufficiency and dominant-negative effect mechanisms has also been identified as the underlying mechanism for severe cases of Neurofibromatosis type 1 (NF1, MIM # 162200), a rare genetic disorder characterized by the development of tumors on nerve tissues throughout the body [ 61 ]. Neurofibromin, encoded by NF1 gene, is a tumor suppressor and a GTPase activating proteins that regulates RAS signaling cascade in various cell types including neuronal cells [ 184 ]. In invitro cellular models, it has been demonstrated that misfolded neurofibromins, encoded by variants in codons 844 to 848, exert a destabilizing effect on the WT protein through protein dimerization in the ER. Heterodimeric complexes are recognized by the ERQC mechanism and marked for degradation via ERAD mechanism. This interaction results in a complete reduction of neurofibromin levels, surpassing the threshold observed in haploinsufficiency alone [ 185 ].

In genetic disorders, dominant-negative effect might also occur when a mutated protein disrupts the function of another protein it unexpectedly interacts with, leading to the manifestation of disease symptoms. This phenomenon is best demonstrated by missense variants of voltage-gated potassium channel (Kv3.3) associated with autosomal dominant spinocerebellar ataxias 13 (SCA13, MIM #176264), encoded by the gene KCNC3 [ 186 ]. These misfolded variants display impaired trafficking, resulting in entrapment within endosomal vesicles and a failure to reach their designated functional location at the plasma membrane [ 60 ]. Intriguingly, they also intracellularly engage with the human epidermal growth factor receptor (EGFR) through an unknown mechanism, implying a pivotal role for EGFR in cerebellum development and, consequently, highlighting its involvement in the pathology of SCA13.

DYT1, also known as early onset torsion dystonia, is an autosomal dominant neurological disease characterized by involuntary muscle contractions (dystonic movements) affecting several parts of the body, resulting in severe disability [ 187 ]. The disease typically begins in childhood or adolescence and represents the most common and severe type of dystonias. DYT1 dystonia is caused by a specific mutation in the TOR1A gene, which involves the deletion of three base pairs (GAG), resulting in the loss of a single glutamic acid residue in the torsinA protein at position 302 (ΔE-torsinA) [ 63 ]. The torsinA protein is an ER-resident glycoprotein and a member of the AAA + (ATPases Associated with diverse cellular Activities) protein family that play key roles in cellular functions related to protein folding, trafficking, and/or degradation [ 188 ]. Oligomerization is a conserved feature of members of the AAA +  family of ATPases, however, unlike WT-torsinA, mutant ΔE-torsinA is mislocalized and forms perinuclear aggregates [ 63 ]. Furthermore, through coimmunoprecipitation assays, it has been shown that WT torsinA interacts with the mutant protein, resulting in a dominant-negative effect by sequestering WT protein to the perinuclear region, where they form multimeric protein complexes [ 64 ]. The number of remaining functional WT-torsinA multimers would depend on the expression ratio of WT-torsinA: ΔE-torsinA. Interestingly, investigations into the degradation pathways of WT and mutant ΔE torsinA proteins have revealed divergent degradation pathways for each. WT-torsinA was found to degrade through autophagy, while ΔE-torsinA, which exhibited a significantly shorter half-life, was selectively and efficiently degraded via the proteasome through ERAD, rendering it a potential target for interventional rescue [ 64 ].

Eye disorders

Retinitis pigmentosa (RP, MIM # 613731) is a genetic degenerative eye disorder that is associated with mutations in numerous genes, which contribute to the heterogeneity of the disease. Mutations in rhodopsin gene ( RHO ) have been identified as one of the most common causes of autosomal dominant PR [ 189 ]. Rhodopsin is a light-sensitive receptor protein that plays a crucial role in the conversion of light signals into electrical signals in rod photoreceptor cells of the retina. RHO mutations have been categorized into seven categories according to their effect on the protein’s structure and function, reviewed in [ 67 ]. Rhodopsin has a high ability to form dimeric and higher order oligomers which is believed to play a key role in the photoreceptor function [ 190 ]. The most common disease-causing misfolded rhodopsin variants P23H and K296E were found to form ER-retained aggregates followed by proteasomal degradation. But if degradation was not complete, mutant rhodopsin can accumulate in photoreceptor cells, leading to cell degeneration and contributing to the development of the disease phenotypes [ 66 ]. In addition, It was demonstrated using fluorescence microscopy and immunoblot analysis that co-expression of variants P23H or G188R, together with the WT rhodopsin has resulted in the entrapment of WT rhodopsin in the ER. Misfolded dimers aggregate with the WT Rhodopsin exerting a dominant-negative effect through hetero-oligomerization [ 68 , 69 ].

Primary open angle glaucoma (POAG, # 137750), has also been identified as a leading cause for irreversible blindness due to damaged optic nerve [ 191 ]. Mutations in the myocilin gene ( MYOC ) have been associated with the disorder in several families with early onset of visual impairment. Total loss of myocilin in samples of patients harboring heterozygous mutations has been attributed to a combinational mechanism of haploinsufficiency and dominant-negative effects exerted by the entrapped mutant myocilin on the WT expressed from the functional allele [ 72 ].

Furthermore, Wolfram syndrome (WS, MIM # 222300) is a multisystemic syndrome that is characterized primarily by diabetes mellitus, optic atrophy which represent a major feature affecting nearly all reported patients, in addition to sensorineural deafness, neurodegeneration and psychological imbalances [ 192 ]. The autosomal dominant form of the disease is caused by heterozygous mutations in the WFS1 gene that encodes wolframin, a transmembrane protein that regulates calcium homeostasis within the ER. In contrast to homozygous mutants, It has been reported by many that some heterozygous misfolded wolframin exhibit a dominant-negative effect on the WT as it aggregates in the ER lumen causing ER stress and cellular toxicity [ 75 , 193 , 194 ].

Serpinopathies

Serpins are a large group of serine protease inhibitors that play a key role in regulating proteases activities across various organs [ 195 ]. Mutations in these genes result in the aggregation of mutant proteins, inducing cellular dysfunction and giving rise to a spectrum of monogenic disorders collectively termed serpinopathies. Serpins are inherently unstable, and this is mainly due to their mechanism of action, as they alternate between folded and unfolded state in order to perform their inhibitory function. Mutations that lead to unfolded proteins destabilize this fine balance and promote protein aggregate formation [ 196 ]. Heterozygous mutations in SERPINC1, SERPINA1and SERPING1 have been associated with autosomal dominant antithrombin deficiency (MIM #107300), Alpha-1-antitrypsin deficiency (A1ATD, MIM # 613490) and hereditary angioedema type 1 (HAE1,MIM # 106100), respectively. Dominant-negative variants of these three genes have been associated with the formation of mutant/WT protein aggregates in the ER, resulting in significant reduced plasma levels of the respective proteins and correlating with severe disease phenotypes [ 78 , 79 , 81 ].

Therapeutic challenges and emerging strategies in dominant-negative disorders

Treating conditions that include dominant-negative effect as a contributing mechanism can be a difficult task for medical professionals, as it presents a significant therapeutic challenge. Simply increasing protein levels is not always an effective strategy because as highlighted earlier, the mutant protein may interfere with the function of its WT counterpart [ 197 ]. This combination of the "poisoning" effect and potential ER retention and aggregation, resulting from the ER machinery involvement, requires alternative therapeutic approaches. Strategies designed to address the pathological consequences of some dominant-negative mutations fall into three main categories, utilizing diverse tools and techniques summarized in (Fig.  3 ).

Therapeutic Strategies for Dominant-negative Disorders. A Genetic modulation directly tackles the faulty gene through diverse techniques by introducing a functional copy, eliminating the mutated allele, combining both approaches, or even editing the mutation itself using advanced tools like CRISPR/Cas9 and base editing techniques B ) Post-translational modulation mainly targets correcting the underlying folding or structural deformity through chemical and pharmacological chaperones, or through directly manipulating specific components of the ER quality control machinery. For some diseases, recombinant proteins are administered to compensate for the loss of the WT protein C ) Pharmacological bypass therapy uses drugs or different pharmacological compounds to mimic the function of the WT protein or compensate for its absence, even without repairing the gene, to relieve the underlying clinical symptoms by targeting downstream pathways affected by the mutation

Therapeutic interventions aimed at counteracting dominant-negative effects may show promise for disorders characterized by ER-retention dominant-negative mechanisms. However, their efficacy depends on factors such as the nature of the disorder, the specific genetic mutation involved, and the mechanism of action of the intervention.

Genetic modulation

The straightforward approach in genetic modulation that comes to mind is to introduce a functional copy of the defective gene into the diseased cell. Therapeutic approaches aimed at increasing the amount of WT protein in autosomal dominant diseases caused by dominant-negative variants can also be effective for variants exhibiting the combinational mechanism of ER retention and dominant-negative effects. The underlying principle is the same: enhancing the availability of functional WT protein to compensate for the defective mutant protein. By boosting the levels of WT protein, these therapies can mitigate the impact of the dominant-negative mutant, regardless of whether the mutation leads to ER retention or other misfolding issues. This strategy holds promise for improving cellular function and alleviating disease symptoms across a range of genetic disorders with similar pathogenic mechanisms. In RP disorder for example, increasing WT rhodopsin to three-fold its normal level in the eyes of transgenic mice carrying the P23H ER-retained/dominant-negative variant has been shown to protects the retina, suggesting gene therapies that carefully boost rhodopsin levels could alleviate such diseases [ 198 ]. Delivering a normal copy of the RHO gene via adeno-associated virus serotype 5 (AAV) vector prevented retinal degeneration in P23H transgenic mice through the increased expression of WT rhodopsin. This aims to increase the WT to mutant protein ratio, potentially out-competing the mutant protein and subsequently restoring some function [ 199 ]. Similarly, the introduction of a WT copy of the GABRG2 gene into transgenic mice carrying the dominant-negative Q390X variant (Gabrg2 + /Q390X) associated with Dravet syndrome (epileptic encephalopathy) significantly rescued their underlying seizures [ 58 ]. However, mutated proteins with dominant-negative effects may still exert detrimental effects even with increased WT protein expression. Therefore, treating such conditions might necessitates targeting the mutant allele at the DNA or RNA levels [ 200 ]. AAV vectors have been employed to selectively disrupt the expression of the dominant-negative allele in the COL1A1 gene through the insertion of a neomycin resistance cassette to the first exon of the gene in mesenchymal stem cells (MSCs) derived from patients presented with OI, successfully demonstrating targeted gene modification in adult human stem cells [ 201 ]. Alternatively, various methodologies can be used to silence the mutated allele at the transcription level via antisense oligodeoxyribonucleotides (ODNs), short interfering RNA (siRNA), and hammerhead ribozymes. In this context, highly specific siRNA has been designed to selectively suppress the mutant torsin A protein, the primary causative factor in the most common form of primary generalized dystonia [ 202 ]. It efficiently suppressed the mutant torsin A in cells mimicking the heterozygous state without affecting the WT allele.

Given the limitations of each approach individually in effectively bypassing the underlying defect, especially for cells sensitive to haploinsufficiency, their synergistic application emerges as a viable solution. Dotzler SM and colleagues presented a therapeutic solution by incorporating a suppression-and-replacement genetic approach for LQT1 syndrome that utilizes a two-component strategy [ 203 ]. The first component is based on the use of a short hairpin RNA (shRNA) to specifically suppress the expression of the patient's endogenous, mutated KCNQ1 gene. Secondly, the introduction of a codon-altered, shRNA-immune copy of KCNQ1 , thereby achieving functional replacement of the defective allele. This dual-pronged approach demonstrates promising preclinical efficacy, as evidenced by the successful restoration of normal function in induced pluripotent stem cell-derived cardiomyocytes harboring diverse LQT1-causing KCNQ1 variants. Furthermore, it represents a feasible therapeutic strategy that can effectively address the double whammy of ER-retention and dominant negative effects by specifically silencing the mutant allele, which prevents the production of the defective protein, thereby reducing its detrimental interactions with the WT protein. Additionally, it helps in mitigating issues related to ER retention, as fewer mutant proteins are available to be retained in the ER. Consequently, more WT proteins can function correctly, improving cellular function and potentially ameliorate disease symptoms.

Fueled by the discovery of CRISPR/Cas9 technology, genetic tools have been developed to directly correct the disease-causing variant in different genetic diseases [ 204 ]. CRISPR/Cas9-mediated gene correction has been implemented in OI patients’ derived iPSCs which were differentiated to Osteoblast cells with recovered type I collagen levels [ 205 ]. Besides that, Huang et al. leveraged cutting-edge base editing technology to precisely repair a disease-causing mutation (FBN1; T7498C) in MFS, demonstrating the potential of this approach for gene therapy in MFS and other genetic disorders [ 26 ]. Unlike CRISPR/Cas9 base editing technology, the proposed technology is more precise with minimal risk of unintended mutations as it does not require the generation of a double-strand break to correct the intended nucleotide [ 206 ].

Post-translational modulation

Instead of genetically manipulating the affected gene, administration of exogenous WT proteins through protein replacement therapy has shown successful outcomes in a few diseases with dominant-negative pathophysiology. Although not universally applicable to dominant-negative disorders, the clinical success of recombinant intravenous (IV) C1INH formulations in hereditary angioedema patients underscores the therapeutic potential of protein replacement therapy for this class of diseases [ 207 ]. It demonstrates its ability to mitigate the pathological protein misfolding and abnormal ER aggregation caused by the underlying heterozygous SERPING1 variations. It's important to recognize that protein replacement therapy, despite its success in some dominant-negative diseases, may not be feasible for all due to technological limitations and individual patient factors.

Interventions that promote proper folding and prevent aggregation of the mutated protein show promise in rescuing the WT protein from ER entrapment. Pharmacological chaperones (Pcs) have been used in this context to specifically bind to the mutated protein promoting its proper folding and stabilization which will subsequently prevent its retention and premature degradation along with its WT counterpart [ 208 ]. Therefore, the application of Pcs presents a compelling strategy for targeting the combinational mechanism of dominant negative effects exerted by ER-retained mutant variants. Several studies have demonstrated the potential of retinoid analogs to act as specific PC compounds for the P23H mutation in rhodopsin, which causes RP [ 209 ]. These chaperones enhance the folding of the mutant protein and reduce its dominant-negative effect on the processing of the WT form [ 69 ]. Similarly, the IN3 PC compound corrects folding errors of several GnRH receptor (GnRHR) mutants; causative of hypogonadotropic hypogonadism, and promotes its correct intracellular trafficking along with its interacting WT subunits [ 210 ]. Unlike the targeted approach of PCs, chemical chaperones exhibit a broad-spectrum effect stabilizing various proteins and preventing aggregation in a non-specific manner [ 211 ]. For example, 4-phenylbutyrate (4-PBA) is a clinically approved medication for urea cycle disorders that showed its potential to prevent P23H rhodopsin aggregation and reduce the associated ER stress in RP [ 67 ]. In addition, protein rescue may also involve targeting specific components of ERAD and the ER machinery. Proteasomal inhibitors such as MG-132, MG-115, lactacystin, or proteasome inhibitor I prevented the premature degradation of ER-tagged caveolin-3 mutants, rescuing their interacting WT forms in a LGMD-1C cellular model [ 34 ]. Moreover, targeting the abberent activation of the UPR pathway due to ER stress in cells with accumulated misfolded proteins may offer a potential therapeutic approach in dominant-negative diseases. In a mouse model of RP, knocking out ATF4 in mice expressing the dominant-negative T17M rhodopsin mutation halted retinal degeneration. Blocking ATF4 expression lead to the downregulation of multiple UPR components like pEIF2α, ATF6, and CHOP, ultimately blocking the activation of cell death pathways [ 212 ]. Overall, addressing distinct elements within the ER machinery, aiming to mitigate the dominant-negative consequences caused by misfolded proteins and restore the WT from the underlying damage, signifies an innovative and promising frontier where cell biology intersects with medicine.

Pharmacological bypass therapy

Besides, several therapeutic interventions have been utilized to bypass the need to directly manipulate the underlying defect with various agents or pharmacological medications, often referred to as phenotypic correctors, that resemble the downstream effects of the WT protein. In ISS therapy, long-term growth hormone (GH) treatment can increase the height in childhood and adult life of familial and nonfamilial ISS cases including patients carrying heterozygous variants in the NPR2 gene showing dominant-negative effects [ 213 ]. Despite the response variability towards GH therapy, several NPR2 cases showed promising responses in height correction, especially with earlier (before puberty) and long-term administration [ 32 , 214 ]. On the other hand, myoblast cultures derived from patients with UCMD, caused by mutations in COL6A1, COL6A2, or COL6A3 genes, displayed increased cellular apoptosis. Oral treatment with cyclosporine A (an immunosuppressive drug; CsA) for one month significantly reduced apoptosis through the normalization of the mitochondrial membrane potential of the tested muscle cells [ 215 ]. The overall conclusion from this pilot study is that long-term CsA treatment influences myofiber regeneration and ameliorates muscle cell performance in treated patients. HAE1, characterized by uncontrolled plasma kallikrein due to C1INH deficiency even with heterozygous carriers, shows enhanced treatment response to drugs inhibiting kallikrein, leading to significant clinical improvement [ 207 ].

Future perspectives and conclusions

The dominant-negative effects exerted by mutant proteins on either their WT allele or interacting partners represent a major mechanism underlying various autosomal dominant genetic diseases and may contribute significantly to their wide spectrum of phenotypic clinical manifestations. Furthermore, an additional combined mechanism emerges when ER-retained mutant proteins form mixed complexes with WT counterparts or multi-subunit partners, resulting in the mis-localization and premature degradation of these WT partners. As a consequence, an additional loss of functional protein occurs, further compromising cellular function and exacerbating disease phenotypes. Thus, the dual additive impact of the dominant-negative effects and ERAD-mediated degradation is playing a pivotal role in the complexity of disease pathogenesis in numerous autosomal genetic disorders. Notably and surprisingly, this specific and highly damaging combinatorial mechanism remains relatively understudied and underappreciated in the field. This review represents an initial effort to illuminate and highlight this aspect of research, presenting significant potential for elucidating the factors influencing variant-associated phenotypic variability and detailed disease pathogenesis in numerous conditions. By highlighting these complex interactions, this review aims to promote further exploration and potentially uncover novel avenues for understanding and addressing mechanisms underlying autosomal dominant diseases. Furthermore, understanding these intricate mechanisms may offer insights into potential novel therapeutic strategies aimed at mitigating clinical presentations in these diseases including ameliorating their severity.

Availability of data and materials

All dataset was incorporated in this manuscript.

Abbreviations

4-Phenylbutyrate

Activating transcription factor 6

Bethlem myopathy disorder

Cystic fibrosis transmembrane conductance regulator

C-type natriuretic peptide

Calnexin/calreticulin

Dystrophic epidermolysis bullosa

Extracellular matrix

Ehlers-Danlos syndrome

Epidermal growth factor receptor

Endoplasmic reticulum

ER-associated protein degradation

ER quality control

Gamma-aminobutyric acid

Febrile seizures plus

Growth hormone

GnRH receptor

Hereditary haemorrhagic telangiectasia type 1

Hereditary haemorrhagic telangiectasia type 2

Heat shock proteins

Inositol requiring enzyme 1

Idiopathic short stature

Intravenous

Loeys-Dietz Syndrome

Limb-girdle muscular dystrophy

LQT syndromes

Marfan syndrome

Mesenchymal stem cells

Myocilin gene

Nonsense-mediated decay

Neurofibromatosis Type 1

Oligodeoxyribo nucleotides

Osteogenesis imperfecta

Pulmonary arterial hypertension

Pharmacological chaperones

Protein kinase RNA like endoplasmic reticulum kinase

Primary open angle glaucoma

Rhodopsin gene

Retinitis pigmentosa

Short hairpin RNA

Short interfering RNA

Stickler syndrome type1

Stickler syndrome type 2

Transforming growth factor beta

Ullrich congenital muscular dystrophy

UDP-glucose: glycoprotein glucosyltransferase

Unfolded protein response

Von Willebrand disease

Von Willebrand factor

Wolfram syndrome

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This work was supported by ASPIRE, the technology program management pillar of Abu Dhabi’s Advanced Technology Research Council (ATRC), via individual grant AARE19-086 and the ASPIRE Precision Medicine Research Institute grant VRI-20–10.

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Gariballa, N., Mohamed, F., Badawi, S. et al. The double whammy of ER-retention and dominant-negative effects in numerous autosomal dominant diseases: significance in disease mechanisms and therapy. J Biomed Sci 31 , 64 (2024). https://doi.org/10.1186/s12929-024-01054-1

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DOI : https://doi.org/10.1186/s12929-024-01054-1

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