A new brand for Disease Models & Mechanisms and The Company of Biologists

Summary: The launch of a new brand and website for DMM.Regular readers of Disease Models & Mechanisms (DMM) during 2015 will have noticed some changes to the journal. This is part of the gradual implementation of a new Company brand and migration to a new, better, web platform. This culminated in October with the launch of a new website for The Company of Biologists (www.biologists.com), and a brand new look and feel for the DMM website (dmm.biologists.org) and the articles it publishes (see Fig. 1). The new DMM website (and those of its sister journals Development, Journal of Cell Science, Journal of Experimental Biology and Biology Open) is the result of a mammoth project to ensure that users have an enhanced experience when visiting our pages. The site is easier to navigate and uncluttered, making it even quicker to search and find the content you need. We hope it looks good too. Open in a separate windowFig. 1.The Company of Biologists and DMM: supporting biologists, inspiring biology.Although our five journals are well known, fewer people are aware of the other areas of support that The Company of Biologists brings to the biological community. Our new brand will help us to increase the awareness of our work, and strengthen the links between our journals and charitable activities.     

The power of Drosophila in modeling human disease mechanisms

Six years ago, DMM launched a subject collection called ‘Drosophila as a Disease Model’. This collection features Review-type articles and original research that highlight the power of Drosophila research in many aspects of human disease modeling. In the ensuing years, Drosophila research has further expanded to capitalize on genome editing, development of resources, and further interest in studying rare disease mechanisms. In the current issue of DMM, we again highlight the versatility, breadth, and scope of Drosophila research in human disease modeling and translational medicine. While many researchers have embraced the power of the fly, many more could still be encouraged to appreciate the strengths of Drosophila and how such research can integrate across species in a multi-pronged approach. Only when we truly acknowledge that all models contribute to our understanding of human biology, can we take advantage of the scope of current research endeavors.

Summary: This Editorial encourages us to embrace the power of the fly in studying human disease and highlights how Drosophila studies can be integrated with research in other species to further our understanding of human biology.

For over a century, scientists have used the fruit fly to learn about fundamental and evolutionarily conserved genetic and cellular processes. The pioneering work of Thomas Hunt Morgan and his students, in the early 20th century, proved that genes are located on chromosomes and led to the first chromosome linkage maps (Morgan, 1910). In the 1980s, Ed Lewis, Christiane Nüsslein-Volhard and Eric Wieschaus showed that individual genes could be mutated to cause characteristic embryonic patterning defects (Lewis, 1978; Nüsslein-Vollhard and Wieschaus, 1980). Their genetic studies allowed them to order genes within functional pathways through epistasis analyses. The genes they identified have counterparts across species and play key roles in development and disease from flies to humans. Indeed, much of the molecular circuitry for key signaling pathways, such as RAS, Notch, Hedgehog and Wnt, was elucidated in Drosophila (Ashton-Beaucage and Therrien, 2017; Bejsovec, 2018; Ingham, 2018; Salazar and Yamamoto, 2018). This rich history has established Drosophila as a powerful tool in biology, paving the way for further advances in basic and translational research.     

Envisioning the next human genome reference

Summary: We provide an Editorial perspective on approaches to improve ethnic representation in the human genome reference sequence, enabling its widespread use in genomic studies and precision medicine to benefit all peoples.

This year marks the 20th anniversary of the announced completion of the draft human genome sequence. The reference genome was a transformative accomplishment for human biological and medical research and is often referred to as biology''s moonshot. Over the past 20 years, the availability of this reference, and its refinement, has had the predicted transformative impact on our understanding of human genetic diseases, and, in many ways, has revolutionized the practice of medicine and medical diagnosis. These advances are mainly due to the emergence and refinement of rapid sequencing technology, which has facilitated our ability to generate genomic data, and to corresponding advances in computational analysis of these data, which have solidified the significant role of genomic alterations in disease etiology. Along these lines, large international projects have enriched our understanding of human genomic diversity in the context of cancer (Campbell et al., 2020), psychiatric genetics (Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2018; Cleynen et al., 2021), autism (Satterstrom et al., 2020; Trost et al., 2020) and many other diseases. Such studies have mainly catalogued individual and ancestry-based variation in human genomes, albeit to a limited extent. The inherent limitation in scope has been reflective of a predominant focus on populations of European ancestry in the earliest studies, such as the 1000 Genomes Project. More recent attempts to address these disparities have illuminated the challenges in recruiting diverse populations that either have a justifiable lack of trust in medical research or have cultural complexities regarding consent to participate. By improving diversity and inclusion in these studies, there would be increased hope that genomic studies will more broadly benefit populations. In order for the human genome and genomics to have a more significant and equitable impact in the future, accordingly, there is much more to be done. Medical and scientific communities need to consult with and listen to diverse populations and cultures to understand their concerns and needs, and, importantly, to make corresponding changes in our research practices that ensures accountability to these groups. Open in a separate windowImage reproduced under the terms of the Pixabay License.Ongoing large-scale population studies that link with individual clinical information are beginning to shape newer capabilities in predicting complex genetic disease susceptibility, primarily focused on developing and testing polygenic risk scores (Shen et al., 2020; Vujkovic et al., 2020; Riveros-Mckay et al., 2021; Weale et al., 2021). These efforts have the potential to radically change the practice of medicine, from a reactive to a proactive model of care delivery, based on an individual''s likelihood to experience predicted health challenges during their life course. As such, not only is current genomics-based diagnosis being imperiled by a lack of understanding of genomic variation based on ancestry (Sirugo et al., 2019), but future health care aspects also will be compromised in an ancestry-specific way, further compounding the impact of systemic racism that continues to make ethnic minorities more vulnerable in this setting (Yudell et al., 2020). In aggregate, this means that health disparities in many underserved populations will continue. In addition to these disparities in genomic representation, we also still lack a fundamental understanding across all ancestries, of what genotypes define as ‘healthy’ relative to our significant and growing understanding of ‘diseased’.There is renewed hope as newer projects strive to improve inclusivity, and here we highlight several examples arising in the United States. The National Institutes of Health (NIH)’s All of Us Research Program has set laudable goals for inclusion of diverse ethnic groups based on recent metrics, wherein over 50% of the currently enrolled 394,000 participants are ethnic minorities. This is a promising beginning, and, with a planned recruitment of 1 million participants, it will be interesting to see the final percentages toward the stated goal. More recently, the NIH posted a request for applications in support of research leading to the creation of best practices for the study of population identifiers. Local projects that focus on specific populations are also emerging, with a variety of funding mechanisms. For example, a study funded by the New York Genome Center plans to enroll minority participants from the broad diversity found throughout the New York City metropolitan area, with an aim to sequence whole genomes and collect health-related information, as discussed by Harold Varmus, one of the study''s leaders (Varmus, 2019). In Columbus, Ohio, the Institute for Genomic Medicine has opened an Institutional Review Board-approved study to consent, produce and database whole-genome sequences from unrelated individuals of Somali descent, to better inform our genomics-based diagnostic efforts for Somali children. Similarly, at Yale University, the Generations Project aims to increase diversity by recruiting in the Connecticut area, which is closely aligned with diversity in US consensus metrics. The exome sequencing and genotyping data from this project will be linked to electronic health records, allowing an opportunity to study and advance genomic health in under-represented minorities. Olufunmilayo Olopade, at the University of Chicago, has also discussed her work investigating genetic risk factors for breast cancer in Black women in studies based in Chicago and West Africa that aim to improve early detection, prevention and treatment in these populations (Olopade, 2021). Similar efforts outside the United States include the Human Heredity and Health in Africa Initiative (H3Africa), GenomeAsia 100K, ChileGenomico and the oriGen Project based in Mexico, among others.Technology continues to impact our human genome reference, predominantly using long-read single-molecule sequencing technologies to generate data, and algorithms capable of assembling these reads into long stretches of human chromosomes, permitting a more complete understanding of structural variation and unique content. Recently, an ‘end-to-end’ assembly of a complete hydatidiform mole cell line was reported, providing contiguity across centromeric and other complex repeats in the human genome, as described in a preprint (Nurk et al., 2021). However, the ancestry of this sample is European. Importantly, the Pangenome Project will aim to produce high-quality long-read sequencing for 300 individuals originally profiled in the 1000 Genomes Project. These comprehensive reference genomes will also include sequences of highly repetitive regions, including centromeres, segmental duplications and ribosomal DNA (rDNA) arrays on telomeres. In addition, the population diversity provided by these genomes will give researchers the option to choose a reference that is more closely related to any given sequenced individual, resulting in improved variant discovery.In addition to the influence of genomic technology, we have branched out from sole focus on DNA sequence to cataloguing RNA expression, isoforms and other types of characterization by applying next-generation and single-molecule sequencing, which, when integrated with DNA information, can provide significant insights into the sequences actively being expressed in tissues, as well as those being silenced by chromatin conformation or methylation. Such studies reveal that there is much more to be learned, and emphasize the importance of cataloguing normal tissue gene expression, which is available at GTEx, the Allen Brain Atlas and other internet resources. Exquisite new knowledge of gene expression profiles at the single-cell level from normal and diseased human tissue is emerging from the Human Cell Atlas projects, revealing the intricacies of human biology at high resolution (Ponting, 2019; Lindeboom et al., 2021).Yet, the concern about inclusion persists, even for these newest technological avenues that may indeed reveal important, ancestry-relevant differences with respect to disease susceptibility, physiologic specificity, pharmacogenomics and other pertinent areas (Okada et al., 2018). Without broadening the scope of diversity, we are concerned that individuals and populations will be left behind in many aspects of genomic medicine, effectively broadening disparities. Considering worldwide disparities that exist, such as poor access to health care, even in countries with high income and/or universal health care, the question remains about how to effectively foster inclusion and ensure that under-represented populations will benefit from expanded genomic research. Several strategies for increasing diversity and inclusion have been published (Cooke Bailey et al., 2020; Essien and Ufomata, 2021; Rotimi and Adeyemo, 2021; Nature Editorial, 2021). Here, we would like to highlight the following approaches. First, diversity in research subjects and samples starts with a diverse workforce at all levels, including leadership of major consortium efforts. To enable the creation of a diverse workforce, researchers need to engage with these communities to encourage and support them in pursuing such career paths and overcoming institutional barriers to achieve these goals. Researchers from under-represented groups that truly understand the communities being studied should have the opportunity to participate at all levels of a project, including leading the project and consenting participants (Bonham and Green, 2021). This facilitates surmounting socio-economic and cultural barriers that make it difficult to recruit under-represented minorities and engages the study team to meet diversity recruitment goals, while ensuring that the interpretation and outcomes of research are broadly beneficial. Second, there needs to be increased funding of institutions with diverse staff and students, such as Historically Black Colleges and Universities or community colleges with 2-year associate programs, as well as internship programs that bring minority students from inner-city high schools into genomics laboratories to learn about genomics research and its applicability to human health. Such programs ensure that leadership opportunities and training in genomics will directly benefit the communities that we intend to recruit. Equally important in this regard is education directed at researchers and medical providers that illuminates ongoing issues concerning racism, diversity and inclusion in science and health care. Third, long-term funding must be dedicated to build infrastructure and collaborative networks to enable the facile recruitment of diverse cohorts. H3Africa is a good model that could be replicated in other under-represented regions across the world, including diverse populations in large inner-city settings, emphasizing needed focus on consultation within these communities to understand their wants, needs and concerns regarding genetics and genomics. Lastly, funding agencies need to switch mindsets from having diversity as an optional goal to being a measurable milestone that must be met. The Human Cell Atlas in their recent funding round for the Pediatric Cell Atlas provides one example of explicit ancestry recruitment goals. Longer term, we must take responsibility to put in place mechanisms that both ensure accessibility to data and quantify the benefit of these studies to all populations.In reflecting on the 20 years since the published draft human genome, it is time to recognize that the combination of technologies, computational algorithms, and the diversity and inclusion of participants gives us the opportunity, this time around, to design cohort studies to benefit ALL of us. Certainly, there is a responsibility for journals, such as DMM, to address the issue of diversity and inclusion, by encouraging the publication of research that advances our understanding of diseases over-represented in individuals of diverse ancestries, and also encouraging reviewers to be conscious that access to technology is not equivalent in all countries, when requesting revisions for publication. DMM''s policies include aims to engage diverse and inclusive groups of authors, reviewers, Editors, Editorial Board members, readers and the communities being studied, and the journal is a signatory of the Royal Society of Chemistry''s initiative ‘Joint commitment for action on inclusion and diversity in publishing’. Journals can also seek out and publish pieces that address these important (and sometimes difficult) conversations, and openly discuss the ongoing challenges as well as approaches employed by others, as we strive to identify solutions that benefit everyone.     

A Real-Time All-Atom Structural Search Engine for Proteins

Protein designers use a wide variety of software tools for de novo design, yet their repertoire still lacks a fast and interactive all-atom search engine. To solve this, we have built the Suns program: a real-time, atomic search engine integrated into the PyMOL molecular visualization system. Users build atomic-level structural search queries within PyMOL and receive a stream of search results aligned to their query within a few seconds. This instant feedback cycle enables a new “designability”-inspired approach to protein design where the designer searches for and interactively incorporates native-like fragments from proven protein structures. We demonstrate the use of Suns to interactively build protein motifs, tertiary interactions, and to identify scaffolds compatible with hot-spot residues. The official web site and installer are located at http://www.degradolab.org/suns/ and the source code is hosted at https://github.com/godotgildor/Suns (PyMOL plugin, BSD license), https://github.com/Gabriel439/suns-cmd (command line client, BSD license), and https://github.com/Gabriel439/suns-search (search engine server, GPLv2 license).

This is a PLOS Computational Biology Software Article

     

PathVisio 3: An Extendable Pathway Analysis Toolbox

PathVisio is a commonly used pathway editor, visualization and analysis software. Biological pathways have been used by biologists for many years to describe the detailed steps in biological processes. Those powerful, visual representations help researchers to better understand, share and discuss knowledge. Since the first publication of PathVisio in 2008, the original paper was cited more than 170 times and PathVisio was used in many different biological studies. As an online editor PathVisio is also integrated in the community curated pathway database WikiPathways.Here we present the third version of PathVisio with the newest additions and improvements of the application. The core features of PathVisio are pathway drawing, advanced data visualization and pathway statistics. Additionally, PathVisio 3 introduces a new powerful extension systems that allows other developers to contribute additional functionality in form of plugins without changing the core application.PathVisio can be downloaded from http://www.pathvisio.org and in 2014 PathVisio 3 has been downloaded over 5,500 times. There are already more than 15 plugins available in the central plugin repository. PathVisio is a freely available, open-source tool published under the Apache 2.0 license (http://www.apache.org/licenses/LICENSE-2.0). It is implemented in Java and thus runs on all major operating systems. The code repository is available at http://svn.bigcat.unimaas.nl/pathvisio. The support mailing list for users is available on https://groups.google.com/forum/#!forum/wikipathways-discuss and for developers on https://groups.google.com/forum/#!forum/wikipathways-devel.

This is a PLOS Computational Biology software article.

     

Ascochyta rabiei: A threat to global chickpea production

The necrotrophic fungus Ascochyta rabiei causes Ascochyta blight (AB) disease in chickpea. A. rabiei infects all aerial parts of the plant, which results in severe yield loss. At present, AB disease occurs in most chickpea‐growing countries. Globally increased incidences of A. rabiei infection and the emergence of new aggressive isolates directed the interest of researchers toward understanding the evolution of pathogenic determinants in this fungus. In this review, we summarize the molecular and genetic studies of the pathogen along with approaches that are helping in combating the disease. Possible areas of future research are also suggested.Taxonomykingdom Mycota, phylum Ascomycota, class Dothideomycetes, subclass Coelomycetes, order Pleosporales, family Didymellaceae, genus Ascochyta, species rabiei. Primary host A. rabiei survives primarily on Cicer species.Disease symptoms A. rabiei infects aboveground parts of the plant including leaves, petioles, stems, pods, and seeds. The disease symptoms first appear as watersoaked lesions on the leaves and stems, which turn brown or dark brown. Early symptoms include small circular necrotic lesions visible on the leaves and oval brown lesions on the stem. At later stages of infection, the lesions may girdle the stem and the region above the girdle falls off. The disease severity increases at the reproductive stage and rounded lesions with concentric rings, due to asexual structures called pycnidia, appear on leaves, stems, and pods. The infected pod becomes blighted and often results in shrivelled and infected seeds.Disease management strategiesCrop failures may be avoided by judicious practices of integrated disease management based on the use of resistant or tolerant cultivars and growing chickpea in areas where conditions are least favourable for AB disease development. Use of healthy seeds free of A. rabiei, seed treatments with fungicides, and proper destruction of diseased stubbles can also reduce the fungal inoculum load. Crop rotation with nonhost crops is critical for controlling the disease. Planting moderately resistant cultivars and prudent application of fungicides is also a way to combat AB disease. However, the scarcity of AB‐resistant accessions and the continuous evolution of the pathogen challenges the disease management process.Useful websites https://www.ndsu.edu/pubweb/pulse‐info/resourcespdf/Ascochyta%20blight%20of%20chickpea.pdf https://saskpulse.com/files/newsletters/180531_ascochyta_in_chickpeas‐compressed.pdf http://www.pulseaus.com.au/growing‐pulses/bmp/chickpea/ascochyta‐blight http://agriculture.vic.gov.au/agriculture/pests‐diseases‐and‐weeds/plant‐diseases/grains‐pulses‐and‐cereals/ascochyta‐blight‐of‐chickpea http://www.croppro.com.au/crop_disease_manual/ch05s02.php https://www.northernpulse.com/uploads/resources/722/handout‐chickpeaascochyta‐nov13‐2011.pdf http://oar.icrisat.org/184/1/24_2010_IB_no_82_Host_Plant https://www.crop.bayer.com.au/find‐crop‐solutions/by‐pest/diseases/ascochyta‐blight     

Wham: Identifying Structural Variants of Biological Consequence

Existing methods for identifying structural variants (SVs) from short read datasets are inaccurate. This complicates disease-gene identification and efforts to understand the consequences of genetic variation. In response, we have created Wham (Whole-genome Alignment Metrics) to provide a single, integrated framework for both structural variant calling and association testing, thereby bypassing many of the difficulties that currently frustrate attempts to employ SVs in association testing. Here we describe Wham, benchmark it against three other widely used SV identification tools–Lumpy, Delly and SoftSearch–and demonstrate Wham’s ability to identify and associate SVs with phenotypes using data from humans, domestic pigeons, and vaccinia virus. Wham and all associated software are covered under the MIT License and can be freely downloaded from github (https://github.com/zeeev/wham), with documentation on a wiki (http://zeeev.github.io/wham/). For community support please post questions to https://www.biostars.org/.

This is PLOS Computational Biology software paper.

     

Risk Factors Associated with Recurrent Diarrheal Illnesses among Children in Kabul,Afghanistan: A Prospective Cohort Study

IntroductionChildhood diarrheal illnesses are a major public health problem. In low-income settings data on disease burden and factors associated with diarrheal illnesses are poorly defined, precluding effective prevention programs. This study explores factors associated with recurrent diarrheal illnesses among children in Kabul, Afghanistan.MethodsA cohort of 1–11 month old infants was followed for 18 months from 2007–2009. Data on diarrheal episodes were gathered through active and passive surveillance. Information on child health, socioeconomics, water and sanitation, and hygiene behaviors was collected. Factors associated with recurrent diarrheal illnesses were analyzed using random effects recurrent events regression models.Results3,045 children were enrolled and 2,511 (82%) completed 18-month follow-up. There were 14,998 episodes of diarrheal disease over 4,200 child-years (3.51 episodes/child-year, 95%CI 3.40–3.62). Risk of diarrheal illness during the winter season was 63% lower than the summer season (HR = 0.37, 95%CI 0.35–0.39, P<0.001). Soap for hand washing was available in 72% of households and 11.9% had toilets with septic/canalization. Half of all mothers reported using soap for hand washing. In multivariate analysis diarrheal illness was lower among children born to mothers with post-primary education (aHR = 0.79, 95%CI 0.69–0.91, p = 0.001), from households where maternal hand washing with soap was reported (aHR = 0.83, 95%CI 0.74–0.92, p<0.001) and with improved sanitation facilities (aHR = 0.76, 95%CI 0.63–0.93, p = 0.006). Malnourished children from impoverished households had significantly increased risks for recurrent disease [(aHR = 1.15, 95%CI 1.03–1.29, p = 0.016) and (aHR = 1.20, 95%CI 1.05–1.37, p = 0.006) respectively].ConclusionsMaternal hand washing and improved sanitation facilities were protective, and represent important prevention points among public health endeavors. The discrepancy between soap availability and utilization suggests barriers to access and knowledge, and programs simultaneously addressing these aspects would likely be beneficial. Enhanced maternal education and economic status were protective in this population and these findings support multi-sector interventions to combat illness.

Trial Registration

www.ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00548379","term_id":"NCT00548379"}}NCT00548379 https://www.clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT00548379","term_id":"NCT00548379"}}NCT00548379     

International conference on “Photosynthesis research for sustainability-2013: in honor of Jalal A. Aliyev”, held during June 5–9, 2013, Baku, Azerbaijan

In this brief report, we provide a pictorial essay on an international conference “Photosynthesis Research for Sustainability-2013 in honor of Jalal A. Aliyev” that was held in Baku, Azerbaijan, during June 5–9, 2013 (http://photosynthesis2013.cellreg.org/). We begin this report with a brief note on Jalal Aliyev, the honored scientist, and on John Walker (1997 Nobel laureate in Chemistry) who was a distinguished guest and lecturer at the Conference. We briefly describe the Conference, and the program. In addition to the excellent scientific program, a special feature of the Conference was the presentation of awards to nine outstanding young investigators; they are recognized in this report. We have also included several photographs to show the pleasant ambience at this conference. (See http://photosynthesis2013.cellreg.org/Photo-Gallery.php; https://www.dropbox.com/sh/qcr124dajwffwh6/TlcHBvFu4H?m; and https://www.copy.com/s/UDlxb9fgFXG9/Baku for more photographs taken by the authors as well as by others.) We invite the readers to the next conferences on “Photosynthesis Research for Sustainability—2014: in honor of Vladimir A. Shuvalov” to be held during June 2–7, 2014, in Pushchino, Russia. Detailed information for this will be posted at the Website: http://photosynthesis2014.cellreg.org/, and for the subsequent conference on “Photosynthesis Research for Sustainability—2015” to be held in May or June 2015, in Baku, Azerbaijan, at http://photosynthesis2015.cellreg.org/.     

Host genetic architecture and the landscape of microbiome composition: humans weigh in

Comparative analyses of the control of mammalian microbiomes by host genetic architecture reveal striking conserved features that have implications for the evolution of host–microbiome interactions.See related Research article: http://www.genomebiology.com/2015/16/1/191     

The Year of the Wisent

Delving into European prehistory, two recent studies analyze ancient DNA from bison species depicted by our ancestors on the walls of their caves. The DNA tells a story of migrations driven by climate change but leaves some mystery clouding the genetic descent and climate preference of the still-extant wisent, otherwise known as the European bison.See research articles: https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-016-0317-7 http://www.nature.com/articles/ncomms13158     

The Conformational Dynamics of Cas9 Governing DNA Cleavage Are Revealed by Single-Molecule FRET

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SGK1 Governs the Reciprocal Development of Th17 and Regulatory T Cells

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Peroxisome Proliferator Activated Receptor Gamma Controls Mature Brown Adipocyte Inducibility through Glycerol Kinase

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