Molecular basis of cross‐species ACE2 interactions with SARS‐CoV‐2‐like viruses of pangolin origin

Correction to: The EMBO Journal (2021) 40: e107786. DOI 10.15252/embj.2021107786 | Published online 8 June 2021The authors would like to add three references to the paper: Starr et al and Zahradník et al also reported that the Q498H or Q498R mutation has enhanced binding affinity to ACE2; and Liu et al reported on the binding of bat coronavirus to ACE2.Starr et al and Zahradník et al have now been cited in the Discussion section, and the following sentence has been corrected from:“According to our data, the SARS‐CoV‐2 RBD with Q498H increases the binding strength to hACE2 by 5‐fold, suggesting the Q498H mutant is more ready to interact with human receptor than the wildtype and highlighting the necessity for more strict control of virus and virus‐infected animals”.to“Here, according to our data and two recently published papers, the SARS‐CoV‐2 RBD with Q498H or Q498R increases the binding strength to hACE2 (Starr et al, 2020; Zahradník et al, 2021), suggesting the mutant with Q498H or Q498R is more ready to interact with human receptor than the wild type and highlighting the necessity for more strict control of virus and virus‐infected animals”.The Liu et al citation has been added to the following sentence:“In another paper published by our group recently, RaTG13 RBD was found to bind to hACE2 with much lower binding affinity than SARS‐CoV‐2 though RaTG13 displays the highest whole‐genome sequence identity (96.2%) with the SARS‐CoV‐2 (Liu et al, 2021)”.Additionally, the authors have added the GISAID accession IDs to the sequence names of the SARS‐CoV‐2 in two human samples (Discussion section). To make identification unambiguous, the sequence names have been updated from “SA‐lsf‐27 and SA‐lsf‐37” to “GISAID accession ID: EPI_ISL_672581 and EPI_ISL_672589”.Lastly, the authors declare in the Materials and Methods section that all experiments employed SARS‐CoV‐2 pseudovirus in cultured cells. These experiments were performed in a BSL‐2‐level laboratory and approved by Science and Technology Conditions Platform Office, Institute of Microbiology, Chinese Academy of Sciences.These changes are herewith incorporated into the paper.     

CircHIPK3 sponges miR‐558 to suppress heparanase expression in bladder cancer cells

Correction to: EMBO Reports (2017) 18(9): 1646–1659. DOI: 10.15252/embr.201643581 ¦ Published online 9 August 2017The authors contacted the journal after being alerted to issues in the figures. The authors state that while preparing the figures, images were mislabelled leading to partial duplications in two figure panels. The authors requested to withdraw the affected panels and to replace them with correct representative images that had been generated at the time of the original experimentation. The panels listed below are therefore withdrawn and replaced. The related source data are published with this note.Figure 4DThe transwell assay image for UMUC3 cells showing invasion behaviour upon miR‐558 mimic treatment (“miR‐558”) had been incorrect. An image showing the invasion behaviour of UMUC3 cells upon depletion of circHIPK3 (“si‐circHIPK3#1”) showing the same cells as depicted in Fig 2H was erroneously used. A representative image of the correct data is now displayed in the paper.Figure 4EThe transwell assay image for UMUC3 cells showing migration behaviour upon treatment with an miR‐588 anti‐miR (“anti‐miR‐558”) had been incorrect. An image showing the migration behaviour of UMUC3 cells upon circHIPK3 overexpression (“circHIPK3”) showing the same cells as those depicted in Fig 2D was erroneously used. A representative image of the correct data is now displayed in the paper.Figure 5CThe Western blot image showing the β‐actin loading control for T24T cells had been incorrect. A representative image of the correct data is now displayed in the paper.Figure 5FThe image for UMUC3 cells showing tube formation upon treatment with a control mimic and overexpression of circHIPK3 “mimicNC+circHIPK3” had been incorrect. A representative image of the correct data is now displayed in the paper.The figure issues described above are herewith corrected. The authors state that the errors do not affect the results or conclusions of the study and apologize for any confusion these errors may have caused. Figure 4D. Original. Figure 4D. Corrected. Figure 4E. Original. Figure 4E. Corrected. Figure 5C. Original. Figure 5C. Corrected. Figure 5F. Original. Figure 5F. Corrected.      

Posttranscriptional regulation of colonic epithelial repair by RNA binding protein IMP1/IGF2BP1

Correction to: EMBO Reports (2019) 20: e47074. DOI 10.15252/embr.201847074 | Published online 6 May 2019The authors noticed that the control and disease labels had been inverted in their data analysis resulting in publication of incorrect data in Figure 1C. The corrected figure is displayed below. This change affects the conclusions as detailed below. The authors apologize for this error and any confusion it may have caused.In the legend of 1C, change from, “Differential gene expression analysis of pediatric ileal CD patient samples (n = 180) shows increased (> 4‐fold) IMP1 expression as compared to non‐inflammatory bowel disease (IBD) pediatric samples (n = 43)”.Open in a separate windowFigure 1CCorrected Open in a separate windowFigure 1COriginal To, "Differential gene expression analysis of pediatric ileal CD patient samples (n = 180) shows decreased (> 4‐fold) IMP1 expression as compared to non‐inflammatory bowel disease (IBD) pediatric samples (n = 43)”.In abstract, change from, “Here, we report increased IMP1 expression in patients with Crohn''s disease and ulcerative colitis”.To, “Here, we report increased IMP1 expression in adult patients with Crohn''s disease and ulcerative colitis”.In results, change from, “Consistent with these findings, analysis of published the Pediatric RISK Stratification Study (RISK) cohort of RNA‐sequencing data 38 from pediatric patients with Crohn''s disease (CD) patients revealed that IMP1 is upregulated significantly compared to control patients and that this effect is specific to IMP1 (i.e., other distinct isoforms, IMP2 and IMP3, are not changed; Fig 1C)”.To, “Contrary to our findings in colon tissue from adults, analysis of published RNA‐sequencing data from the Pediatric RISK Stratification Study (RISK) cohort of ileal tissue from children with Crohn’s disease (CD) 38 revealed that IMP1 is downregulated significantly compared to control patients in the RISK cohort and that this effect is specific to IMP1 (i.e., other distinct isoforms, IMP2 and IMP3, are not changed; Fig 1C)”.In discussion, change from, “Indeed, we report that IMP1 is upregulated in patients with Crohn''s disease and ulcerative colitis and that mice with Imp1 loss exhibit enhanced repair following DSS‐mediated damage”.To “Indeed, we report that IMP1 is upregulated in adult patients with Crohn''s disease and ulcerative colitis and that mice with Imp1 loss exhibit enhanced repair following DSS‐mediated damage”.     

LncRNA‐PAGBC acts as a microRNA sponge and promotes gallbladder tumorigenesis

Correction to: EMBO Reports (2017) 18: 1837–1853. DOI: 10.15252/embr.201744147 ¦ Published online 8 September 2017The authors contacted the journal after becoming aware of duplications between Figs 3 and 6 and identified additional errors in the process of reanalysing their data. Figure 3B: The authors state that the representative images of the migration and invasion assays of EH‐GB1 cells in the Lv‐Control groups had been incorrectly selected from images belonging to the control groups. The figure is herewith corrected. Figure 6B: The authors state that they had incorrectly displayed representative images for the vector group of SGC‐996, and the vector and PAGBC‐mut (miR‐133b) groups of EH‐GB1. The figure is herewith corrected.In addition, the authors are adding a demarcating line to the PCR product of the 5′‐RACE in Fig EV2B, separating the marker lane, which had been inadvertently omitted. Source data for Fig EV2 were published in the original paper.The source data and replicate data for Figs 3B and 6B are published with this corrigendum.The authors apologize for this oversight and any confusion it may have caused and declare that the conclusions of the study are not affected by these changes.     

Cytosolic GDH1 degradation restricts protein synthesis to sustain tumor cell survival following amino acid deprivation

Correction to: The EMBO Journal (2021) 40: e107480. DOI 10.15252/embj.2020107480 ¦ Published online 6 July 2021The authorship of this research paper is herewith corrected to indicate that Jialiang Shao, Tiezhu Shi, Hua Yu, and Yufeng Ding are all equal co‐first authors.     

Inactive variants of death receptor p75NTR reduce Alzheimer’s neuropathology by interfering with APP internalization

Correction to: The EMBO Journal (2021) 40: e104450. DOI 10.15252/embj.2020104450 | Published online 1 December 2020The authors correct Figure 6A of this paper. During the revision process, images from p75^NTR‐expressing mice were inadvertently used in place of p75^NTR knock‐out neurons. The corrected figure, showing lack of p75^NTR labeling in knock‐out neurons, along with their corresponding internalized APP, is shown here. This error only concerns the images used to illustrate the quantitative data. It does not affect the analysis itself nor the conclusions derived from it. The authors apologize for this oversight and agree with this corrigendum; no response could be obtained from KT. Figure 6A. Original Figure 6A. Corrected     

Biodiversity 2030: a road paved with good intentions: The new EU Commission's biodiversity Strategy risks to remain an empty husk without proper implementation

The EU''s Biodiversity Strategy for 2030 makes great promises about halting the decline of biodiversity but it offers little in terms of implementation. Subject Categories: S&S: Economics & Business, Ecology, S&S: Ethics

Earth is teeming with a stunning variety of life forms. Despite hundreds of years of exploration and taxonomic research, and with 1.2 million species classified, we still have no clear picture of the real extent of global biodiversity, with estimates ranging from 3 to 100 million species. A highly quoted—although not universally accepted—study predicted some 8.7 million species, of which about 2.2 million are marine (Mora et al, 2011). Although nearly any niche on the surface of Earth has been colonized by life, species richness is all but evenly distributed. A large share of the known species is concentrated in relatively small areas, especially in the tropics (Fig 1). Ultimately, it is the network of the interactions among life forms and the physical environment that make up the global ecosystem we call biosphere and that supports life itself.Open in a separate windowFigure 1Biological hotspots of the worldA total of 36 currently recognized hotspots make up < 3% of the planet''s land area but harbor half of the world''s endemic plant species and 42% of all terrestrial vertebrates. Overall, hotspots have lost more than 80% of their original extension. Credit: Richard J. Weller, Claire Hoch, and Chieh Huang, 2017, Atlas for the End of the World, http://atlas‐for‐the‐end‐of‐the‐world.com/. Reproduced with permission.Driven by a range of complex and interwoven causes–such as changes in land and sea use, habitat destruction, overexploitation of organisms, climate change, pollution, and invasive species–biodiversity is declining at an alarming pace. A report by the Intergovernmental Science‐Policy Platform on Biodiversity and Ecosystem Services (IPBES) issued a clear warning: “An average of around 25 per cent of species in assessed animal and plant groups are threatened, suggesting that around 1 million species already face extinction, many within decades, unless action is taken to reduce the intensity of drivers of biodiversity loss. Without such action, there will be a further acceleration in the global rate of species extinction, which is already at least tens to hundreds of times higher than it has averaged over the past 10 million years” (IPBES, 2019) (Fig 2). Although focused on a smaller set of organisms, a more recent assessment by WWF has reached similar conclusions. Their Living Planet Index, that tracks the abundance of thousands of populations of mammals, birds, fish, reptiles, and amphibians around the world, shows a stark decline in monitored populations (WWF, 2020). As expected, the trend of biodiversity decline is not homogeneous with tropical areas paying a disproportionately high price, mostly because of unrestrained deforestation and exploitation of natural resources.Open in a separate windowFigure 2The global, rapid decline of biodiversity(A) Percentage of species threatened with extinction in taxonomic groups that have been assessed comprehensively, or through a “sampled” approach, or for which selected subsets have been assessed by the IUCN Red List of Threatened Species. Groups are ordered according to the best estimate, assuming that data‐deficient species are as threatened as non‐data deficient species. (B) Extinctions since 1500 for vertebrate groups. (C) Red List Index of species survival for taxonomic groups that have been assessed for the IUCN Red List at least twice. A value of 1 is equivalent to all species being categorized as Least Concern; a value of zero is equivalent to all species being classified as Extinct. Data for all panels from www.iucnredlist.org. Reproduced from (IPBES, 2019), with permission.

Driven by a range of complex and interwoven causes […] biodiversity is declining at an alarming pace.

Against this dire background, the EU has drafted a Biodiversity Strategy 2030, an ambitious framework aimed to tackling the key reasons behind biodiversity loss. The plan hinges around a few main elements, such as the establishment of protected areas for at least 30% of Europe''s lands and seas (Fig 3); a significant increase of biodiversity‐rich landscape features on agricultural land by establishing buffer zones like hedges and fallow fields; halting and reversing the decline of pollinators; and planting 3 billion trees by 2030 (https://ec.europa.eu/info/strategy/priorities‐2019‐2024/european‐green‐deal/actions‐being‐taken‐eu/eu‐biodiversity‐strategy‐2030_en). The budget for implementing these measures was set at €20 billion per year.Open in a separate windowFigure 3Natura 2000, the EU''s network of protected areasIn 2019, 18% of land in the EU was protected as Natura 2000, with the lowest share of protected land in Denmark (8%) and the highest in Slovenia (38%). In 2019, the largest national network of terrestrial Natura 2000 sites was located in Spain, covering 138,111 km², followed by France (70,875 km²) and Poland (61,168 km²). Reproduced from Eurostat: https://ec.europa.eu/eurostat/statistics‐explained/index.php?title=Main_Page “Nature is vital for our physical and mental wellbeing, it filters our air and water, it regulates the climate and it pollinates our crops. But we are acting as if it didn''t matter, and losing it at an unprecedented rate”, said Virginijus Sinkevičius, Commissioner for the Environment, Oceans and Fisheries, at the press launch of the new EU action (https://ec.europa.eu/commission/presscorner/detail/en/ip_20_884). “This new Biodiversity Strategy builds on what has worked in the past, and adds new tools that will set us on a path to true sustainability, with benefits for all. The EU''s aim is to protect and restore nature, to contribute to economic recovery from the current crisis, and to lead the way for an ambitious global framework to protect biodiversity around the planet”.Environmental groups and other stakeholders have welcomed the EU''s pledge in principle. “This is a unique opportunity to shape a new society in harmony with nature”, applauded Wetlands International. “We must not forget that the biodiversity and climate crisis is a much bigger and persistent challenge for humanity than COVID‐19”, (https://europe.wetlands.org/news/welcoming‐the‐eu‐biodiversity‐strategy‐for‐2030/). EuroNatur, a foundation focused on conservation, stated that the goals set out by the new strategy provide a strong basis for improving the state of nature in the EU (www.euronatur.org).Alongside the voices of praise, however, many have expressed concerns that the strategy could turn into a little more than a wish list. “The big issue of the strategy is that while setting a goal for financial funds, the EU does not specify where the money is supposed to come from. It only says it should include ‘EU funds and national and private funding’”, commented the European Wilderness Society, an environmental advocacy non‐profit organization headquartered in Tamsweg, Austria. “Goals are important, but do not create change without an organized and sustainable implementation. It''s a good and ambitious document, but what is also obvious is the lack of strategy of how to implement it, and a lack of discussion of why previous documents of this type failed” (https://wilderness‐society.org/ambitious‐eu‐biodiversity‐strategy‐2030/).

Alongside the voices of praise, however, many have expressed concerns that the strategy could turn into a little more than a wish list.

The Institute for European Environmental Policy (IEEP) is on the same page. The sustainability think‐tank based in Brussels and London noted that the outgoing EU 2020 biodiversity strategy showed major implementation problems, especially because of lack of engagement at national level and of ad hoc legislation supporting the meeting of key targets. Therefore, “[it] can be argued that a legally binding approach to the biodiversity governance framework is urgently needed unless Member States and other key stakeholders can show greater intrinsic ownership to deliver on agreed objectives”, (https://ieep.eu/news/first‐impressions‐of‐the‐eu‐biodiversity‐strategy‐to‐2030). In addition, IEEP remarked that money is an issue, since the €20 billion figure appears more as an estimate than a certified obligation.“The intentions of the Commission are good and the strategy contains a number of measures and targets that can really make a difference. However, implementation depends critically on the member states and experiences with the Common Agricultural Policy the past decade or so have taught us that many of them are more interested in short‐term economic objectives than in safeguarding the natural wealth of their country for future generations”, commented David Kleijn, an ecologist and nature conservation expert at the Wageningen University, the Netherlands. “I think it is important that we now have an ambitious Biodiversity Strategy but at the same time I have little hope that we will be able to achieve its objectives”.

I think it is important that we now have an ambitious Biodiversity Strategy but at the same time I have little hope that we will be able to achieve its objectives.

There is further criticism against specific measures, such as the proposal of planting 3 billion trees. “To have lots of trees planted in an area does not necessarily translate into an increase of biodiversity. Biodiverse ecosystems are the result of million years of complex multi‐species interactions and evolutionary processes, which are not as easy to restore”, explained plant ecologist Susana Gómez‐González, from the University of Cádiz, Spain. Planting a large number of trees is a too simplistic approach for saving European forests from the combined effects of excessive anthropic pressure and climate change, and could even have detrimental effects (see Box 1). More emphasis should be placed instead in reducing tree harvesting in sensitive areas and in promoting natural forest renewal processes (Gómez‐González et al, 2020). “For a biodiversity strategy, increasing the number of trees, or even increasing the forest area, should not be an objective; priority should be given to the conservation and restoration of natural ecosystems, forests and non‐forests”, Gómez‐González said.In other cases, it could be difficult, if not impossible, to reach some of the goals because of lack of information. For example, one of the roadmap''s targets is to restore at least 25,000 km of Europe''s rivers back to free‐flowing state. However, the number of barriers dispersed along European rivers will probably prevent even getting close to the mark. An international research team has collected detailed information on existing instream barriers for 147 rivers in 36 European countries, coming up with the impressive figure of over 1.2 million obstacles that inevitably impact on river ecosystems, affecting the transport and dispersion of aquatic organisms, nutrients, and sediments (Belletti et al, 2020). Existing inventories mainly focused on dams and other large barriers, while, in fact, a large number of artificial structures are much smaller, such like weirs, locks, ramps, and fords. As a result, river fragmentation has been largely underestimated, and the models used to plan flow restoration might be seriously flawed. “To avoid ‘death by a thousand cuts’, a paradigm shift is necessary: to recognize that although large dams may draw most of the attention, it is the small barriers that collectively do most of the damage. Small is not beautiful”, concluded the authors (Belletti et al, 2020).

Box 1: Why many trees don''t (always) make a forestForests are cathedrals of biodiversity. They host by far the largest number of species on land, which provide food and essential resources for hundreds of millions of people worldwide. However, forests are disappearing and degrading at an alarming pace. The loss of these crucial ecosystems has given new impulses to a variety of projects aimed at stopping this devastation and possibly reversing the trend.Once it is gone, can you rebuild a forest? Many believe the answer is yes, and the obvious solution is to plant trees. Several countries have thus launched massive tree‐planting programs, notably India and Ethiopia, where 350 million trees have been planted in single day (https://www.unenvironment.org/news‐and‐stories/story/ethiopia‐plants‐over‐350‐million‐trees‐day‐setting‐new‐world‐record). The World Economic Forum has set up its own One Trillion Tree initiative (https://www.1t.org/) “to conserve, restore, and grow one trillion trees by 2030”. Launched in January last year at Davos, 1t.org was conceived as a platform for governments, companies and NGOs/civil society groups to support the UN Decade on Ecosystem Restoration (2021–2030). The initiative has been christened by renowned naturalist Jane Goodall, who commented: “1t.org offers innovative technologies which will serve to connect tens of thousands of small and large groups around the world that are engaged in tree planting and forest restoration”, (https://www.weforum.org/agenda/2020/01/one‐trillion‐trees‐world‐economic‐forum‐launches‐plan‐to‐help‐nature‐and‐the‐climate/).However, things are way more complicated than they appear: large‐scale tree planting schemes are rarely a viable solution and can even be harmful. “[A] large body of literature shows that even the best planned restoration projects rarely fully recover the biodiversity of intact forests, owing to a lack of sources of forest‐dependent flora and fauna in deforested landscapes, as well as degraded abiotic conditions resulting from anthropogenic activities”, commented Karen Holl from the University of Caliornia, Santa Cruz, and Pedro Brancalion from the University of São Paulo (Holl & Brancalion, 2020). A common problem of tree plantations, for example, is the low survival rate of seedlings, mostly because the wrong tree species are selected and due to poor maintenance after planting. Moreover, grasslands and savannas, which are often targeted for establishing new forests, are themselves treasure troves of biodiversity. Ending indiscriminate deforestation, improving the protection of existing forests, and promoting their restoration would therefore be a more efficient strategy to preserve biodiversity in the shorter term. If tree planting is indeed necessary, it should be well planned by selecting the right areas for reforestation, using suitable tree species that can maximize biodiversity, and involving local populations to maintain the plantations, Holl and Brancalion argue (Holl & Brancalion, 2020).

…even the best planned restoration projects rarely fully recover the biodiversity of intact forests, owing to a lack of sources of forest‐dependent flora and fauna in deforested landscapes…

The health of soil, where a high proportion of biodiversity is hosted, is another problem the new strategy should address in a more focused manner. “In my opinion, the EU Biodiversity Strategy is already a leap forward in terms of policy interest in soils in general and in soil biodiversity in particular. Compared with other nations/regions of the world, Europe is by far in the forefront regarding this issue”, commented Carlos António Guerra at the German Centre for Integrative Biodiversity Research (iDiv) in Leipzig, Germany, and Co‐leader of the Global Soil Biodiversity Observation Network (https://geobon.org/bons/thematic‐bon/soil‐bon/). “Nevertheless, the connection between soil biodiversity and ecological functions needs further commitments. Soils allow for horizontal integration of several policy agendas, from climate to agriculture and, very importantly, nature conservation. This is not explicit in the EU Biodiversity Strategy in regard to soils”. It remains to be seen if EU restoration plan will emphasize soil biodiversity, or consider it as a mere side effect of other initiatives, Guerra added. “A soil nature conservation plan should be proposed”, he said. “Only such a plan, that implies that current and future protected areas have to consider, describe and protect their soil biodiversity would make a significant push to help protect such a valuable resource”.More generally, research shows that the current paradigm of protection must be shifted to prevent further losses to biodiversity. In fact, an analysis of LIFE projects—a cornerstone of EU nature protection—found that conservation efforts are extremely polarized and strongly taxonomically biased (Mammola et al, 2020). From 1992 to 2018, investment in vertebrates was sixfold higher than that for invertebrates, with birds and mammals alone accounting for 72% of the targeted species and 75% of the total budget. In relative terms, investment per species for vertebrates has been 468 times higher than for invertebrates (Fig 4). There is no sound scientific reasoning behind this uneven conservation attention, but just popularity. “[T]he species covered by a greater number of LIFE projects were also those which attracted the most interest online, suggesting that conservation in the EU is largely driven by species charisma, rather than objective features”, the researchers wrote (Mammola et al, 2020).Open in a separate windowFigure 4Taxonomic bias in EU fauna protection effortsBreakdown of the number of projects (A) and budget allocation (B) across main animal groups covered by the LIFE projects (n = 835). (C) The most covered 30 species of vertebrates (out of 410) and invertebrates (out of 78) in the LIFE projects analyzed (n = 835). The vertical bar represents monetary investment and the blue scatter line the number of LIFE projects devoted to each species. Reproduced from (Mammola et al, 2020), with permission.     

Experts in science communication: A shift from neutral encyclopedia to equal participant in dialogue

Even if the predominant model of science communication with the public is now based on dialogue, many experts still adhere to the outdated deficit model of informing the public. Subject Categories: Genetics, Gene Therapy & Genetic Disease, S&S: History & Philosophy of Science, S&S: Ethics

During the past decades, public communication of science has undergone profound changes: from policy‐driven to policy‐informing, from promoting science to interpreting science, and from dissemination to interaction (Burgess, 2014). These shifts in communication paradigms have an impact on what is expected from scientists who engage in public communication: they should be seen as fellow citizens rather than experts whose task is to increase scientific literacy of the lay public. Many scientists engage in science communication, because they see this as their responsibility toward society (Loroño‐Leturiondo & Davies, 2018). Yet, a significant proportion of researchers still “view public engagement as an activity of talking to rather than with the public” (Hamlyn et al, 2015). The highly criticized “deficit model” that sees the role of experts as educating the public to mitigate skepticism still persists (Simis et al, 2016; Suldovsky, 2016).Indeed, a survey we conducted among experts in training seems to corroborate the persistence of the deficit model even among younger scientists. Based on these results and our own experience with organizing public dialogues about human germline gene editing (Box 1), we discuss the implications of this outdated science communication model and an alternative model of public engagement, that aims to align science with the needs and values of the public.Box 1

The DNA‐dialogue project

The Dutch DNA‐dialogue project invited citizens to discuss and form opinions about human germline gene editing. During 2019 and 2020, this project organized twenty‐seven dialogues with professionals, such as embryologists and midwives, and various lay audiences. Different scenarios of a world in 2039 (https://www.rathenau.nl/en/making‐perfect‐lives/discussing‐modification‐heritable‐dna‐embryos) served as the starting point. Participants expressed their initial reactions to these scenarios with emotion‐cards and thereby explored the values they themselves and other participants deemed important as they elaborated further. Starting each dialogue in this way provides a context that enables everyone to participate in dialogue about complex topics such as human germline gene editing and demonstrates that scientific knowledge should not be a prerequisite to participate.An important example of “different” relevant knowledge surfaced during a dialogue with children between 8 and 12 years in the Sophia Children’s Hospital in Rotterdam (Fig 1). Most adults in the DNA‐dialogues accepted human germline gene modification for severe genetic diseases, as they wished the best possible care and outcome for their children. The children at Sophia, however, stated that they would find it terrible if their parents had altered something about them before they had been born; their parents would not even have known them. Some children went so far to say they would no longer be themselves without their genetic condition, and that their condition had also given them experiences they would rather not have missed.Open in a separate windowFigure 1 Children participating in a DNA‐dialogue meeting. Photographed by Levien Willemse.     

Mycobacterium tuberculosis: the honey badger of pathogens

Mycobacterium tuberculosis is a fascinating object of study: it is one of the deadliest pathogens of humankind, able to fend off persistent attacks by the immune system or drugs Subject Categories: Immunology, Microbiology, Virology & Host Pathogen Interaction, Chemical Biology

I have always been interested in infectious diseases since I began to study biology. As a graduate student, my pathogen of choice was Salmonella typhimurium, which typically causes diarrhea that can potentially lead to death. Salmonella''s rapid doubling time, and the availability of elegant genetic tools, a wealth of reagents, and a robust animal infection model put this bug at the apex of ideal host–pathogen systems to study. After I finished my PhD studies—and for reasons to be told another day—my career took an unexpected detour into an area of research I never thought I would be interested in: I went from the sublime to the ridiculous, from Salmonella to Mycobacterium tuberculosis (Mtb), an excruciatingly slow‐growing bacillus with few genetic tools, a paucity of reagents, and an animal model in which an experiment can take a year or longer. Having said all of that, I love working on this pathogen.For those of you who do not know much about Mtb, it is the world''s deadliest bacterium that causes the disease tuberculosis (TB). As Mtb is spread in aerosol droplets coughed up by infected individuals, TB is highly contagious, and about one‐third of the world''s population may be infected with Mtb, although this number has been reasonably challenged (Behr et al, 2021). Even if the numbers of latent or asymptomatic infections are debated, there are some back‐of‐the‐envelope estimates that Mtb has killed more than a billion humans over the millennia. Although TB is often treatable with antibiotics and most Mtb‐infected healthy individuals are asymptomatic, the appearance of multi‐drug‐resistant Mtb and HIV/AIDS has further increased the number of deaths caused by this pathogen.How has Mtb become such a successful pathogen? For one, we lack an effective vaccine to prevent infection. Many readers may point out that they have themselves been given a TB vaccine; known as “BCG” for bacille Calmette–Guérin, this is a laboratory‐attenuated strain of a species related to Mtb called Mycobacterium bovis. While BCG does provide some protection for children against TB, BCG is essentially ineffective against pulmonary TB in adults. For this reason, it is not used in the USA and many other countries.Another major challenge to treating TB has been a lack of antimicrobials that can access Mtb bacilli in privileged sites known as granulomas, which are cell‐fortified structures our immune system builds to contain microbial growth. In addition to the granuloma walls, Mtb has a highly complex cell envelope that protects it from many small molecules. I imagine that antimicrobial molecules have the challenging task of reaching an enemy shielded in armor, hiding deep inside a castle keep, and surrounded by a vast moat, and an army of orcs.On top of these therapeutic barriers, most antimicrobials work on metabolically active or growing bacteria. Mtb, however, grows very slowly, with a doubling time under optimal laboratory conditions of about 20 h—compared with 20 min for Salmonella. Moreover, Mtb is believed to enter a “persistent” or “latent” state in its natural host with limited cell divisions. This extremely slow growth makes treatment a long and tedious prospect: 6–12 months of antibiotic treatment are generally required, during which time one cannot drink alcohol due to the potential liver toxicity of the drugs. Believe it or not, there are people who would rather refuse TB treatment than give up alcohol for a few months. Additionally, the perception of “feeling cured” after a few weeks of TB therapy can also lead to a lapse in compliance. The consequence of failing to clear a partially treated infection is the emergence of drug resistance, which has created strains that are extensively resistant to most frontline TB drugs.When thinking about the difficulty of curing Mtb infections, I am reminded of the fierce and fearless honey badger, which came to fame through a viral YouTube video. The narrator points out how honey badgers “don''t care” about battling vicious predators in order to get food: venomous snakes, stinging bees—you name it. I once saw a photo of a honey badger that looked more like a pin cushion, harpooned with numerous porcupine quills. This battle royale of the wilderness is a perfect analogy of Mtb versus the immune system: Like the honey badger, Mtb really don''t care.Vaccines primarily work by coaxing our immune system to make antibodies that neutralize foreign invaders, most typically viruses, but also bacteria, some of which have evolved mechanisms to evade detection by antibodies or otherwise render them useless. In most cases, phagocytes then gobble up and kill invading bacteria. While phagocytes are critical in controlling Mtb infections, it is unclear which of their molecules or “effectors” act as executioners of Mtb. For example, nitric oxide and copper play roles in controlling Mtb in a mouse model, but it is unknown how these molecules exert their host‐protective activity, and whether or not they play a similar role in humans. Furthermore, despite the production of these antibacterial effectors—the “porcupine quills”—Mtb often persists due to intrinsic resistance mechanisms. Thus, while our immune system may have the tools to keep Mtb under control, it falls short of eradicating it from our bodies and, in many cases, fails to prevent the progression of the disease. Perhaps a most worrying observation is that prior infection, which is generally considered the most effective path to immunity for many infectious diseases, does not consistently protect against reinfection with Mtb.The above facts have left the TB field scrambling to identify new ways to fight this disease. Much of this work requires that researchers understand both the fundamental processes of the bacterium and its host. Studies of human populations around the globe have revealed differences in susceptibility to infection, the genetic and immunological bases of which are being investigated (Bellamy et al, 2000; Berry et al, 2010; Möller et al, 2010). These studies have made researchers increasingly aware that how the immune system responds to Mtb may play a critical role in disease control. For example, understanding why some individuals or populations are more or less susceptible to TB may help in the development of better vaccines. Also, the more we understand what makes this pathogen so resilient to the immune system could facilitate the development of new antibacterial drugs or host‐directed therapies. These questions can only be answered once we fully understand how the host combats Mtb infections, and how the bacteria counteract these host defenses. While it is a daunting endeavor, my hope is that the efforts of many laboratories around the world will get a better understanding of the host–Mtb interface and ultimately help to eradicate this disease for good.     

Putting the brakes on phagocytosis: “don't‐eat‐me” signaling in physiology and disease

Timely removal of dying or pathogenic cells by phagocytes is essential to maintaining host homeostasis. Phagocytes execute the clearance process with high fidelity while sparing healthy neighboring cells, and this process is at least partially regulated by the balance of “eat‐me” and “don''t‐eat‐me” signals expressed on the surface of host cells. Upon contact, eat‐me signals activate “pro‐phagocytic” receptors expressed on the phagocyte membrane and signal to promote phagocytosis. Conversely, don''t‐eat‐me signals engage “anti‐phagocytic” receptors to suppress phagocytosis. We review the current knowledge of don''t‐eat‐me signaling in normal physiology and disease contexts where aberrant don''t‐eat‐me signaling contributes to pathology.     

Molecular Pathology of Rare Bleeding Disorders (RBDs) in India: A Systematic Review

Background

Though rare in occurrence, patients with rare bleeding disorders (RBDs) are highly heterogeneous and may manifest with severe bleeding diathesis. Due to the high rate of consanguinity in many caste groups, these autosomal recessive bleeding disorders which are of rare occurrence in populations across the world, may not be as rare in India.

Objectives

To comprehensively analyze the frequency and nature of mutations in Indian patients with RBDs.

Methods

Pubmed search was used (www.pubmed.com) to explore the published literature from India on RBDs using the key words “rare bleeding disorders”, “mutations”, “India”, “fibrinogen”, “afibrinogenemia”, “factor II deficiency”, “prothrombin” “factor VII deficiency”, “factor V deficiency”, “factor X deficiency”, “factor XI deficiency”, “combined factor V and VIII deficiency”, “factor XIII deficiency”, “Bernard Soulier syndrome” and “Glanzmanns thrombasthenia” in different combinations. A total of 60 relevant articles could be retrieved. The distribution of mutations from India was compared with that of the world literature by referring to the Human Gene Mutation Database (HGMD) (www.hgmd.org).

Results

Taken together, 181 mutations in 270 patients with different RBDs have been reported from India. Though the types of mutations reported from India and their percentage distribution with respect to the world data are largely similar, yet much higher percentage of small deletions, duplication mutations, insertions, indels were observed in this analysis. Besides the identification of novel mutations and polymorphisms, several common mutations have also been reported, which will allow to develop a strategy for mutation screening in Indian patients with RBDs.

Conclusion

There is a need for a consortium of Institutions working on the molecular pathology of RBDs in India. This will facilitate a quicker and cheaper diagnosis of RBDs besides its utility in first trimester prenatal diagnosis of the affected families.     

DOMINO: a network‐based active module identification algorithm with reduced rate of false calls

Algorithms for active module identification (AMI) are central to analysis of omics data. Such algorithms receive a gene network and nodes'' activity scores as input and report subnetworks that show significant over‐representation of accrued activity signal (“active modules”), thus representing biological processes that presumably play key roles in the analyzed conditions. Here, we systematically evaluated six popular AMI methods on gene expression and GWAS data. We observed that GO terms enriched in modules detected on the real data were often also enriched on modules found on randomly permuted data. This indicated that AMI methods frequently report modules that are not specific to the biological context measured by the analyzed omics dataset. To tackle this bias, we designed a permutation‐based method that empirically evaluates GO terms reported by AMI methods. We used the method to fashion five novel AMI performance criteria. Last, we developed DOMINO, a novel AMI algorithm, that outperformed the other six algorithms in extensive testing on GE and GWAS data. Software is available at https://github.com/Shamir‐Lab.     

COVID‐19 Disease Map,a computational knowledge repository of virus‐host interaction mechanisms

The authors requested to correct the spelling of Egon Willighagen and Andrea Senff‐Ribeiro''s names, as well as the following affiliations: Charles Auffray to: “European Institute for Systems Biology and Medicine (EISBM), Vourles, France”; Noriko Hiori to: “Graduate School of Media and Governance, Keio Research Institute at SFC, Keio University, Kanagawa, Japan”; and Leonard Schmeister to: “Center for Mathematics, Chair of Mathematical Modeling of Biological Systems, Technische Universität München, Garching, Germany and Helmholtz Zentrum München – German Research Center for Environmental Health, Institute of Computational Biology, Neuherberg, Germany”.     

Which Single Intervention Would Do the Most to Improve the Health of Those Living on Less Than $1 Per Day?

Background to the debate: PLoS Medicine is participating in the Council of Science Editors'' global theme issue on poverty and human development on October 22, 2007 (http://www.councilscienceeditors.org/globalthemeissue.cfm). Over 200 scientific and medical journals are taking part. For our theme issue, we asked a wide variety of commentators worldwide—including clinicians, medical researchers, health reporters, policy makers, health activists, and development experts—to name the single intervention that they think would improve the health of those living in poverty. We also asked four individuals living in poor, rural agricultural communities in the Santillana district, province of Huanta, Ayacucho, Peru to give us their response to the question, “What do you think would do the most to improve your health and the health of your family?” (The four community members were Severino Rojas Poma, Mercedes Vargas Soto, Julián De La Cruz Chahua, and Martín Rojas Poma). Our October 2007 Editorial discusses this debate further.     

Phenotypic plasticity in life‐history traits of Daphnia galeata in response to temperature – a comparison across clonal lineages separated in time

Climatic changes are projected to result in rapid adaptive events with considerable phenotypic shifts. In order to reconstruct the impact of increased mean water temperatures during past decades and to reveal possible thermal micro‐evolution, we applied a resurrection ecology approach using dormant eggs of the freshwater keystone species Daphnia galeata. To this end, we compared the adaptive response of D. galeata clones from Lake Constance of two different time periods, 1965–1974 (“historical”) versus 2000–2009 (“recent”), to experimentally increased temperature regimes. In order to distinguish between genetic versus environmentally induced effects, we performed a common garden experiment in a flow‐through system and measured variation in life‐history traits. Experimental thermal regimes were chosen according to natural temperature conditions during the reproductive period of D. galeata in Central European lakes, with one additional temperature regime exceeding the currently observable maximum (+2°C). Increased water temperatures were shown to significantly affect measured life‐history traits, and significant “temperature × clonal age” interactions were revealed. Compared to historical clones, recent clonal lineages exhibited a shorter time to first reproduction and a higher survival rate, which may suggest temperature‐driven micro‐evolution over time but does not allow an explicit conclusion on the adaptive nature of such responses.     

The 2015 Bioinformatics Open Source Conference (BOSC 2015)

The Bioinformatics Open Source Conference (BOSC) is organized by the Open Bioinformatics Foundation (OBF), a nonprofit group dedicated to promoting the practice and philosophy of open source software development and open science within the biological research community. Since its inception in 2000, BOSC has provided bioinformatics developers with a forum for communicating the results of their latest efforts to the wider research community. BOSC offers a focused environment for developers and users to interact and share ideas about standards; software development practices; practical techniques for solving bioinformatics problems; and approaches that promote open science and sharing of data, results, and software. BOSC is run as a two-day special interest group (SIG) before the annual Intelligent Systems in Molecular Biology (ISMB) conference. BOSC 2015 took place in Dublin, Ireland, and was attended by over 125 people, about half of whom were first-time attendees. Session topics included “Data Science;” “Standards and Interoperability;” “Open Science and Reproducibility;” “Translational Bioinformatics;” “Visualization;” and “Bioinformatics Open Source Project Updates”. In addition to two keynote talks and dozens of shorter talks chosen from submitted abstracts, BOSC 2015 included a panel, titled “Open Source, Open Door: Increasing Diversity in the Bioinformatics Open Source Community,” that provided an opportunity for open discussion about ways to increase the diversity of participants in BOSC in particular, and in open source bioinformatics in general. The complete program of BOSC 2015 is available online at http://www.open-bio.org/wiki/BOSC_2015_Schedule.Open in a separate window     

Patterns of genomic and allochronic strain divergence in the fall armyworm,Spodoptera frugiperda (J.E. Smith)

Speciation is the process through which reproductive isolation develops between distinct populations. Because this process takes time, speciation studies often necessarily examine populations within a species that are at various stages of divergence. The fall armyworm, Spodoptera frugiperda (J.E. Smith), is comprised of two strains (R = Rice & C = Corn) that serve as a novel system to explore population divergence in sympatry. Here, we use ddRADSeq data to show that fall armyworm strains in the field are largely genetically distinct, but some interstrain hybridization occurs. Although we detected F1 hybrids of both R‐ and C‐strain maternal origin, only hybrids with R‐strain mtDNA were found to contribute to subsequent generations, possibly indicating a unidirectional barrier to gene flow. Although these strains have been previously defined as “host plant‐associated,” we recovered an equal proportion of R‐ and C‐strain moths in fields dominated by C‐strain host plants. As an alternative to host‐associated divergence, we tested the hypothesis that differences in nightly activity patterns could account for reproductive isolation by genotyping temporally collected moths. Our data indicates that strains exhibit a significant shift in the timing of their nightly activities in the field. This divergence in phenology creates a prezygotic reproductive barrier that likely maintains the genetic isolation between strains. Thus, we conclude that it may be ecologically inaccurate to refer to the C‐ and R‐ strain as “host‐associated” and they should more appropriately be considered “allochronic strains.”     

Uniform binding and negative catalysis at the origin of enzymes

Enzymes are well known for their catalytic abilities, some even reaching “catalytic perfection” in the sense that the reaction they catalyze has reached the physical bound of the diffusion rate. However, our growing understanding of enzyme superfamilies has revealed that only some share a catalytic chemistry while others share a substrate‐handle binding motif, for example, for a particular phosphate group. This suggests that some families emerged through a “substrate‐handle‐binding‐first” mechanism (“binding‐first” for brevity) instead of “chemistry‐first” and we are, therefore, left to wonder what the role of non‐catalytic binders might have been during enzyme evolution. In the last of their eight seminal, back‐to‐back articles from 1976, John Albery and Jeremy Knowles addressed the question of enzyme evolution by arguing that the simplest mode of enzyme evolution is what they defined as “uniform binding” (parallel stabilization of all enzyme‐bound states to the same degree). Indeed, we show that a uniform‐binding proto‐catalyst can accelerate a reaction, but only when catalysis is already present, that is, when the transition state is already stabilized to some degree. Thus, we sought an alternative explanation for the cases where substrate‐handle‐binding preceded any involvement of a catalyst. We find that evolutionary starting points that exhibit negative catalysis can redirect the reaction''s course to a preferred product without need for rate acceleration or product release; that is, if they do not stabilize, or even destabilize, the transition state corresponding to an undesired product. Such a mechanism might explain the emergence of “binding‐first” enzyme families like the aldolase superfamily.     

Phyletic Profiling with Cliques of Orthologs Is Enhanced by Signatures of Paralogy Relationships

New microbial genomes are sequenced at a high pace, allowing insight into the genetics of not only cultured microbes, but a wide range of metagenomic collections such as the human microbiome. To understand the deluge of genomic data we face, computational approaches for gene functional annotation are invaluable. We introduce a novel model for computational annotation that refines two established concepts: annotation based on homology and annotation based on phyletic profiling. The phyletic profiling-based model that includes both inferred orthologs and paralogs—homologs separated by a speciation and a duplication event, respectively—provides more annotations at the same average Precision than the model that includes only inferred orthologs. For experimental validation, we selected 38 poorly annotated Escherichia coli genes for which the model assigned one of three GO terms with high confidence: involvement in DNA repair, protein translation, or cell wall synthesis. Results of antibiotic stress survival assays on E. coli knockout mutants showed high agreement with our model''s estimates of accuracy: out of 38 predictions obtained at the reported Precision of 60%, we confirmed 25 predictions, indicating that our confidence estimates can be used to make informed decisions on experimental validation. Our work will contribute to making experimental validation of computational predictions more approachable, both in cost and time. Our predictions for 998 prokaryotic genomes include ∼400000 specific annotations with the estimated Precision of 90%, ∼19000 of which are highly specific—e.g. “penicillin binding,” “tRNA aminoacylation for protein translation,” or “pathogenesis”—and are freely available at http://gorbi.irb.hr/.     

Vaccines beyond antibodies: Spurred by pandemic research,are T‐cell vaccines moving closer to reality?

Lessons learned from the vaccines against SARS‐CoV‐2 has encouraged research and vaccine development aimed at mustering strong T cell responses against the pathogen. Subject Categories: Microbiology, Virology & Host Pathogen Interaction, Pharmacology & Drug Discovery

The new vaccines against SARS‐CoV‐2 elicited strong antibody responses in initial trials, which encouraged optimism amongst immunologists and public health experts who expected good efficacy. “With viral infections, it is almost unheard of to have a prophylactic vaccine that doesn’t work ultimately by generating neutralising antibody responses”, explained immunologist Kingston Mills at Trinity College Dublin in Ireland. However, the antibody response is not the whole story. “Efforts to explain how immunity is working against viruses to the general public has forced everyone to try to make things so simple that now what is left is a ridiculous oversimplified picture of the vertebrate immune system”, commented Antonio Bertoletti, infectious disease scientist at Duke‐National University of Singapore. In fact, there is increasing research focus on the role of T cells in mediating the cellular response to infections and how to stimulate these cells through vaccines.Antibodies work by recognising and attaching to surface structures of a virus or bacterium, which prevents the pathogen from infecting its target cells and mark it for destruction by other immune cells. However, pathogens can escape the antibody response via mutations that decrease the efficiency of antibodies from infection or vaccination. “You will still potentially get infected if you’re vaccinated, because the antibody response is not as strong as it was”, explained immunologist Luke O’Neill at Trinity College Dublin, Ireland. “But then the T cells will kick in and stop the virus when it is inside cells”. Simply put, antibodies tend to prevent infection, while T cells combat infection and illness. Specifically, CD4 helper T cells primarily encourage B cells to generate antibodies whereas CD8 “killer” T cells eliminate cancerous and virally infected cells.