nils-herrmann/clean_scirepeval huggingface dataset:
Proteolytic Origin of the Soluble Human IL-6R In Vivo and a Decisive Role of N-Glycosylation
Venue: PLoS biology

Signaling of the cytokine interleukin-6 (IL-6) via its soluble IL-6 receptor (sIL-6R) is responsible for the proinflammatory properties of IL-6 and constitutes an attractive therapeutic target, but how the sIL-6R is generated in vivo remains largely unclear. Here, we use liquid chromatography–mass spectrometry to identify an sIL-6R form in human serum that originates from proteolytic cleavage, map its cleavage site between Pro-355 and Val-356, and determine the occupancy of all O- and N-glycosylation sites of the human sIL-6R. The metalloprotease a disintegrin and metalloproteinase 17 (ADAM17) uses this cleavage site in vitro, and mutation of Val-356 is sufficient to completely abrogate IL-6R proteolysis. N- and O-glycosylation were dispensable for signaling of the IL-6R, but proteolysis was orchestrated by an N- and O-glycosylated sequon near the cleavage site and an N-glycan exosite in domain D1. Proteolysis of an IL-6R completely devoid of glycans is significantly impaired. Thus, glycosylation is an important regulator for sIL-6R generation.
A Webcast of Bird Nesting as a State-of-the-Art Citizen Science
Venue: PLoS biology

The quality of people’s knowledge of nature has always had a significant influence on their approach to wildlife and nature conservation. However, direct interactions of people with nature are greatly limited nowadays, especially because of urbanization and modern lifestyles. As a result, our isolation from the natural world has been growing. Here, we present an example of a state-of-the-art Citizen Science project with its educational, scientific, and popularizing benefits. We conclude that modern media and new forms of education offer an effective opportunity for inspiring children and others to have fun learning to act like scientists. This approach provides broad opportunities for developing the hitherto neglected educational potential of Citizen Science.
Marine Reserve Targets to Sustain and Rebuild Unregulated Fisheries
Venue: PLoS biology

Overfishing threatens the sustainability of coastal marine biodiversity, especially in tropical developing countries. To counter this problem, about 200 governments worldwide have committed to protecting 10%–20% of national coastal marine areas. However, associated impacts on fisheries productivity are unclear and could weaken the food security of hundreds of millions of people who depend on diverse and largely unregulated fishing activities. Here, we present a systematic theoretic analysis of the ability of reserves to rebuild fisheries under such complex conditions, and we identify maximum reserve coverages for biodiversity conservation that do not impair long-term fisheries productivity. Our analysis assumes that fishers have no viable alternative to fishing, such that total fishing effort remains constant (at best). We find that realistic reserve networks, which protect 10%–30% of fished habitats in 1–20 km wide reserves, should benefit the long-term productivity of almost any complex fishery. We discover a “rule of thumb” to safeguard against the long-term catch depletion of particular species: individual reserves should export 30% or more of locally produced larvae to adjacent fishing grounds. Specifically on coral reefs, where fishers tend to overexploit species whose dispersal distances as larvae exceed the home ranges of adults, decisions on the size of reserves needed to meet the 30% larval export rule are unlikely to compromise the protection of resident adults. Even achieving the modest Aichi Target 11 of 10% “effective protection” can then help rebuild depleted catch. However, strictly protecting 20%–30% of fished habitats is unlikely to diminish catch even if overfishing is not yet a problem while providing greater potential for biodiversity conservation and fishery rebuilding if overfishing is substantial. These findings are important because they suggest that doubling or tripling the only globally enforced marine reserve target will benefit biodiversity conservation and higher fisheries productivity where both are most urgently needed.
Languages Are Still a Major Barrier to Global Science
Venue: PLoS biology

While it is recognized that language can pose a barrier to the transfer of scientific knowledge, the convergence on English as the global language of science may suggest that this problem has been resolved. However, our survey searching Google Scholar in 16 languages revealed that 35.6% of 75,513 scientific documents on biodiversity conservation published in 2014 were not in English. Ignoring such non-English knowledge can cause biases in our understanding of study systems. Furthermore, as publication in English has become prevalent, scientific knowledge is often unavailable in local languages. This hinders its use by field practitioners and policy makers for local environmental issues; 54% of protected area directors in Spain identified languages as a barrier. We urge scientific communities to make a more concerted effort to tackle this problem and propose potential approaches both for compiling non-English scientific knowledge effectively and for enhancing the multilingualization of new and existing knowledge available only in English for the users of such knowledge.
Transient Duplication-Dependent Divergence and Horizontal Transfer Underlie the Evolutionary Dynamics of Bacterial Cell–Cell Signaling
Venue: PLoS biology

Evolutionary expansion of signaling pathway families often underlies the evolution of regulatory complexity. Expansion requires the acquisition of a novel homologous pathway and the diversification of pathway specificity. Acquisition can occur either vertically, by duplication, or through horizontal transfer, while divergence of specificity is thought to occur through a promiscuous protein intermediate. The way by which these mechanisms shape the evolution of rapidly diverging signaling families is unclear. Here, we examine this question using the highly diversified Rap-Phr cell–cell signaling system, which has undergone massive expansion in the genus Bacillus. To this end, genomic sequence analysis of >300 Bacilli genomes was combined with experimental analysis of the interaction of Rap receptors with Phr autoinducers and downstream targets. Rap-Phr expansion is shown to have occurred independently in multiple Bacillus lineages, with >80 different putative rap-phr alleles evolving in the Bacillius subtilis group alone. The specificity of many rap-phr alleles and the rapid gain and loss of Rap targets are experimentally demonstrated. Strikingly, both horizontal and vertical processes were shown to participate in this expansion, each with a distinct role. Horizontal gene transfer governs the acquisition of already diverged rap-phr alleles, while intralocus duplication and divergence of the phr gene create the promiscuous intermediate required for the divergence of Rap-Phr specificity. Our results suggest a novel role for transient gene duplication and divergence during evolutionary shifts in specificity.
Cell Fate Decision as High-Dimensional Critical State Transition
Venue: PLoS biology

Cell fate choice and commitment of multipotent progenitor cells to a differentiated lineage requires broad changes of their gene expression profile. But how progenitor cells overcome the stability of their gene expression configuration (attractor) to exit the attractor in one direction remains elusive. Here we show that commitment of blood progenitor cells to the erythroid or myeloid lineage is preceded by the destabilization of their high-dimensional attractor state, such that differentiating cells undergo a critical state transition. Single-cell resolution analysis of gene expression in populations of differentiating cells affords a new quantitative index for predicting critical transitions in a high-dimensional state space based on decrease of correlation between cells and concomitant increase of correlation between genes as cells approach a tipping point. The detection of “rebellious cells” that enter the fate opposite to the one intended corroborates the model of preceding destabilization of a progenitor attractor. Thus, early warning signals associated with critical transitions can be detected in statistical ensembles of high-dimensional systems, offering a formal theory-based approach for analyzing single-cell molecular profiles that goes beyond current computational pattern recognition, does not require knowledge of specific pathways, and could be used to predict impending major shifts in development and disease.
Collective Resistance in Microbial Communities by Intracellular Antibiotic Deactivation
Venue: PLoS biology

The structure and composition of bacterial communities can compromise antibiotic efficacy. For example, the secretion of β-lactamase by individual bacteria provides passive resistance for all residents within a polymicrobial environment. Here, we uncover that collective resistance can also develop via intracellular antibiotic deactivation. Real-time luminescence measurements and single-cell analysis demonstrate that the opportunistic human pathogen Streptococcus pneumoniae grows in medium supplemented with chloramphenicol (Cm) when resistant bacteria expressing Cm acetyltransferase (CAT) are present. We show that CAT processes Cm intracellularly but not extracellularly. In a mouse pneumonia model, more susceptible pneumococci survive Cm treatment when coinfected with a CAT-expressing strain. Mathematical modeling predicts that stable coexistence is only possible when antibiotic resistance comes at a fitness cost. Strikingly, CAT-expressing pneumococci in mouse lungs were outcompeted by susceptible cells even during Cm treatment. Our results highlight the importance of the microbial context during infectious disease as a potential complicating factor to antibiotic therapy.
Shedding Light on the Grey Zone of Speciation along a Continuum of Genomic Divergence
Venue: PLoS biology

Speciation results from the progressive accumulation of mutations that decrease the probability of mating between parental populations or reduce the fitness of hybrids—the so-called species barriers. The speciation genomic literature, however, is mainly a collection of case studies, each with its own approach and specificities, such that a global view of the gradual process of evolution from one to two species is currently lacking. Of primary importance is the prevalence of gene flow between diverging entities, which is central in most species concepts and has been widely discussed in recent years. Here, we explore the continuum of speciation thanks to a comparative analysis of genomic data from 61 pairs of populations/species of animals with variable levels of divergence. Gene flow between diverging gene pools is assessed under an approximate Bayesian computation (ABC) framework. We show that the intermediate "grey zone" of speciation, in which taxonomy is often controversial, spans from 0.5% to 2% of net synonymous divergence, irrespective of species life history traits or ecology. Thanks to appropriate modeling of among-locus variation in genetic drift and introgression rate, we clarify the status of the majority of ambiguous cases and uncover a number of cryptic species. Our analysis also reveals the high incidence in animals of semi-isolated species (when some but not all loci are affected by barriers to gene flow) and highlights the intrinsic difficulty, both statistical and conceptual, of delineating species in the grey zone of speciation.
Single-Cell-Based Analysis Highlights a Surge in Cell-to-Cell Molecular Variability Preceding Irreversible Commitment in a Differentiation Process
Venue: PLoS biology

In some recent studies, a view emerged that stochastic dynamics governing the switching of cells from one differentiation state to another could be characterized by a peak in gene expression variability at the point of fate commitment. We have tested this hypothesis at the single-cell level by analyzing primary chicken erythroid progenitors through their differentiation process and measuring the expression of selected genes at six sequential time-points after induction of differentiation. In contrast to population-based expression data, single-cell gene expression data revealed a high cell-to-cell variability, which was masked by averaging. We were able to show that the correlation network was a very dynamical entity and that a subgroup of genes tend to follow the predictions from the dynamical network biomarker (DNB) theory. In addition, we also identified a small group of functionally related genes encoding proteins involved in sterol synthesis that could act as the initial drivers of the differentiation. In order to assess quantitatively the cell-to-cell variability in gene expression and its evolution in time, we used Shannon entropy as a measure of the heterogeneity. Entropy values showed a significant increase in the first 8 h of the differentiation process, reaching a peak between 8 and 24 h, before decreasing to significantly lower values. Moreover, we observed that the previous point of maximum entropy precedes two paramount key points: an irreversible commitment to differentiation between 24 and 48 h followed by a significant increase in cell size variability at 48 h. In conclusion, when analyzed at the single cell level, the differentiation process looks very different from its classical population average view. New observables (like entropy) can be computed, the behavior of which is fully compatible with the idea that differentiation is not a “simple” program that all cells execute identically but results from the dynamical behavior of the underlying molecular network.
Lifemap: Exploring the Entire Tree of Life
Venue: PLoS biology

The Tree of Life (ToL) is meant to be a unique representation of the evolutionary relationships between all species on earth. Huge efforts are made to assemble such a large tree, helped by the decrease of sequencing costs and improved methods to reconstruct and combine phylogenies, but no tool exists today to explore the ToL in its entirety in a satisfying manner. By combining methods used in modern cartography, such as OpenStreetMap, with a new way of representing tree-like structures, I created Lifemap, a tool allowing the exploration of a complete representation of the ToL (between 800,000 and 2.2 million species depending on the data source) in a zoomable interface. A server version of Lifemap also allows users to visualize their own trees. This should help researchers in ecology and evolutionary biology in their everyday work, but may also permit the diffusion to a broader audience of our current knowledge of the evolutionary relationships linking all organisms.
Why Having a (Nonfinancial) Interest Is Not a Conflict of Interest
Venue: PLoS biology

A current debate about conflicts of interest related to biomedical research is to question whether the focus on financial conflicts of interest overshadows “nonfinancial” interests that could put scientific judgment at equal or greater risk of bias. There is substantial evidence that financial conflicts of interest such as commercial sponsorship of research and investigators lead to systematic biases in scientific research at all stages of the research process. Conflation of “conflicts of interest” with “interests” in general serves to muddy the waters about how to manage conflicts of interest. We call for heightened disclosure of conflicts of interest and policy action beyond disclosure as the sole management strategy. We propose a different strategy to manage interests more broadly to ensure fair representation and accountability.
Suppression of Dopamine Neurons Mediates Reward
Venue: PLoS biology

Massive activation of dopamine neurons is critical for natural reward and drug abuse. In contrast, the significance of their spontaneous activity remains elusive. In Drosophila melanogaster, depolarization of the protocerebral anterior medial (PAM) cluster dopamine neurons en masse signals reward to the mushroom body (MB) and drives appetitive memory. Focusing on the functional heterogeneity of PAM cluster neurons, we identified that a single class of PAM neurons, PAM-γ3, mediates sugar reward by suppressing their own activity. PAM-γ3 is selectively required for appetitive olfactory learning, while activation of these neurons in turn induces aversive memory. Ongoing activity of PAM-γ3 gets suppressed upon sugar ingestion. Strikingly, transient inactivation of basal PAM-γ3 activity can substitute for reward and induces appetitive memory. Furthermore, we identified the satiety-signaling neuropeptide Allatostatin A (AstA) as a key mediator that conveys inhibitory input onto PAM-γ3. Our results suggest the significance of basal dopamine release in reward signaling and reveal a circuit mechanism for negative regulation.
Selection for Mitochondrial Quality Drives Evolution of the Germline
Venue: PLoS biology

The origin of the germline–soma distinction is a fundamental unsolved question. Plants and basal metazoans do not have a germline but generate gametes from pluripotent stem cells in somatic tissues (somatic gametogenesis). In contrast, most bilaterians sequester a dedicated germline early in development. We develop an evolutionary model which shows that selection for mitochondrial quality drives germline evolution. In organisms with low mitochondrial replication error rates, segregation of mutations over multiple cell divisions generates variation, allowing selection to optimize gamete quality through somatic gametogenesis. Higher mutation rates promote early germline sequestration. We also consider how oogamy (a large female gamete packed with mitochondria) alters selection on the germline. Oogamy is beneficial as it reduces mitochondrial segregation in early development, improving adult fitness by restricting variation between tissues. But it also limits variation between early-sequestered oocytes, undermining gamete quality. Oocyte variation is restored through proliferation of germline cells, producing more germ cells than strictly needed, explaining the random culling (atresia) of precursor cells in bilaterians. Unlike other models of germline evolution, selection for mitochondrial quality can explain the stability of somatic gametogenesis in plants and basal metazoans, the evolution of oogamy in all plants and animals with tissue differentiation, and the mutational forces driving early germline sequestration in active bilaterians. The origins of predation in motile bilaterians in the Cambrian explosion is likely to have increased rates of tissue turnover and mitochondrial replication errors, in turn driving germline evolution and the emergence of complex developmental processes.
Regulation of the Human Telomerase Gene TERT by Telomere Position Effect—Over Long Distances (TPE-OLD): Implications for Aging and Cancer
Venue: PLoS biology

Telomerase is expressed in early human development and then becomes silenced in most normal tissues. Because ~90% of primary human tumors express telomerase and generally maintain very short telomeres, telomerase is carefully regulated, particularly in large, long-lived mammals. In the current report, we provide substantial evidence for a new regulatory control mechanism of the rate limiting catalytic protein component of telomerase (hTERT) that is determined by the length of telomeres. We document that normal, young human cells with long telomeres have a repressed hTERT epigenetic status (chromatin and DNA methylation), but the epigenetic status is altered when telomeres become short. The change in epigenetic status correlates with altered expression of TERT and genes near to TERT, indicating a change in chromatin. Furthermore, we identified a chromosome 5p telomere loop to a region near TERT in human cells with long telomeres that is disengaged with increased cell divisions as telomeres progressively shorten. Finally, we provide support for a role of the TRF2 protein, and possibly TERRA, in the telomere looping maintenance mechanism through interactions with interstitial TTAGGG repeats. This provides new insights into how the changes in genome structure during replicative aging result in an increased susceptibility to age-related diseases and cancer prior to the initiation of a DNA damage signal.
Lysosomal Re-acidification Prevents Lysosphingolipid-Induced Lysosomal Impairment and Cellular Toxicity
Venue: PLoS biology

Neurodegenerative lysosomal storage disorders (LSDs) are severe and untreatable, and mechanisms underlying cellular dysfunction are poorly understood. We found that toxic lipids relevant to three different LSDs disrupt multiple lysosomal and other cellular functions. Unbiased drug discovery revealed several structurally distinct protective compounds, approved for other uses, that prevent lysosomal and cellular toxicities of these lipids. Toxic lipids and protective agents show unexpected convergence on control of lysosomal pH and re-acidification as a critical component of toxicity and protection. In twitcher mice (a model of Krabbe disease [KD]), a central nervous system (CNS)-penetrant protective agent rescued myelin and oligodendrocyte (OL) progenitors, improved motor behavior, and extended lifespan. Our studies reveal shared principles relevant to several LSDs, in which diverse cellular and biochemical disruptions appear to be secondary to disruption of lysosomal pH regulation by specific lipids. These studies also provide novel protective strategies that confer therapeutic benefits in a mouse model of a severe LSD.
Getting Road Expansion on the Right Track: A Framework for Smart Infrastructure Planning in the Mekong
Venue: PLoS biology

The current unprecedented expansion of infrastructure promises to enhance human wellbeing but risks causing substantial harm to natural ecosystems and the benefits they provide for people. A framework for systematically and proactively identifying the likely benefits and costs of such developments is badly needed. Here, we develop and test at the subregional scale a recently proposed global scheme for comparing the potential gains from new roads for food production with their likely impact on biodiversity and ecosystem services. Working in the Greater Mekong—an exceptionally biodiverse subregion undergoing rapid development—we combined maps of isolation from urban centres, yield gaps, and the current area under 17 crops to estimate where and how far road development could in principle help to increase food production without the need for cropland expansion. We overlaid this information with maps summarising the importance of remaining habitats to terrestrial vertebrates and (as examples of major ecosystem services) to global and local climate regulation. This intersection revealed several largely converted yet relatively low-yielding areas (such as central, eastern, and northeastern Thailand and the Ayeyarwady Delta), where narrowing yield gaps by improving transport links has the potential to substantially increase food production at relatively limited environmental cost. Concentrating new roads and road improvements here while taking strong measures to prevent their spread into areas which are still extensively forested (such as northern Laos, western Yunnan, and southwestern Cambodia) could thus enhance rural livelihoods and regional food production while helping safeguard vital ecosystem services and globally significant biological diversity.