nils-herrmann/clean_scirepeval huggingface dataset:
Autophagy is essential for maintaining the growth of a human (mini-)organ: Evidence from scalp hair follicle organ culture
Venue: PLoS biology

Autophagy plays a crucial role in health and disease, regulating central cellular processes such as adaptive stress responses, differentiation, tissue development, and homeostasis. However, the role of autophagy in human physiology is poorly understood, highlighting a need for a model human organ system to assess the efficacy and safety of strategies to therapeutically modulate autophagy. As a complete, cyclically remodelled (mini-)organ, the organ culture of human scalp hair follicles (HFs), which, after massive growth (anagen), spontaneously enter into an apoptosis-driven organ involution (catagen) process, may provide such a model. Here, we reveal that in anagen, hair matrix keratinocytes (MKs) of organ-cultured HFs exhibit an active autophagic flux, as documented by evaluation of endogenous lipidated Light Chain 3B (LC3B) and sequestosome 1 (SQSTM1/p62) proteins and the ultrastructural visualization of autophagosomes at all stages of the autophagy process. This autophagic flux is altered during catagen, and genetic inhibition of autophagy promotes catagen development. Conversely, an anti–hair loss product markedly enhances intrafollicular autophagy, leading to anagen prolongation. Collectively, our data reveal a novel role of autophagy in human hair growth. Moreover, we show that organ-cultured scalp HFs are an excellent preclinical research model for exploring the role of autophagy in human tissue physiology and for evaluating the efficacy and tissue toxicity of candidate autophagy-modulatory agents in a living human (mini-)organ.
Rapid evolution of a voltage-gated sodium channel gene in a lineage of electric fish leads to a persistent sodium current
Venue: PLoS biology

Most weakly electric fish navigate and communicate by sensing electric signals generated by their muscle-derived electric organs. Adults of one lineage (Apteronotidae), which discharge their electric organs in excess of 1 kHz, instead have an electric organ derived from the axons of specialized spinal neurons (electromotorneurons [EMNs]). EMNs fire spontaneously and are the fastest-firing neurons known. This biophysically extreme phenotype depends upon a persistent sodium current, the molecular underpinnings of which remain unknown. We show that a skeletal muscle–specific sodium channel gene duplicated in this lineage and, within approximately 2 million years, began expressing in the spinal cord, a novel site of expression for this isoform. Concurrently, amino acid replacements that cause a persistent sodium current accumulated in the regions of the channel underlying inactivation. Therefore, a novel adaptation allowing extreme neuronal firing arose from the duplication, change in expression, and rapid sequence evolution of a muscle-expressing sodium channel gene.
Evaluation of e-liquid toxicity using an open-source high-throughput screening assay
Venue: PLoS biology

The e-liquids used in electronic cigarettes (E-cigs) consist of propylene glycol (PG), vegetable glycerin (VG), nicotine, and chemical additives for flavoring. There are currently over 7,700 e-liquid flavors available, and while some have been tested for toxicity in the laboratory, most have not. Here, we developed a 3-phase, 384-well, plate-based, high-throughput screening (HTS) assay to rapidly triage and validate the toxicity of multiple e-liquids. Our data demonstrated that the PG/VG vehicle adversely affected cell viability and that a large number of e-liquids were more toxic than PG/VG. We also performed gas chromatography–mass spectrometry (GC-MS) analysis on all tested e-liquids. Subsequent nonmetric multidimensional scaling (NMDS) analysis revealed that e-liquids are an extremely heterogeneous group. Furthermore, these data indicated that (i) the more chemicals contained in an e-liquid, the more toxic it was likely to be and (ii) the presence of vanillin was associated with higher toxicity values. Further analysis of common constituents by electron ionization revealed that the concentration of cinnamaldehyde and vanillin, but not triacetin, correlated with toxicity. We have also developed a publicly available searchable website (www.eliquidinfo.org). Given the large numbers of available e-liquids, this website will serve as a resource to facilitate dissemination of this information. Our data suggest that an HTS approach to evaluate the toxicity of multiple e-liquids is feasible. Such an approach may serve as a roadmap to enable bodies such as the Food and Drug Administration (FDA) to better regulate e-liquid composition.
Experiments in interdisciplinarity: Responsible research and innovation and the public good
Venue: PLoS biology

In Europe, responsible research and innovation (RRI) has emerged as a science policy measure that demands the early integration of a broad range of social actors and perspectives into research and development (R&D). More collaboration of the social sciences and humanities (SSH) with science and engineering appears within this policy framework as a crucial element that will enable better technological development. However, RRI is new to both natural scientists and SSH scholars, and interdisciplinary collaborations are challenging for many reasons. In this paper, we discuss these challenges while suggesting that what RRI can be in a particular project is not a given but remains an empirical question. Natural scientists and SSH scholars need to coresearch RRI in an experimental mode.
Towards an integrated view of vocal development
Venue: PLoS biology

Vocal development is usually studied from the perspective of neuroscience. In this issue, Zhang and Ghazanfar propose a way in which body growth might condition the process. They study the vocalizations of marmoset infants with a wide range of techniques that include computational models and experiments that mimic growth reversal. Their results suggest that the qualitative changes that occur during development are rooted in the nonlinear interaction between the nervous system and the biomechanics involved in respiration. This work illustrates how an integrative approach enriches our understanding of behavior.
Inflammation arising from obesity reduces taste bud abundance and inhibits renewal
Venue: PLoS biology

Despite evidence that the ability to taste is weakened by obesity and can be rescued with weight loss intervention, few studies have investigated the molecular effects of obesity on the taste system. Taste bud cells undergo continual turnover even in adulthood, exhibiting an average life span of only a few weeks, tightly controlled by a balance of proliferation and cell death. Recent data reveal that an acute inflammation event can alter this balance. We demonstrate that chronic low-grade inflammation brought on by obesity reduces the number of taste buds in gustatory tissues of mice—and is likely the cause of taste dysfunction seen in obese populations—by upsetting this balance of renewal and cell death.
Memory instability as a gateway to generalization
Venue: PLoS biology

Our present frequently resembles our past. Patterns of actions and events repeat throughout our lives like a motif. Identifying and exploiting these patterns are fundamental to many behaviours, from creating grammar to the application of skill across diverse situations. Such generalization may be dependent upon memory instability. Following their formation, memories are unstable and able to interact with one another, allowing, at least in principle, common features to be extracted. Exploiting these common features creates generalized knowledge that can be applied across varied circumstances. Memory instability explains many of the biological and behavioural conditions necessary for generalization and offers predictions for how generalization is produced.
Which experimental systems should we use for human microbiome science?
Venue: PLoS biology

Microbiome science is revealing that the phenotype and health of animals, including humans, depend on the sustained function of their resident microorganisms. In this essay, I argue for thoughtful choice of model systems for human microbiome science. A greater variety of experimental systems, including wider use of invertebrate models, would benefit biomedical research, while systems ill-suited to experimental and genetic manipulation can be used to address very limited sets of scientific questions. Microbiome science benefits from the coordinated use of multiple systems, which is facilitated by networks of researchers with expertise in different experimental systems.
A population genetic interpretation of GWAS findings for human quantitative traits
Venue: PLoS biology

Human genome-wide association studies (GWASs) are revealing the genetic architecture of anthropomorphic and biomedical traits, i.e., the frequencies and effect sizes of variants that contribute to heritable variation in a trait. To interpret these findings, we need to understand how genetic architecture is shaped by basic population genetics processes—notably, by mutation, natural selection, and genetic drift. Because many quantitative traits are subject to stabilizing selection and because genetic variation that affects one trait often affects many others, we model the genetic architecture of a focal trait that arises under stabilizing selection in a multidimensional trait space. We solve the model for the phenotypic distribution and allelic dynamics at steady state and derive robust, closed-form solutions for summary statistics of the genetic architecture. Our results provide a simple interpretation for missing heritability and why it varies among traits. They predict that the distribution of variances contributed by loci identified in GWASs is well approximated by a simple functional form that depends on a single parameter: the expected contribution to genetic variance of a strongly selected site affecting the trait. We test this prediction against the results of GWASs for height and body mass index (BMI) and find that it fits the data well, allowing us to make inferences about the degree of pleiotropy and mutational target size for these traits. Our findings help to explain why the GWAS for height explains more of the heritable variance than the similarly sized GWAS for BMI and to predict the increase in explained heritability with study sample size. Considering the demographic history of European populations, in which these GWASs were performed, we further find that most of the associations they identified likely involve mutations that arose shortly before or during the Out-of-Africa bottleneck at sites with selection coefficients around s = 10−3.
Negative regulation of amino acid signaling by MAPK-regulated 4F2hc/Girdin complex
Venue: PLoS biology

Amino acid signaling mediated by the activation of mechanistic target of rapamycin complex 1 (mTORC1) is fundamental to cell growth and metabolism. However, how cells negatively regulate amino acid signaling remains largely unknown. Here, we show that interaction between 4F2 heavy chain (4F2hc), a subunit of multiple amino acid transporters, and the multifunctional hub protein girders of actin filaments (Girdin) down-regulates mTORC1 activity. 4F2hc interacts with Girdin in mitogen-activated protein kinase (MAPK)- and amino acid signaling–dependent manners to translocate to the lysosome. The resultant decrease in cell surface 4F2hc leads to lowered cytoplasmic glutamine (Gln) and leucine (Leu) content, which down-regulates amino acid signaling. Consistently, Girdin depletion augments amino acid-induced mTORC1 activation and inhibits amino acid deprivation–induced autophagy. These findings uncovered the mechanism underlying negative regulation of amino acid signaling, which may play a role in tightly regulated cell growth and metabolism.
The speed of parietal theta frequency drives visuospatial working memory capacity
Venue: PLoS biology

The speed of theta brain oscillatory activity is thought to play a key role in determining working memory (WM) capacity. Individual differences in the length of a theta cycle (ranging between 4 and 7 Hz) might determine how many gamma cycles (>30 Hz) can be nested into a theta wave. Gamma cycles are thought to represent single memory items; therefore, this interplay could determine individual memory capacity. We directly tested this hypothesis by means of parietal transcranial alternating current stimulation (tACS) set at slower (4 Hz) and faster (7 Hz) theta frequencies during a visuospatial WM paradigm. Accordingly, we found that 4-Hz tACS enhanced WM capacity, while 7-Hz tACS reduced WM capacity. Notably, these effects were found only for items presented to the hemifield contralateral to the stimulation site. This provides causal evidence for a frequency-dependent and spatially specific organization of WM storage, supporting the theta–gamma phase coupling theory of WM capacity.
Taxonomy based on science is necessary for global conservation
Venue: PLoS biology

Author(s): Thomson, Scott A; Pyle, Richard L; Ahyong, Shane T; Alonso-Zarazaga, Miguel; Ammirati, Joe; Araya, Juan Francisco; Ascher, John S; Audisio, Tracy Lynn; Azevedo-Santos, Valter M; Bailly, Nicolas; Baker, William J; Balke, Michael; Barclay, Maxwell VL; Barrett, Russell L; Benine, Ricardo C; Bickerstaff, James RM; Bouchard, Patrice; Bour, Roger; Bourgoin, Thierry; Boyko, Christopher B; Breure, Abraham SH; Brothers, Denis J; Byng, James W; Campbell, David; Ceriaco, Luis MP; Cernak, Istvan; Cerretti, Pierfilippo; Chang, Chih-Han; Cho, Soowon; Copus, Joshua M; Costello, Mark J; Cseh, Andras; Csuzdi, Csaba; Culham, Alastair; D'Elia, Guillermo; d'Udekem d'Acoz, Cedric; Daneliya, Mikhail E; Dekker, Rene; Dickinson, Edward C; Dickinson, Timothy A; van Dijk, Peter Paul; Dijkstra, Klaas-Douwe B; Dima, Balint; Dmitriev, Dmitry A; Duistermaat, Leni; Dumbacher, John P; Eiserhardt, Wolf L; Ekrem, Torbjorn; Evenhuis, Neal L; Faille, Arnaud; Fernandez-Triana, Jose L; Fiesler, Emile; Fishbein, Mark; Fordham, Barry G; Freitas, Andre VL; Friol, Natalia R; Fritz, Uwe; Froslev, Tobias; Funk, Vicki A; Gaimari, Stephen D; Garbino, Guilherme ST; Garraffoni, Andre RS; Geml, Jozsef; Gill, Anthony C; Gray, Alan; Grazziotin, Felipe G; Greenslade, Penelope; Gutierrez,  He, Kai; He, Xiaolan; Helfer, Stephan; Helgen, Kristofer M; van Heteren, Anneke H; Hita Garcia, Francisco; Holstein, Norbert; Horvath, Margit K; Hovenkamp, Peter H; Hwang, Wei Song; Hyvonen, Jaakko; Islam, Melissa B; Iverson, John B; Ivie, Michael A; Jaafar,
Modifying and reacting to the environmental pH can drive bacterial interactions
Venue: PLoS biology

Microbes usually exist in communities consisting of myriad different but interacting species. These interactions are typically mediated through environmental modifications; microbes change the environment by taking up resources and excreting metabolites, which affects the growth of both themselves and also other microbes. We show here that the way microbes modify their environment and react to it sets the interactions within single-species populations and also between different species. A very common environmental modification is a change of the environmental pH. We find experimentally that these pH changes create feedback loops that can determine the fate of bacterial populations; they can either facilitate or inhibit growth, and in extreme cases will cause extinction of the bacterial population. Understanding how single species change the pH and react to these changes allowed us to estimate their pairwise interaction outcomes. Those interactions lead to a set of generic interaction motifs—bistability, successive growth, extended suicide, and stabilization—that may be independent of which environmental parameter is modified and thus may reoccur in different microbial systems.
Recurrent excitation between motoneurones propagates across segments and is purely glutamatergic
Venue: PLoS biology

Spinal motoneurones (Mns) constitute the final output for the execution of motor tasks. In addition to innervating muscles, Mns project excitatory collateral connections to Renshaw cells (RCs) and other Mns, but the latter have received little attention. We show that Mns receive strong synaptic input from other Mns throughout development and into maturity, with fast-type Mns systematically receiving greater recurrent excitation than slow-type Mns. Optical recordings show that activation of Mns in one spinal segment can propagate to adjacent segments even in the presence of intact recurrent inhibition. While it is known that transmission at the neuromuscular junction is purely cholinergic and RCs are excited through both acetylcholine and glutamate receptors, here we show that neurotransmission between Mns is purely glutamatergic, indicating that synaptic transmission systems are differentiated at different postsynaptic targets of Mns.
Science-based taxonomy still needs better governance: Response to Thomson et al.
Venue: PLoS biology

We thank Thompson et al.  for engaging in public debate on improving the governance of taxonomy, even if we are not completely in agreement [2]. As it happens, we think most of their arguments, and concerns about our suggestions, are based on a false premise—it is not we who confuse taxonomy and nomenclature—in fact, nomenclatural rules for taxonomy are a superb example of science governing itself to create a globally acceptable process for naming taxa in an orderly manner. However, the suggestion that they can be tweaked to exclude ‘taxonomic vandals’ may do exactly what we have been accused of doing—stifle taxonomic research. We wish neither to prevent mavericks publishing nor inhibit the excellent work done by the many authors who have contributed to Thomson et al.’s paper. Rather, what we wish to stimulate is a constructive discussion of the process of testing taxonomic hypotheses before they are accepted, not before they are published—this is governance of taxonomy, not nomenclature. Thomson et al.’s suggestion that legislators change their understanding of species to accommodate modern taxonomic thought is unlikely to happen while there is disagreement about species definitions. Instead, even now, lawyers are actively seeking to impose their own definitions of species, as demonstrated by a recent petition for the United States to adopt the Biological Species Concept as the taxonomic standard for the Endangered Species Act . We proposed a process whereby taxonomists themselves could take the initiative, with lawyers providing advice on the wording of definitions that would make them defensible from just the sort of legal approach now the subject of the petition. Now it seems taxonomists will be advising lawyers on species definitions, not the other way around. Given the increasing economic impact of taxonomic decisions, one might indeed have expected the Convention on International Trade in Endangered Species (CITES)  and International Union for Conservation of Nature (IUCN)  to provide a solution, as Thomson et al. suggest. However, both organisations lack a clear governance system for managing taxonomic change in a systematic way. Instead, they follow different taxonomic references for the same groups, with many of the standard texts long out of date. For example, one of the avian texts under CITES dates back to 1975 . In our view, there remain two problems for taxonomic governance outside the realms of nomenclature. The one to which we tried to draw attention, the differing standards for species definition adopted for mammals and birds, may currently be insoluble, the differences too deeply institutionalised and our proposals doomed, at least in the short term. As noted above, the law may take this out of the hands of taxonomists anyway. The other is a need for legitimised global checklists that conservation authorities can follow. As Thomson et al. note, many such lists are in place or under development, with even the authors of the four competing global bird checklists now in conversation about how to
Early uneven ear input induces long-lasting differences in left–right motor function
Venue: PLoS biology

How asymmetries in motor behavior become established normally or atypically in mammals remains unclear. An established model for motor asymmetry that is conserved across mammals can be obtained by experimentally inducing asymmetric striatal dopamine activity. However, the factors that can cause motor asymmetries in the absence of experimental manipulations to the brain remain unknown. Here, we show that mice with inner ear dysfunction display a robust left or right rotational preference, and this motor preference reflects an atypical asymmetry in cortico-striatal neurotransmission. By unilaterally targeting striatal activity with an antagonist of extracellular signal-regulated kinase (ERK), a downstream integrator of striatal neurotransmitter signaling, we can reverse or exaggerate rotational preference in these mice. By surgically biasing vestibular failure to one ear, we can dictate the direction of motor preference, illustrating the influence of uneven vestibular failure in establishing the outward asymmetries in motor preference. The inner ear–induced striatal asymmetries identified here intersect with non–ear-induced asymmetries previously linked to lateralized motor behavior across species and suggest that aspects of left–right brain function in mammals can be ontogenetically influenced by inner ear input. Consistent with inner ear input contributing to motor asymmetry, we also show that, in humans with normal ear function, the motor-dominant hemisphere, measured as handedness, is ipsilateral to the ear with weaker vestibular input.
Meta-research: Why research on research matters
Venue: PLoS biology

Meta-research is the study of research itself: its methods, reporting, reproducibility, evaluation, and incentives. Given that science is the key driver of human progress, improving the efficiency of scientific investigation and yielding more credible and more useful research results can translate to major benefits. The research enterprise grows very fast. Both new opportunities for knowledge and innovation and new threats to validity and scientific integrity emerge. Old biases abound, and new ones continuously appear as novel disciplines emerge with different standards and challenges. Meta-research uses an interdisciplinary approach to study, promote, and defend robust science. Major disruptions are likely to happen in the way we pursue scientific investigation, and it is important to ensure that these disruptions are evidence based.
Late Maastrichtian pterosaurs from North Africa and mass extinction of Pterosauria at the Cretaceous-Paleogene boundary
Venue: PLoS biology

Pterosaurs were the first vertebrates to evolve powered flight and the largest animals to ever take wing. The pterosaurs persisted for over 150 million years before disappearing at the end of the Cretaceous, but the patterns of and processes driving their extinction remain unclear. Only a single family, Azhdarchidae, is definitively known from the late Maastrichtian, suggesting a gradual decline in diversity in the Late Cretaceous, with the Cretaceous–Paleogene (K-Pg) extinction eliminating a few late-surviving species. However, this apparent pattern may simply reflect poor sampling of fossils. Here, we describe a diverse pterosaur assemblage from the late Maastrichtian of Morocco that includes not only Azhdarchidae but the youngest known Pteranodontidae and Nyctosauridae. With 3 families and at least 7 species present, the assemblage represents the most diverse known Late Cretaceous pterosaur assemblage and dramatically increases the diversity of Maastrichtian pterosaurs. At least 3 families—Pteranodontidae, Nyctosauridae, and Azhdarchidae—persisted into the late Maastrichtian. Late Maastrichtian pterosaurs show increased niche occupation relative to earlier, Santonian-Campanian faunas and successfully outcompeted birds at large sizes. These patterns suggest an abrupt mass extinction of pterosaurs at the K-Pg boundary.