nils-herrmann/clean_scirepeval huggingface dataset:
The Hong Kong Principles for assessing researchers: Fostering research integrity
Venue: PLoS biology

For knowledge to benefit research and society, it must be trustworthy. Trustworthy research is robust, rigorous, and transparent at all stages of design, execution, and reporting. Assessment of researchers still rarely includes considerations related to trustworthiness, rigor, and transparency. We have developed the Hong Kong Principles (HKPs) as part of the 6th World Conference on Research Integrity with a specific focus on the need to drive research improvement through ensuring that researchers are explicitly recognized and rewarded for behaviors that strengthen research integrity. We present five principles: responsible research practices; transparent reporting; open science (open research); valuing a diversity of types of research; and recognizing all contributions to research and scholarly activity. For each principle, we provide a rationale for its inclusion and provide examples where these principles are already being adopted.
Mechanosensitivity is an essential component of phototransduction in vertebrate rods
Venue: PLoS biology

Photoreceptors are specialized cells devoted to the transduction of the incoming visual signals. Rods are able also to shed from their tip old disks and to synthesize at the base of the outer segment (OS) new disks. By combining electrophysiology, optical tweezers (OTs), and biochemistry, we investigate mechanosensitivity in the rods of Xenopus laevis, and we show that 1) mechanosensitive channels (MSCs), transient receptor potential canonical 1 (TRPC1), and Piezo1 are present in rod inner segments (ISs); 2) mechanical stimulation—of the order of 10 pN—applied briefly to either the OS or IS evokes calcium transients; 3) inhibition of MSCs decreases the duration of photoresponses to bright flashes; 4) bright flashes of light induce a rapid shortening of the OS; and 5) the genes encoding the TRPC family have an ancient association with the genes encoding families of protein involved in phototransduction. These results suggest that MSCs play an integral role in rods’ phototransduction.
The pregnant myometrium is epigenetically activated at contractility-driving gene loci prior to the onset of labor in mice
Venue: PLoS biology

During gestation, uterine smooth muscle cells transition from a state of quiescence to one of contractility, but the molecular mechanisms underlying this transition at a genomic level are not well-known. To better understand these events, we evaluated the epigenetic landscape of the mouse myometrium during the pregnant, laboring, and postpartum stages. We generated gestational time point–specific enrichment profiles for histone H3 acetylation on lysine residue 27 (H3K27ac), histone H3 trimethylation of lysine residue 4 (H3K4me3), and RNA polymerase II (RNAPII) occupancy by chromatin immunoprecipitation with massively parallel sequencing (ChIP-seq), as well as gene expression profiles by total RNA-sequencing (RNA-seq). Our findings reveal that 533 genes, including known contractility-driving genes (Gap junction alpha 1 [Gja1], FBJ osteosarcoma oncogene [Fos], Fos-like antigen 2 [Fosl2], Oxytocin receptor [Oxtr], and Prostaglandin G/H synthase 2 (Ptgs2), for example), are up-regulated at day 19 during active labor because of an increase in transcription at gene bodies. Labor-associated promoters and putative intergenic enhancers, however, are epigenetically activated as early as day 15, by which point the majority of genome-wide H3K27ac or H3K4me3 peaks present in term laboring tissue is already established. Despite this early exhibited histone signature, increased noncoding enhancer RNA (eRNA) production at putative intergenic enhancers and recruitment of RNAPII to the gene bodies of labor-associated loci were detected only during labor. Our findings indicate that epigenetic activation of the myometrial genome precedes active labor by at least 4 days in the mouse model, suggesting that the myometrium is poised for rapid activation of contraction-associated genes in order to exit the state of quiescence.
Age-related accumulation of de novo mitochondrial mutations in mammalian oocytes and somatic tissues
Venue: PLoS biology

Mutations create genetic variation for other evolutionary forces to operate on and cause numerous genetic diseases. Nevertheless, how de novo mutations arise remains poorly understood. Progress in the area is hindered by the fact that error rates of conventional sequencing technologies (1 in 100 or 1,000 base pairs) are several orders of magnitude higher than de novo mutation rates (1 in 10,000,000 or 100,000,000 base pairs per generation). Moreover, previous analyses of germline de novo mutations examined pedigrees (and not germ cells) and thus were likely affected by selection. Here, we applied highly accurate duplex sequencing to detect low-frequency, de novo mutations in mitochondrial DNA (mtDNA) directly from oocytes and from somatic tissues (brain and muscle) of 36 mice from two independent pedigrees. We found mtDNA mutation frequencies 2- to 3-fold higher in 10-month-old than in 1-month-old mice, demonstrating mutation accumulation during the period of only 9 mo. Mutation frequencies and patterns differed between germline and somatic tissues and among mtDNA regions, suggestive of distinct mutagenesis mechanisms. Additionally, we discovered a more pronounced genetic drift of mitochondrial genetic variants in the germline of older versus younger mice, arguing for mtDNA turnover during oocyte meiotic arrest. Our study deciphered for the first time the intricacies of germline de novo mutagenesis using duplex sequencing directly in oocytes, which provided unprecedented resolution and minimized selection effects present in pedigree studies. Moreover, our work provides important information about the origins and accumulation of mutations with aging/maturation and has implications for delayed reproduction in modern human societies. Furthermore, the duplex sequencing method we optimized for single cells opens avenues for investigating low-frequency mutations in other studies.
Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0
Venue: PLoS biology

Improving the reproducibility of biomedical research is a major challenge. Transparent and accurate reporting is vital to this process; it allows readers to assess the reliability of the findings and repeat or build upon the work of other researchers. The ARRIVE guidelines ( Reporting In Vivo Experiments) were developed in 2010 to help authors and journals identify the minimum information necessary to report in publications describing in vivo experiments. Despite widespread endorsement by the scientific community, the impact of ARRIVE on the transparency of reporting in animal research publications has been limited. We have revised the ARRIVE guidelines to update them and facilitate their use in practice. The revised guidelines are published alongside this paper. This explanation and elaboration document was developed as part of the revision. It provides further information about each of the 21 items in ARRIVE 2.0, including the rationale and supporting evidence for their inclusion in the guidelines, elaboration of details to report, and examples of good reporting from the published literature. This document also covers advice and best practice in the design and conduct of animal studies to support researchers in improving standards from the start of the experimental design process through to publication.
PiVR: An affordable and versatile closed-loop platform to study unrestrained sensorimotor behavior
Venue: PLoS biology

Tools enabling closed-loop experiments are crucial to delineate causal relationships between the activity of genetically labeled neurons and specific behaviors. We developed the Raspberry Pi Virtual Reality (PiVR) system to conduct closed-loop optogenetic stimulation of neural functions in unrestrained animals. PiVR is an experimental platform that operates at high temporal resolution (70 Hz) with low latencies (<30 milliseconds), while being affordable (<US$500) and easy to build (<6 hours). Through extensive documentation, this tool was designed to be accessible to a wide public, from high school students to professional researchers studying systems neuroscience. We illustrate the functionality of PiVR by focusing on sensory navigation in response to gradients of chemicals (chemotaxis) and light (phototaxis). We show how Drosophila adult flies perform negative chemotaxis by modulating their locomotor speed to avoid locations associated with optogenetically evoked bitter taste. In Drosophila larvae, we use innate positive chemotaxis to compare behavior elicited by real- and virtual-odor gradients. Finally, we examine how positive phototaxis emerges in zebrafish larvae from the modulation of turning maneuvers to orient in virtual white-light gradients. Besides its application to study chemotaxis and phototaxis, PiVR is a versatile tool designed to bolster efforts to map and to functionally characterize neural circuits.
The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research
Venue: PLoS biology

Reproducible science requires transparent reporting. The ARRIVE guidelines ( Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and divide the items of the guidelines into 2 sets, the “ARRIVE Essential 10,” which constitutes the minimum requirement, and the “Recommended Set,” which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration (E&E) document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts, and (3) to provide illustrative examples. We aim, through these changes, to help ensure that researchers, reviewers, and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.
Rest-task modulation of fMRI-derived global signal topography is mediated by transient coactivation patterns
Venue: PLoS biology

Recent resting-state functional MRI (fMRI) studies have revealed that the global signal (GS) exhibits a nonuniform spatial distribution across the gray matter. Whether this topography is informative remains largely unknown. We therefore tested rest-task modulation of GS topography by analyzing static GS correlation and dynamic coactivation patterns in a large sample of an fMRI dataset (n = 837) from the Human Connectome Project. The GS topography in the resting state and in seven different tasks was first measured by correlating the GS with the local time series (GSCORR). In the resting state, high GSCORR was observed mainly in the primary sensory and motor regions, whereas low GSCORR was seen in the association brain areas. This pattern changed during the seven tasks, with mainly decreased GSCORR in sensorimotor cortex. Importantly, this rest-task modulation of GSCORR could be traced to transient coactivation patterns at the peak period of GS (GS-peak). By comparing the topography of GSCORR and respiration effects, we observed that the topography of respiration mimicked the topography of GS in the resting state, whereas both differed during the task states; because of such partial dissociation, we assume that GSCORR could not be equated with a respiration effect. Finally, rest-task modulation of GS topography could not be exclusively explained by other sources of physiological noise. Together, we here demonstrate the informative nature of GS topography by showing its rest-task modulation, the underlying dynamic coactivation patterns, and its partial dissociation from respiration effects during task states.
Structural basis of human full-length kindlin-3 homotrimer in an auto-inhibited state
Venue: PLoS biology

Kindlin-1, -2, and -3 directly bind integrin β cytoplasmic tails to regulate integrin activation and signaling. Despite their functional significance and links to several diseases, structural information on full-length kindlin proteins remains unknown. Here, we report the crystal structure of human full-length kindlin-3, which reveals a novel homotrimer state. Unlike kindlin-3 monomer, which is the major population in insect and mammalian cell expression systems, kindlin-3 trimer does not bind integrin β cytoplasmic tail as the integrin-binding pocket in the F3 subdomain of 1 protomer is occluded by the pleckstrin homology (PH) domain of another protomer, suggesting that kindlin-3 is auto-inhibited upon trimer formation. This is also supported by functional assays in which kindlin-3 knockout K562 erythroleukemia cells reconstituted with the mutant kindlin-3 containing trimer-disrupting mutations exhibited an increase in integrin-mediated adhesion and spreading on fibronectin compared with those reconstituted with wild-type kindlin-3. Taken together, our findings reveal a novel mechanism of kindlin auto-inhibition that involves its homotrimer formation.
High-fidelity SaCas9 identified by directional screening in human cells
Venue: PLoS biology

CRISPR-Staphylococcus aureus Cas9 (CRISPR-SaCas9) has been harnessed as an effective in vivo genome-editing tool to manipulate genomes. However, off-target effects remain a major bottleneck that precludes safe and reliable applications in genome editing. Here, we characterize the off-target effects of wild-type (WT) SaCas9 at single-nucleotide (single-nt) resolution and describe a directional screening system to identify novel SaCas9 variants with desired properties in human cells. Using this system, we identified enhanced-fidelity SaCas9 (efSaCas9) (variant Mut268 harboring the single mutation of N260D), which could effectively distinguish and reject single base-pair mismatches. We demonstrate dramatically reduced off-target effects (approximately 2- to 93-fold improvements) of Mut268 compared to WT using targeted deep-sequencing analyses. To understand the structural origin of the fidelity enhancement, we find that N260, located in the REC3 domain, orchestrates an extensive network of contacts between REC3 and the guide RNA-DNA heteroduplex. efSaCas9 can be broadly used in genome-editing applications that require high fidelity. Furthermore, this study provides a general strategy to rapidly evolve other desired CRISPR-Cas9 traits besides enhanced fidelity, to expand the utility of the CRISPR toolkit.
Principles for creating a single authoritative list of the world’s species
Venue: PLoS biology

Lists of species underpin many fields of human endeavour, but there are currently no universally accepted principles for deciding which biological species should be accepted when there are alternative taxonomic treatments (and, by extension, which scientific names should be applied to those species). As improvements in information technology make it easier to communicate, access, and aggregate biodiversity information, there is a need for a framework that helps taxonomists and the users of taxonomy decide which taxa and names should be used by society whilst continuing to encourage taxonomic research that leads to new species discoveries, new knowledge of species relationships, and the refinement of existing species concepts. Here, we present 10 principles that can underpin such a governance framework, namely (i) the species list must be based on science and free from nontaxonomic considerations and interference, (ii) governance of the species list must aim for community support and use, (iii) all decisions about list composition must be transparent, (iv) the governance of validated lists of species is separate from the governance of the names of taxa, (v) governance of lists of accepted species must not constrain academic freedom, (vi) the set of criteria considered sufficient to recognise species boundaries may appropriately vary between different taxonomic groups but should be consistent when possible, (vii) a global list must balance conflicting needs for currency and stability by having archived versions, (viii) contributors need appropriate recognition, (ix) list content should be traceable, and (x) a global listing process needs both to encompass global diversity and to accommodate local knowledge of that diversity. We conclude by outlining issues that must be resolved if such a system of taxonomic list governance and a unified list of accepted scientific names generated are to be universally adopted.
Resting-state brain and spinal cord networks in humans are functionally integrated
Venue: PLoS biology

In the absence of any task, both the brain and spinal cord exhibit spontaneous intrinsic activity organised in a set of functionally relevant neural networks. However, whether such resting-state networks (RSNs) are interconnected across the brain and spinal cord is unclear. Here, we used a unique scanning protocol to acquire functional images of both brain and cervical spinal cord (CSC) simultaneously and examined their spatiotemporal correspondence in humans. We show that the brain and spinal cord activities are strongly correlated during rest periods, and specific spinal cord regions are functionally linked to consistently reported brain sensorimotor RSNs. The functional organisation of these networks follows well-established anatomical principles, including the contralateral correspondence between the spinal hemicords and brain hemispheres as well as sensory versus motor segregation of neural pathways along the brain–spinal cord axis. Thus, our findings reveal a unified functional organisation of sensorimotor networks in the entire central nervous system (CNS) at rest.
Paradoxical activation of AMPK by glucose drives selective EP300 activity in colorectal cancer
Venue: PLoS biology

Coordination of gene expression with nutrient availability supports proliferation and homeostasis and is shaped by protein acetylation. Yet how physiological/pathological signals link acetylation to specific gene expression programs and whether such responses are cell-type–specific is unclear. AMP-activated protein kinase (AMPK) is a key energy sensor, activated by glucose limitation to resolve nutrient supply–demand imbalances, critical for diabetes and cancer. Unexpectedly, we show here that, in gastrointestinal cancer cells, glucose activates AMPK to selectively induce EP300, but not CREB-binding protein (CBP). Consequently, EP300 is redirected away from nuclear receptors that promote differentiation towards β-catenin, a driver of proliferation and colorectal tumorigenesis. Importantly, blocking glycogen synthesis permits reactive oxygen species (ROS) accumulation and AMPK activation in response to glucose in previously nonresponsive cells. Notably, glycogen content and activity of the ROS/AMPK/EP300/β-catenin axis are opposite in healthy versus tumor sections. Glycogen content reduction from healthy to tumor tissue may explain AMPK switching from tumor suppressor to activator during tumor evolution.
Different states of priority recruit different neural representations in visual working memory
Venue: PLoS biology

We used functional magnetic resonance imaging (fMRI) to investigate the neural codes for representing stimulus information held in different states of priority in working memory. Human participants (male and female) performed delayed recall for 2 oriented gratings that could appear in any of several locations. Priority status was manipulated by a retrocue, such that one became the prioritized memory item (PMI) and another the unprioritized memory item (UMI). Using inverted encoding models (IEMs), we found that, in early visual cortex, the orientation of the UMI was represented in a neural representation that was rotated relative to the PMI. In intraparietal sulcus (IPS), we observed the analogous effect for the representation of the location of the UMI. Taken together, these results provide evidence for a common remapping mechanism that may be responsible for representing stimulus identity and stimulus context with different levels of priority in working memory.
Mapping trends in insecticide resistance phenotypes in African malaria vectors
Venue: PLoS biology

Mitigating the threat of insecticide resistance in African malaria vector populations requires comprehensive information about where resistance occurs, to what degree, and how this has changed over time. Estimating these trends is complicated by the sparse, heterogeneous distribution of observations of resistance phenotypes in field populations. We use 6,423 observations of the prevalence of resistance to the most important vector control insecticides to inform a Bayesian geostatistical ensemble modelling approach, generating fine-scale predictive maps of resistance phenotypes in mosquitoes from the Anopheles gambiae complex across Africa. Our models are informed by a suite of 111 predictor variables describing potential drivers of selection for resistance. Our maps show alarming increases in the prevalence of resistance to pyrethroids and DDT across sub-Saharan Africa from 2005 to 2017, with mean mortality following insecticide exposure declining from almost 100% to less than 30% in some areas, as well as substantial spatial variation in resistance trends.
The protean prion protein
Venue: PLoS biology

The prion protein, PrP, can adopt at least 2 conformations, the overwhelmingly prevalent cellular conformation (PrPC) and the scrapie conformation (PrPSc). PrPC features a globular C-terminal domain containing 3 α-helices and a short β-sheet and a long flexible N-terminal tail whose exact conformation in vivo is not yet known and a metastable subdomain with β-strand propensity has been identified within it. The PrPSc conformation is very rare and has the characteristics of an amyloid. Furthermore, PrPSc is a prion, i.e., it is infectious. This involves 2 steps: (1) PrPSc can template PrPC and coerce it to adopt the PrPSc conformation and (2) PrPSc can be transmitted between individuals, by oral, parenteral, and other routes and thus propagate as an infectious agent. However, this is a simplification: On the one hand, PrPSc is not a single conformation, but rather, a set of alternative similar but distinct conformations. Furthermore, other amyloid conformations of PrP exist with different biochemical and propagative properties. In this issue of PLOS Biology, Asante and colleagues describe the first murine model of familial human prion disease and demonstrate the emergence and propagation of 2 PrP amyloid conformers. Of these, one causes neurodegeneration, whereas the other does not. With its many conformers, PrP is a truly protean protein.