nils-herrmann/clean_scirepeval huggingface dataset:
In vivo clonal analysis reveals spatiotemporal regulation of thalamic nucleogenesis
Venue: PLoS biology

The thalamus, a crucial regulator of cortical functions, is composed of many nuclei arranged in a spatially complex pattern. Thalamic neurogenesis occurs over a short period during mammalian embryonic development. These features have hampered the effort to understand how regionalization, cell divisions, and fate specification are coordinated and produce a wide array of nuclei that exhibit distinct patterns of gene expression and functions. Here, we performed in vivo clonal analysis to track the divisions of individual progenitor cells and spatial allocation of their progeny in the developing mouse thalamus. Quantitative analysis of clone compositions revealed evidence for sequential generation of distinct sets of thalamic nuclei based on the location of the founder progenitor cells. Furthermore, we identified intermediate progenitor cells that produced neurons populating more than one thalamic nuclei, indicating a prolonged specification of nuclear fate. Our study reveals an organizational principle that governs the spatial and temporal progression of cell divisions and fate specification and provides a framework for studying cellular heterogeneity and connectivity in the mammalian thalamus.
The neural system of metacognition accompanying decision-making in the prefrontal cortex
Venue: PLoS biology

Decision-making is usually accompanied by metacognition, through which a decision maker monitors uncertainty regarding a decision and may then consequently revise the decision. These metacognitive processes can occur prior to or in the absence of feedback. However, the neural mechanisms of metacognition remain controversial. One theory proposes an independent neural system for metacognition in the prefrontal cortex (PFC); the other, that metacognitive processes coincide and overlap with the systems used for the decision-making process per se. In this study, we devised a novel “decision–redecision” paradigm to investigate the neural metacognitive processes involved in redecision as compared to the initial decision-making process. The participants underwent a perceptual decision-making task and a rule-based decision-making task during functional magnetic resonance imaging (fMRI). We found that the anterior PFC, including the dorsal anterior cingulate cortex (dACC) and lateral frontopolar cortex (lFPC), were more extensively activated after the initial decision. The dACC activity in redecision positively scaled with decision uncertainty and correlated with individual metacognitive uncertainty monitoring abilities—commonly occurring in both tasks—indicating that the dACC was specifically involved in decision uncertainty monitoring. In contrast, the lFPC activity seen in redecision processing was scaled with decision uncertainty reduction and correlated with individual accuracy changes—positively in the rule-based decision-making task and negatively in the perceptual decision-making task. Our results show that the lFPC was specifically involved in metacognitive control of decision adjustment and was subject to different control demands of the tasks. Therefore, our findings support that a separate neural system in the PFC is essentially involved in metacognition and further, that functions of the PFC in metacognition are dissociable.
Elasticity-based boosting of neuroepithelial nucleokinesis via indirect energy transfer from mother to daughter
Venue: PLoS biology

Neural progenitor cells (NPCs), which are apicobasally elongated and densely packed in the developing brain, systematically move their nuclei/somata in a cell cycle–dependent manner, called interkinetic nuclear migration (IKNM): apical during G2 and basal during G1. Although intracellular molecular mechanisms of individual IKNM have been explored, how heterogeneous IKNMs are collectively coordinated is unknown. Our quantitative cell-biological and in silico analyses revealed that tissue elasticity mechanically assists an initial step of basalward IKNM. When the soma of an M-phase progenitor cell rounds up using actomyosin within the subapical space, a microzone within 10 μm from the surface, which is compressed and elastic because of the apical surface’s contractility, laterally pushes the densely neighboring processes of non–M-phase cells. The pressed processes then recoil centripetally and basally to propel the nuclei/somata of the progenitor’s daughter cells. Thus, indirect neighbor-assisted transfer of mechanical energy from mother to daughter helps efficient brain development.
On ways to overcome the magical capacity limit of working memory
Venue: PLoS biology

The ability to simultaneously process and maintain multiple pieces of information is limited. Over the past 50 years, observational methods have provided a large amount of insight regarding the neural mechanisms that underpin the mental capacity that we refer to as “working memory.” More than 20 years ago, a neural coding scheme was proposed for working memory. As a result of technological developments, we can now not only observe but can also influence brain rhythms in humans. Building on these novel developments, we have begun to externally control brain oscillations in order to extend the limits of working memory.
Ups and downs in early electron cryo-microscopy
Venue: PLoS biology

This is a tale of two scientists who, in their younger days, had their scientific judgement clouded by the promise of a big discovery. Two years later, they found that their conclusions had been considerably exaggerated. They were lucky, though, as their later work would prove to be significant. Now, more than 30 years after those events, they met again and put in writing their understanding of what went wrong.
The gender gap in science: How long until women are equally represented?
Venue: PLoS biology

Women comprise a minority of the Science, Technology, Engineering, Mathematics, and Medicine (STEMM) workforce. Quantifying the gender gap may identify fields that will not reach parity without intervention, reveal underappreciated biases, and inform benchmarks for gender balance among conference speakers, editors, and hiring committees. Using the PubMed and arXiv databases, we estimated the gender of 36 million authors from >100 countries publishing in >6000 journals, covering most STEMM disciplines over the last 15 years, and made a web app allowing easy access to the data (https://lukeholman.github.io/genderGap/). Despite recent progress, the gender gap appears likely to persist for generations, particularly in surgery, computer science, physics, and maths. The gap is especially large in authorship positions associated with seniority, and prestigious journals have fewer women authors. Additionally, we estimate that men are invited by journals to submit papers at approximately double the rate of women. Wealthy countries, notably Japan, Germany, and Switzerland, had fewer women authors than poorer ones. We conclude that the STEMM gender gap will not close without further reforms in education, mentoring, and academic publishing.
Unconventional function of an Achaete-Scute homolog as a terminal selector of nociceptive neuron identity
Venue: PLoS biology

Proneural genes are among the most early-acting genes in nervous system development, instructing blast cells to commit to a neuronal fate. Drosophila Atonal and Achaete-Scute complex (AS-C) genes, as well as their vertebrate orthologs, are basic helix-loop-helix (bHLH) transcription factors with such proneural activity. We show here that a C. elegans AS-C homolog, hlh-4, functions in a fundamentally different manner. In the embryonic, larval, and adult nervous systems, hlh-4 is expressed exclusively in a single nociceptive neuron class, ADL, and its expression in ADL is maintained via transcriptional autoregulation throughout the life of the animal. However, in hlh-4 null mutants, the ADL neuron is generated and still appears neuronal in overall morphology and expression of panneuronal and pansensory features. Rather than acting as a proneural gene, we find that hlh-4 is required for the ADL neuron to function properly, to adopt its correct morphology, to express its unusually large repertoire of olfactory receptor–encoding genes, and to express other known features of terminal ADL identity, including neurotransmitter phenotype, neuropeptides, ion channels, and electrical synapse proteins. hlh-4 is sufficient to induce ADL identity features upon ectopic expression in other neuron types. The expression of ADL terminal identity features is directly controlled by HLH-4 via a phylogenetically conserved E-box motif, which, through bioinformatic analysis, we find to constitute a predictive feature of ADL-expressed terminal identity markers. The lineage that produces the ADL neuron was previously shown to require the conventional, transient proneural activity of another AS-C homolog, hlh-14, demonstrating sequential activities of distinct AS-C-type bHLH genes in neuronal specification. Taken together, we have defined here an unconventional function of an AS-C-type bHLH gene as a terminal selector of neuronal identity and we speculate that such function could be reflective of an ancestral function of an “ur-” bHLH gene.
Dectin-1/2–induced autocrine PGE2 signaling licenses dendritic cells to prime Th2 responses
Venue: PLoS biology

The molecular mechanisms through which dendritic cells (DCs) prime T helper 2 (Th2) responses, including those elicited by parasitic helminths, remain incompletely understood. Here, we report that soluble egg antigen (SEA) from Schistosoma mansoni, which is well known to drive potent Th2 responses, triggers DCs to produce prostaglandin E2 (PGE2), which subsequently—in an autocrine manner—induces OX40 ligand (OX40L) expression to license these DCs to drive Th2 responses. Mechanistically, SEA was found to promote PGE2 synthesis through Dectin-1 and Dectin-2, and via a downstream signaling cascade involving spleen tyrosine kinase (Syk), extracellular signal-regulated kinase (ERK), cytosolic phospholipase A2 (cPLA2), and cyclooxygenase 1 and 2 (COX-1 and COX-2). In addition, this pathway was activated independently of the actions of omega-1 (ω-1), a previously described Th2-priming glycoprotein present in SEA. These findings were supported by in vivo murine data showing that ω-1–independent Th2 priming by SEA was mediated by Dectin-2 and Syk signaling in DCs. Finally, we found that Dectin-2−/−, and to a lesser extent Dectin-1−/− mice, displayed impaired Th2 responses and reduced egg-driven granuloma formation following S. mansoni infection, highlighting the physiological importance of this pathway in Th2 polarization during a helminth infection. In summary, we identified a novel pathway in DCs involving Dectin-1/2-Syk-PGE2-OX40L through which Th2 immune responses are induced.
A noncanonical role for dynamin-1 in regulating early stages of clathrin-mediated endocytosis in non-neuronal cells
Venue: PLoS biology

Dynamin Guanosine Triphosphate hydrolases (GTPases) are best studied for their role in the terminal membrane fission process of clathrin-mediated endocytosis (CME), but they have also been proposed to regulate earlier stages of CME. Although highly enriched in neurons, dynamin-1 (Dyn1) is, in fact, widely expressed along with Dyn2 but inactivated in non-neuronal cells via phosphorylation by glycogen synthase kinase-3 beta (GSK3β) kinase. Here, we study the differential, isoform-specific functions of Dyn1 and Dyn2 as regulators of CME. Endogenously expressed Dyn1 and Dyn2 were fluorescently tagged either separately or together in two cell lines with contrasting Dyn1 expression levels. By quantitative live cell dual- and triple-channel total internal reflection fluorescence microscopy, we find that Dyn2 is more efficiently recruited to clathrin-coated pits (CCPs) than Dyn1, and that Dyn2 but not Dyn1 exhibits a pronounced burst of assembly, presumably into supramolecular collar-like structures that drive membrane scission and clathrin-coated vesicle (CCV) formation. Activation of Dyn1 by acute inhibition of GSK3β results in more rapid endocytosis of transferrin receptors, increased rates of CCP initiation, and decreased CCP lifetimes but did not significantly affect the extent of Dyn1 recruitment to CCPs. Thus, activated Dyn1 can regulate early stages of CME that occur well upstream of fission, even when present at low, substoichiometric levels relative to Dyn2. Under physiological conditions, Dyn1 is activated downstream of epidermal growth factor receptor (EGFR) signaling to alter CCP dynamics. We identify sorting nexin 9 (SNX9) as a preferred binding partner to activated Dyn1 that is partially required for Dyn1-dependent effects on early stages of CCP maturation. Together, we decouple regulatory and scission functions of dynamins and report a scission-independent, isoform-specific regulatory role for Dyn1 in CME.
Mitochondrial nicotinamide adenine dinucleotide reduced (NADH) oxidation links the tricarboxylic acid (TCA) cycle with methionine metabolism and nuclear DNA methylation
Venue: PLoS biology

Mitochondrial function affects many aspects of cellular physiology, and, most recently, its role in epigenetics has been reported. Mechanistically, how mitochondrial function alters DNA methylation patterns in the nucleus remains ill defined. Using a cell culture model of induced mitochondrial DNA (mtDNA) depletion, in this study we show that progressive mitochondrial dysfunction leads to an early transcriptional and metabolic program centered on the metabolism of various amino acids, including those involved in the methionine cycle. We find that this program also increases DNA methylation, which occurs primarily in the genes that are differentially expressed. Maintenance of mitochondrial nicotinamide adenine dinucleotide reduced (NADH) oxidation in the context of mtDNA loss rescues methionine salvage and polyamine synthesis and prevents changes in DNA methylation and gene expression but does not affect serine/folate metabolism or transsulfuration. This work provides a novel mechanistic link between mitochondrial function and epigenetic regulation of gene expression that involves polyamine and methionine metabolism responding to changes in the tricarboxylic acid (TCA) cycle. Given the implications of these findings, future studies across different physiological contexts and in vivo are warranted.
Do non-native species contribute to biodiversity?
Venue: PLoS biology

The Convention on Biological Diversity (CBD) emphasises the role of biodiversity in delivering benefits essential for all people and, as a result, seeks to safeguard all life-forms. The indices that are used to measure progress towards international conservation and sustainability goals, however, focus solely on the ‘native’ component of biodiversity. A subset of non-native species can cause undesirable economic, social, or biological effects. But non-native species also contribute to regional biodiversity (species richness and biotic interactions) and ecosystem services. In some regions and cities, non-native species make up more than half of all species. Currently, the contributions of these species to biodiversity and ecosystem services are overlooked. Here, I argue that biodiversity and sustainability indices should include all species. This is not only consistent with definitions of biodiversity but also will promote the idea that long-term, sustainable, human well-being is intricately tied to benefits derived from nature.
Laboratory mouse housing conditions can be improved using common environmental enrichment without compromising data
Venue: PLoS biology

Animal welfare requires the adequate housing of animals to ensure health and well-being. The application of environmental enrichment is a way to improve the well-being of laboratory animals. However, it is important to know whether these enrichment items can be incorporated in experimental mouse husbandry without creating a divide between past and future experimental results. Previous small-scale studies have been inconsistent throughout the literature, and it is not yet completely understood whether and how enrichment might endanger comparability of results of scientific experiments. Here, we measured the effect on means and variability of 164 physiological parameters in 3 conditions: with nesting material with or without a shelter, comparing these 2 conditions to a “barren” regime without any enrichments. We studied a total of 360 mice from each of 2 mouse strains (C57BL/6NTac and DBA/2NCrl) and both sexes for each of the 3 conditions. Our study indicates that enrichment affects the mean values of some of the 164 parameters with no consistent effects on variability. However, the influence of enrichment appears negligible compared to the effects of other influencing factors. Therefore, nesting material and shelters may be used to improve animal welfare without impairment of experimental outcome or loss of comparability to previous data collected under barren housing conditions.
Biocuration: Distilling data into knowledge
Venue: PLoS biology

Data, including information generated from them by processing and analysis, are an asset with measurable value. The assets that biological research funding produces are the data generated, the information derived from these data, and, ultimately, the discoveries and knowledge these lead to. From the time when Henry Oldenburg published the first scientific journal in 1665 ( to the founding of the United States National Library of Medicine in 1879 to the present, there has been a sustained drive to improve how researchers can record and discover what is known. Researchers’ experimental work builds upon years and (collectively) billions of dollars’ worth of earlier work. Today, researchers are generating data at ever-faster rates because of advances in instrumentation and technology, coupled with decreases in production costs. Unfortunately, the ability of researchers to manage and disseminate their results has not kept pace, so their work cannot achieve its maximal impact. Strides have recently been made, but more awareness is needed of the essential role that biological data resources, including biocuration, play in maintaining and linking this ever-growing flood of data and information. The aim of this paper is to describe the nature of data as an asset, the role biocurators play in increasing its value, and consistent, practical means to measure effectiveness that can guide planning and justify costs in biological research information resources’ development and management.
Organic cation transporter 1 (OCT1) modulates multiple cardiometabolic traits through effects on hepatic thiamine content
Venue: PLoS biology

A constellation of metabolic disorders, including obesity, dysregulated lipids, and elevations in blood glucose levels, has been associated with cardiovascular disease and diabetes. Analysis of data from recently published genome-wide association studies (GWAS) demonstrated that reduced-function polymorphisms in the organic cation transporter, OCT1 (SLC22A1), are significantly associated with higher total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride (TG) levels and an increased risk for type 2 diabetes mellitus, yet the mechanism linking OCT1 to these metabolic traits remains puzzling. Here, we show that OCT1, widely characterized as a drug transporter, plays a key role in modulating hepatic glucose and lipid metabolism, potentially by mediating thiamine (vitamin B1) uptake and hence its levels in the liver. Deletion of Oct1 in mice resulted in reduced activity of thiamine-dependent enzymes, including pyruvate dehydrogenase (PDH), which disrupted the hepatic glucose–fatty acid cycle and shifted the source of energy production from glucose to fatty acids, leading to a reduction in glucose utilization, increased gluconeogenesis, and altered lipid metabolism. In turn, these effects resulted in increased total body adiposity and systemic levels of glucose and lipids. Importantly, wild-type mice on thiamine deficient diets (TDs) exhibited impaired glucose metabolism that phenocopied Oct1 deficient mice. Collectively, our study reveals a critical role of hepatic thiamine deficiency through OCT1 deficiency in promoting the metabolic inflexibility that leads to the pathogenesis of cardiometabolic disease.
The ecology of immune state in a wild mammal, Mus musculus domesticus
Venue: PLoS biology

The immune state of wild animals is largely unknown. Knowing this and what affects it is important in understanding how infection and disease affects wild animals. The immune state of wild animals is also important in understanding the biology of their pathogens, which is directly relevant to explaining pathogen spillover among species, including to humans. The paucity of knowledge about wild animals' immune state is in stark contrast to our exquisitely detailed understanding of the immunobiology of laboratory animals. Making an immune response is costly, and many factors (such as age, sex, infection status, and body condition) have individually been shown to constrain or promote immune responses. But, whether or not these factors affect immune responses and immune state in wild animals, their relative importance, and how they interact (or do not) are unknown. Here, we have investigated the immune ecology of wild house mice—the same species as the laboratory mouse—as an example of a wild mammal, characterising their adaptive humoral, adaptive cellular, and innate immune state. Firstly, we show how immune variation is structured among mouse populations, finding that there can be extensive immune discordance among neighbouring populations. Secondly, we identify the principal factors that underlie the immunological differences among mice, showing that body condition promotes and age constrains individuals’ immune state, while factors such as microparasite infection and season are comparatively unimportant. By applying a multifactorial analysis to an immune system-wide analysis, our results bring a new and unified understanding of the immunobiology of a wild mammal.
The rostromedial tegmental nucleus is essential for non-rapid eye movement sleep
Venue: PLoS biology

The rostromedial tegmental nucleus (RMTg), also called the GABAergic tail of the ventral tegmental area, projects to the midbrain dopaminergic system, dorsal raphe nucleus, locus coeruleus, and other regions. Whether the RMTg is involved in sleep–wake regulation is unknown. In the present study, pharmacogenetic activation of rat RMTg neurons promoted non-rapid eye movement (NREM) sleep with increased slow-wave activity (SWA). Conversely, rats after neurotoxic lesions of 8 or 16 days showed decreased NREM sleep with reduced SWA at lights on. The reduced SWA persisted at least 25 days after lesions. Similarly, pharmacological and pharmacogenetic inactivation of rat RMTg neurons decreased NREM sleep. Electrophysiological experiments combined with optogenetics showed a direct inhibitory connection between the terminals of RMTg neurons and midbrain dopaminergic neurons. The bidirectional effects of the RMTg on the sleep–wake cycle were mimicked by the modulation of ventral tegmental area (VTA)/substantia nigra compacta (SNc) dopaminergic neuronal activity using a pharmacogenetic approach. Furthermore, during the 2-hour recovery period following 6-hour sleep deprivation, the amount of NREM sleep in both the lesion and control rats was significantly increased compared with baseline levels; however, only the control rats showed a significant increase in SWA compared with baseline levels. Collectively, our findings reveal an essential role of the RMTg in the promotion of NREM sleep and homeostatic regulation.