nils-herrmann/clean_scirepeval huggingface dataset:
DENR–MCTS1 heterodimerization and tRNA recruitment are required for translation reinitiation
Venue: PLoS biology

The succession of molecular events leading to eukaryotic translation reinitiation—whereby ribosomes terminate translation of a short open reading frame (ORF), resume scanning, and then translate a second ORF on the same mRNA—is not well understood. Density-regulated reinitiation and release factor (DENR) and multiple copies in T-cell lymphoma-1 (MCTS1) are implicated in promoting translation reinitiation both in vitro in translation extracts and in vivo. We present here the crystal structure of MCTS1 bound to a fragment of DENR. Based on this structure, we identify and experimentally validate that DENR residues Glu42, Tyr43, and Tyr46 are important for MCTS1 binding and that MCTS1 residue Phe104 is important for tRNA binding. Mutation of these residues reveals that DENR-MCTS1 dimerization and tRNA binding are both necessary for DENR and MCTS1 to promote translation reinitiation in human cells. These findings thereby link individual residues of DENR and MCTS1 to specific molecular functions of the complex. Since DENR–MCTS1 can bind tRNA in the absence of the ribosome, this suggests the DENR–MCTS1 complex could recruit tRNA to the ribosome during reinitiation analogously to the eukaryotic initiation factor 2 (eIF2) complex in cap-dependent translation.
A sensory-motor neuron type mediates proprioceptive coordination of steering in C. elegans via two TRPC channels
Venue: PLoS biology

Animal locomotion is mediated by a sensory system referred to as proprioception. Defects in the proprioceptive coordination of locomotion result in uncontrolled and inefficient movements. However, the molecular mechanisms underlying proprioception are not fully understood. Here, we identify two transient receptor potential cation (TRPC) channels, trp-1 and trp-2, as necessary and sufficient for proprioceptive responses in C. elegans head steering locomotion. Both channels are expressed in the SMDD neurons, which are required and sufficient for head bending, and mediate coordinated head steering by sensing mechanical stretches due to the contraction of head muscle and orchestrating dorsal head muscle contractions. Moreover, the SMDD neurons play dual roles to sense muscle stretch as well as to control muscle contractions. These results demonstrate that distinct locomotion patterns require dynamic and homeostatic modulation of feedback signals between neurons and muscles.
METTL3-mediated m6A modification is required for cerebellar development
Venue: PLoS biology

N6-methyladenosine (m6A) RNA methylation is the most abundant modification on mRNAs and plays important roles in various biological processes. The formation of m6A is catalyzed by a methyltransferase complex including methyltransferase-like 3 (METTL3) as a key factor. However, the in vivo functions of METTL3 and m6A modification in mammalian development remain unclear. Here, we show that specific inactivation of Mettl3 in mouse nervous system causes severe developmental defects in the brain. Mettl3 conditional knockout (cKO) mice manifest cerebellar hypoplasia caused by drastically enhanced apoptosis of newborn cerebellar granule cells (CGCs) in the external granular layer (EGL). METTL3 depletion–induced loss of m6A modification causes extended RNA half-lives and aberrant splicing events, consequently leading to dysregulation of transcriptome-wide gene expression and premature CGC death. Our findings reveal a critical role of METTL3-mediated m6A in regulating the development of mammalian cerebellum.
The zinc transporter ZIPT-7.1 regulates sperm activation in nematodes
Venue: PLoS biology

Sperm activation is a fascinating example of cell differentiation, in which immotile spermatids undergo a rapid and dramatic transition to become mature, motile sperm. Because the sperm nucleus is transcriptionally silent, this transition does not involve transcriptional changes. Although Caenorhabditis elegans is a leading model for studies of sperm activation, the mechanisms by which signaling pathways induce this transformation remain poorly characterized. Here we show that a conserved transmembrane zinc transporter, ZIPT-7.1, regulates the induction of sperm activation in Caenorhabditis nematodes. The zipt-7.1 mutant hermaphrodites cannot self-fertilize, and males reproduce poorly, because mutant spermatids are defective in responding to activating signals. The zipt-7.1 gene is expressed in the germ line and functions in germ cells to promote sperm activation. When expressed in mammalian cells, ZIPT-7.1 mediates zinc transport with high specificity and is predominantly located on internal membranes. Finally, genetic epistasis places zipt-7.1 at the end of the spe-8 sperm activation pathway, and ZIPT-7.1 binds SPE-4, a presenilin that regulates sperm activation. Based on these results, we propose a new model for sperm activation. In spermatids, inactive ZIPT-7.1 is localized to the membranous organelles, which contain higher levels of zinc than the cytoplasm. When sperm activation is triggered, ZIPT-7.1 activity increases, releasing zinc from internal stores. The resulting increase in cytoplasmic zinc promotes the phenotypic changes characteristic of activation. Thus, zinc signaling is a key step in the signal transduction process that mediates sperm activation, and we have identified a zinc transporter that is central to this activation process.
Zinc: A small molecule with a big impact on sperm function
Venue: PLoS biology

Zinc is an essential mineral, but our understanding of its uses in the body is limited. Capitalizing on approaches available in the model system Caenorhabditis elegans, Zhao and colleagues show that zinc transduces a signal that induces sperm to become motile. This is an enigmatic process because sperm in all sexually-reproducing animals are transcriptionally inactive. Zinc levels inside sperm are regulated by an evolutionarily conserved zinc transporter called Zrt- and Irt-like Protein Transporter 7.1 (ZIPT-7.1). This zinc transporter localizes to intracellular organelles, suggesting that it primarily controls zinc levels by releasing zinc into the cytoplasm from internal stores rather than importing it from the external environment. The zinc released within cells acts as a messenger in a signaling pathway to promote mobility acquisition. These studies reveal an important role for zinc as an intracellular second messenger that generates physiological changes vital for sperm motility and fertility.
The bench is closer to the bedside than we think: Uncovering the ethical ties between preclinical researchers in translational neuroscience and patients in clinical trials
Venue: PLoS biology

Millions of people worldwide currently suffer from serious neurological diseases and injuries for which there are few, and often no, effective treatments. The paucity of effective interventions is, no doubt, due in large part to the complexity of the disorders, as well as our currently limited understanding of their pathophysiology. The bleak picture for patients, however, is also attributable to avoidable impediments stemming from quality concerns in preclinical research that often escape detection by research regulation efforts. In our essay, we connect the dots between these concerns about the quality of preclinical research and their potential ethical impact on the patients who volunteer for early trials of interventions informed by it. We do so in hopes that a greater appreciation among preclinical researchers of these serious ethical consequences can lead to a greater commitment within the research community to adopt widely available tools and measures that can help to improve the quality of research.
Vitellogenin-like A–associated shifts in social cue responsiveness regulate behavioral task specialization in an ant
Venue: PLoS biology

Division of labor and task specialization explain the success of human and insect societies. Social insect colonies are characterized by division of labor, with workers specializing in brood care early and foraging later in life. Theory posits that this task switching requires shifts in responsiveness to task-related cues, yet experimental evidence is weak. Here, we show that a Vitellogenin (Vg) ortholog identified in an RNAseq study on the ant T. longispinosus is involved in this process: using phylogenetic analyses of Vg and Vg-like genes, we firstly show that this candidate gene does not cluster with the intensively studied honey bee Vg but falls into a separate Vg-like A cluster. Secondly, an experimental knockdown of Vg-like A in the fat body caused a reduction in brood care and an increase in nestmate care in young ant workers. Nestmate care is normally exhibited by older workers. We demonstrate experimentally that this task switch is at least partly based on Vg-like A–associated shifts in responsiveness from brood to worker cues. We thus reveal a novel mechanism leading to early behavioral maturation via changes in social cue responsiveness mediated by Vg-like A and associated pathways, which proximately play a role in regulating division of labor.
Amygdala activity for the modulation of goal-directed behavior in emotional contexts
Venue: PLoS biology

Choosing valuable objects and rewarding actions is critical for survival. While such choices must be made in a way that suits the animal’s circumstances, the neural mechanisms underlying such context-appropriate behavior are unclear. To address this question, we devised a context-dependent reward-seeking task for macaque monkeys. Each trial started with the appearance of one of many visual scenes containing two or more objects, and the monkey had to choose the good object by saccade to get a reward. These scenes were categorized into two dimensions of emotional context: dangerous versus safe and rich versus poor. We found that many amygdala neurons were more strongly activated by dangerous scenes, by rich scenes, or by both. Furthermore, saccades to target objects occurred more quickly in dangerous than in safe scenes and were also quicker in rich than in poor scenes. Thus, amygdala neuronal activity and saccadic reaction times were negatively correlated in each monkey. These results suggest that amygdala neurons facilitate targeting saccades predictably based on aspects of emotional context, as is necessary for goal-directed and social behavior.
Meaningful syntactic structure in songbird vocalizations?
Venue: PLoS biology

The faculty of language is thought to be uniquely human. Recently, it has been claimed that songbirds are able to associate meaning with sound, comparable to the way that humans do. In human language, the meaning of expressions (semantics) is dependent on a mind-internal hierarchical structure (syntax). Meaning is associated with structure through the principle of compositionality, whereby the meaning of a complex expression is a function of the meaning of its constituent parts and the mode of composition. We argue that while recent experimental findings on songbird call sequences offer exciting novel insights into animal communication, despite claims to the contrary, they are quite unlike what we find in human language. There are indeed remarkable behavioral and neural parallels in auditory-vocal imitation learning between songbirds and human infants that are absent in our closest evolutionary relatives, the great apes. But so far, there is no convincing evidence of syntax-determined meaning in nonhuman animals.
Microsaccade-rhythmic modulation of neural synchronization and coding within and across cortical areas V1 and V2
Venue: PLoS biology

Primates sample their visual environment actively through saccades and microsaccades (MSs). Saccadic eye movements not only modulate neural spike rates but might also affect temporal correlations (synchrony) among neurons. Neural synchrony plays a role in neural coding and modulates information transfer between cortical areas. The question arises of how eye movements shape neural synchrony within and across cortical areas and how it affects visual processing. Through local field recordings in macaque early visual cortex while monitoring eye position and through neural network simulations, we find 2 distinct synchrony regimes in early visual cortex that are embedded in a 3- to 4-Hz MS-related rhythm during visual fixation. In the period shortly after an MS (“transient period”), synchrony was high within and between cortical areas. In the subsequent period (“sustained period”), overall synchrony dropped and became selective to stimulus properties. Only mutually connected neurons with similar stimulus responses exhibited sustained narrow-band gamma synchrony (25–80 Hz), both within and across cortical areas. Recordings in macaque V1 and V2 matched the model predictions. Furthermore, our modeling provides predictions on how (micro)saccade-modulated gamma synchrony in V1 shapes V2 receptive fields (RFs). We suggest that the rhythmic alternation between synchronization regimes represents a basic repeating sampling strategy of the visual system.
Quantitative proteomic characterization and comparison of T helper 17 and induced regulatory T cells
Venue: PLoS biology

The transcriptional network and protein regulators that govern T helper 17 (Th17) cell differentiation have been studied extensively using advanced genomic approaches. For a better understanding of these biological processes, we have moved a step forward, from gene- to protein-level characterization of Th17 cells. Mass spectrometry–based label-free quantitative (LFQ) proteomics analysis were made of in vitro differentiated murine Th17 and induced regulatory T (iTreg) cells. More than 4,000 proteins, covering almost all subcellular compartments, were detected. Quantitative comparison of the protein expression profiles resulted in the identification of proteins specifically expressed in the Th17 and iTreg cells. Importantly, our combined analysis of proteome and gene expression data revealed protein expression changes that were not associated with changes at the transcriptional level. Our dataset provides a valuable resource, with new insights into the proteomic characteristics of Th17 and iTreg cells, which may prove useful in developing treatment of autoimmune diseases and developing tumor immunotherapy.
Import volumes and biosecurity interventions shape the arrival rate of fungal pathogens
Venue: PLoS biology

Global trade and the movement of people accelerate biological invasions by spreading species worldwide. Biosecurity measures seek to allow trade and passenger movements while preventing incursions that could lead to the establishment of unwanted pests, pathogens, and weeds. However, few data exist to evaluate whether changes in trade volumes, passenger arrivals, and biosecurity measures have altered rates of establishment of nonnative species over time. This is particularly true for pathogens, which pose significant risks to animal and plant health and are consequently a major focus of biosecurity efforts but are difficult to detect. Here, we use a database of all known plant pathogen associations recorded in New Zealand to estimate the rate at which new fungal pathogens arrived and established on 131 economically important plant species over the last 133 years. We show that the annual arrival rate of new fungal pathogens increased from 1880 to about 1980 in parallel with increasing import trade volume but subsequently stabilised despite continued rapid growth in import trade and recent rapid increases in international passenger arrivals. Nevertheless, while pathogen arrival rates for crop and pasture species have declined in recent decades, arrival rates have increased for forestry and fruit tree species. These contrasting trends between production sectors reflect differences in biosecurity effort and suggest that targeted biosecurity can slow pathogen arrival and establishment despite increasing trade and international movement of people.
Zbtb7a is a transducer for the control of promoter accessibility by NF-kappa B and multiple other transcription factors
Venue: PLoS biology

Gene expression in eukaryotes is controlled by DNA sequences at promoter and enhancer regions, whose accessibility for binding by regulatory proteins dictates their specific patterns of activity. Here, we identify the protein Zbtb7a as a factor required for inducible changes in accessibility driven by transcription factors (TFs). We show that Zbtb7a binds to a significant fraction of genomic promoters and enhancers, encompassing many target genes of nuclear factor kappa B (NFκB) p65 and a variety of other TFs. While Zbtb7a binding is not alone sufficient to directly activate promoters, it is required to enable TF-dependent control of accessibility and normal gene expression. Using p65 as a model TF, we show that Zbtb7a associates with promoters independently of client TF binding. Moreover, the presence of prebound Zbtb7a can specify promoters that are amenable to TF-induced changes in accessibility. Therefore, Zbtb7a represents a widely used promoter factor that transduces signals from other TFs to enable control of accessibility and regulation of gene expression.
A novel unsupervised analysis of electrophysiological signals reveals new sleep substages in mice
Venue: PLoS biology

Sleep science is entering a new era, thanks to new data-driven analysis approaches that, combined with mouse gene–editing technologies, show a promise in functional genomics and translational research. However, the investigation of sleep is time consuming and not suitable for large-scale phenotypic datasets, mainly due to the need for subjective manual annotations of electrophysiological states. Moreover, the heterogeneous nature of sleep, with all its physiological aspects, is not fully accounted for by the current system of sleep stage classification. In this study, we present a new data-driven analysis approach offering a plethora of novel features for the characterization of sleep. This novel approach allowed for identifying several substages of sleep that were hidden to standard analysis. For each of these substages, we report an independent set of homeostatic responses following sleep deprivation. By using our new substages classification, we have identified novel differences among various genetic backgrounds. Moreover, in a specific experiment with the Zfhx3 mouse line, a recent circadian mutant expressing both shortening of the circadian period and abnormal sleep architecture, we identified specific sleep states that account for genotypic differences at specific times of the day. These results add a further level of interaction between circadian clock and sleep homeostasis and indicate that dissecting sleep in multiple states is physiologically relevant and can lead to the discovery of new links between sleep phenotypes and genetic determinants. Therefore, our approach has the potential to significantly enhance the understanding of sleep physiology through the study of single mutations. Moreover, this study paves the way to systematic high-throughput analyses of sleep.
A G-protein-coupled chemoattractant receptor recognizes lipopolysaccharide for bacterial phagocytosis
Venue: PLoS biology

Phagocytes locate microorganisms via chemotaxis and then consume them using phagocytosis. Dictyostelium amoebas are stereotypical phagocytes that prey on diverse bacteria using both processes. However, as typical phagocytic receptors, such as complement receptors or Fcγ receptors, have not been found in Dictyostelium, it remains mysterious how these cells recognize bacteria. Here, we show that a single G-protein-coupled receptor (GPCR), folic acid receptor 1 (fAR1), simultaneously recognizes the chemoattractant folate and the phagocytic cue lipopolysaccharide (LPS), a major component of bacterial surfaces. Cells lacking fAR1 or its cognate G-proteins are defective in chemotaxis toward folate and phagocytosis of Klebsiella aerogenes. Computational simulations combined with experiments show that responses associated with chemotaxis can also promote engulfment of particles coated with chemoattractants. Finally, the extracellular Venus-Flytrap (VFT) domain of fAR1 acts as the binding site for both folate and LPS. Thus, fAR1 represents a new member of the pattern recognition receptors (PRRs) and mediates signaling from both bacterial surfaces and diffusible chemoattractants to reorganize actin for chemotaxis and phagocytosis.
Unsolved mysteries: How does lipid peroxidation cause ferroptosis?
Venue: PLoS biology

Ferroptosis is a cell death process driven by damage to cell membranes and linked to numerous human diseases. Ferroptosis is caused by loss of activity of the key enzyme that is tasked with repairing oxidative damage to cell membranes—glutathione peroxidase 4 (GPX4). GPX4 normally removes the dangerous products of iron-dependent lipid peroxidation, protecting cell membranes from this type of damage; when GPX4 fails, ferroptosis ensues. Ferroptosis is distinct from apoptosis, necroptosis, necrosis, and other modes of cell death. Several key mysteries regarding how cells die during ferroptosis remain unsolved. First, the drivers of lipid peroxidation are not yet clear. Second, the subcellular location of lethal lipid peroxides remains an outstanding question. Finally, how exactly lipid peroxidation leads to cell death is an unsolved mystery. Answers to these questions will provide insights into the mechanisms of ferroptotic cell death and associated human diseases, as well as new therapeutic strategies for such diseases.
Endoplasmic reticulum-plasma membrane contact sites integrate sterol and phospholipid regulation
Venue: PLoS biology

Tether proteins attach the endoplasmic reticulum (ER) to other cellular membranes, thereby creating contact sites that are proposed to form platforms for regulating lipid homeostasis and facilitating non-vesicular lipid exchange. Sterols are synthesized in the ER and transported by non-vesicular mechanisms to the plasma membrane (PM), where they represent almost half of all PM lipids and contribute critically to the barrier function of the PM. To determine whether contact sites are important for both sterol exchange between the ER and PM and intermembrane regulation of lipid metabolism, we generated Δ-super-tether (Δ-s-tether) yeast cells that lack six previously identified tethering proteins (yeast extended synatotagmin [E-Syt], vesicle-associated membrane protein [VAMP]-associated protein [VAP], and TMEM16-anoctamin homologues) as well as the presumptive tether Ice2. Despite the lack of ER-PM contacts in these cells, ER-PM sterol exchange is robust, indicating that the sterol transport machinery is either absent from or not uniquely located at contact sites. Unexpectedly, we found that the transport of exogenously supplied sterol to the ER occurs more slowly in Δ-s-tether cells than in wild-type (WT) cells. We pinpointed this defect to changes in sterol organization and transbilayer movement within the PM bilayer caused by phospholipid dysregulation, evinced by changes in the abundance and organization of PM lipids. Indeed, deletion of either OSH4, which encodes a sterol/phosphatidylinositol-4-phosphate (PI4P) exchange protein, or SAC1, which encodes a PI4P phosphatase, caused synthetic lethality in Δ-s-tether cells due to disruptions in redundant PI4P and phospholipid regulatory pathways. The growth defect of Δ-s-tether cells was rescued with an artificial "ER-PM staple," a tether assembled from unrelated non-yeast protein domains, indicating that endogenous tether proteins have nonspecific bridging functions. Finally, we discovered that sterols play a role in regulating ER-PM contact site formation. In sterol-depleted cells, levels of the yeast E-Syt tether Tcb3 were induced and ER-PM contact increased dramatically. These results support a model in which ER-PM contact sites provide a nexus for coordinating the complex interrelationship between sterols, sphingolipids, and phospholipids that maintain PM composition and integrity.