nils-herrmann/clean_scirepeval huggingface dataset:
RNA-Binding Proteins Chaperone Ribonucleoprotein Complex Assembly to Solve the RNA-Folding Problem
Venue: Cell

The inherent tendency of RNAs to misfold is a major problem that can impede efficient assembly of essential ribonucleoprotein complexes (RNPs), such as ribosomes. In this issue of Cell, Duss et al., (2019) and Rogers and Woodson (2019) reveal how transient RNA-protein interactions can chaperone RNA folding during RNP assembly.
Screening Human Embryos for Polygenic Traits Has Limited Utility
Venue: Cell

The increasing proportion of variance in human complex traits explained by polygenic scores, along with progress in preimplantation genetic diagnosis, suggests the possibility of screening embryos for traits such as height or cognitive ability. However, the expected outcomes of embryo screening are unclear, which undermines discussion of associated ethical concerns. Here, we use theory, simulations, and real data to evaluate the potential gain of embryo screening, defined as the difference in trait value between the top-scoring embryo and the average embryo. The gain increases very slowly with the number of embryos but more rapidly with the variance explained by the score. Given current technology, the average gain due to screening would be ≈2.5 cm for height and ≈2.5 IQ points for cognitive ability. These mean values are accompanied by wide prediction intervals, and indeed, in large nuclear families, the majority of children top-scoring for height are not the tallest.
Recurrent SMARCB1 Mutations Reveal a Nucleosome Acidic Patch Interaction Site That Potentiates mSWI/SNF Complex Chromatin Remodeling
Venue: Cell

Mammalian switch/sucrose non-fermentable (mSWI/SNF) complexes are multi-component machines that remodel chromatin architecture. Dissection of the subunit- and domain-specific contributions to complex activities is needed to advance mechanistic understanding. Here, we examine the molecular, structural, and genome-wide regulatory consequences of recurrent, single-residue mutations in the putative coiled-coil C-terminal domain (CTD) of the SMARCB1 (BAF47) subunit, which cause the intellectual disability disorder Coffin-Siris syndrome (CSS), and are recurrently found in cancers. We find that the SMARCB1 CTD contains a basic α helix that binds directly to the nucleosome acidic patch and that all CSS-associated mutations disrupt this binding. Furthermore, these mutations abrogate mSWI/SNF-mediated nucleosome remodeling activity and enhancer DNA accessibility without changes in genome-wide complex localization. Finally, heterozygous CSS-associated SMARCB1 mutations result in dominant gene regulatory and morphologic changes during iPSC-neuronal differentiation. These studies unmask an evolutionarily conserved structural role for the SMARCB1 CTD that is perturbed in human disease.
Continual Learning in a Multi-Layer Network of an Electric Fish
Venue: Cell

Distributing learning across multiple layers has proven extremely powerful in artificial neural networks. However, little is known about how multi-layer learning is implemented in the brain. Here, we provide an account of learning across multiple processing layers in the electrosensory lobe (ELL) of mormyrid fish and report how it solves problems well known from machine learning. Because the ELL operates and learns continuously, it must reconcile learning and signaling functions without switching its mode of operation. We show that this is accomplished through a functional compartmentalization within intermediate layer neurons in which inputs driving learning differentially affect dendritic and axonal spikes. We also find that connectivity based on learning rather than sensory response selectivity assures that plasticity at synapses onto intermediate-layer neurons is matched to the requirements of output neurons. The mechanisms we uncover have relevance to learning in the cerebellum, hippocampus, and cerebral cortex, as well as in artificial systems.
Periodic Remodeling in a Neural Circuit Governs Timing of Female Sexual Behavior
Venue: Cell

Behaviors are inextricably linked to internal state. We have identified a neural mechanism that links female sexual behavior with the estrus, the ovulatory phase of the estrous cycle. We find that progesterone-receptor (PR)-expressing neurons in the ventromedial hypothalamus (VMH) are active and required during this behavior. Activating these neurons, however, does not elicit sexual behavior in non-estrus females. We show that projections of PR+ VMH neurons to the anteroventral periventricular (AVPV) nucleus change across the 5-day mouse estrous cycle, with ∼3-fold more termini and functional connections during estrus. This cyclic increase in connectivity is found in adult females, but not males, and regulated by estrogen signaling in PR+ VMH neurons. We further show that these connections are essential for sexual behavior in receptive females. Thus, estrogen-regulated structural plasticity of behaviorally salient connections in the adult female brain links sexual behavior to the estrus phase of the estrous cycle.
A Compendium of Genetic Modifiers of Mitochondrial Dysfunction Reveals Intra-organelle Buffering
Venue: Cell

Mitochondrial dysfunction is associated with a spectrum of human conditions, ranging from rare, inborn errors of metabolism to the aging process. To identify pathways that modify mitochondrial dysfunction, we performed genome-wide CRISPR screens in the presence of small-molecule mitochondrial inhibitors. We report a compendium of chemical-genetic interactions involving 191 distinct genetic modifiers, including 38 that are synthetic sick/lethal and 63 that are suppressors. Genes involved in glycolysis (PFKP), pentose phosphate pathway (G6PD), and defense against lipid peroxidation (GPX4) scored high as synthetic sick/lethal. A surprisingly large fraction of suppressors are pathway intrinsic and encode mitochondrial proteins. A striking example of such "intra-organelle" buffering is the alleviation of a chemical defect in complex V by simultaneous inhibition of complex I, which benefits cells by rebalancing redox cofactors, increasing reductive carboxylation, and promoting glycolysis. Perhaps paradoxically, certain forms of mitochondrial dysfunction may best be buffered with "second site" inhibitors to the organelle.
Clonal Decomposition and DNA Replication States Defined by Scaled Single-Cell Genome Sequencing
Venue: Cell

Accurate measurement of clonal genotypes, mutational processes, and replication states from individual tumor-cell genomes will facilitate improved understanding of tumor evolution. We have developed DLP+, a scalable single-cell whole-genome sequencing platform implemented using commodity instruments, image-based object recognition, and open source computational methods. Using DLP+, we have generated a resource of 51,926 single-cell genomes and matched cell images from diverse cell types including cell lines, xenografts, and diagnostic samples with limited material. From this resource we have defined variation in mitotic mis-segregation rates across tissue types and genotypes. Analysis of matched genomic and image measurements revealed correlations between cellular morphology and genome ploidy states. Aggregation of cells sharing copy number profiles allowed for calculation of single-nucleotide resolution clonal genotypes and inference of clonal phylogenies and avoided the limitations of bulk deconvolution. Finally, joint analysis over the above features defined clone-specific chromosomal aneuploidy in polyclonal populations.
B Cells and T Follicular Helper Cells Mediate Response to Checkpoint Inhibitors in High Mutation Burden Mouse Models of Breast Cancer
Venue: Cell

This study identifies mechanisms mediating responses to immune checkpoint inhibitors using mouse models of triple-negative breast cancer. By creating new mammary tumor models, we find that tumor mutation burden and specific immune cells are associated with response. Further, we developed a rich resource of single-cell RNA-seq and bulk mRNA-seq data of immunotherapy-treated and non-treated tumors from sensitive and resistant murine models. Using this, we uncover that immune checkpoint therapy induces T follicular helper cell activation of B cells to facilitate the anti-tumor response in these models. We also show that B cell activation of T cells and the generation of antibody are key to immunotherapy response and propose a new biomarker for immune checkpoint therapy. In total, this work presents resources of new preclinical models of breast cancer with large mRNA-seq and single-cell RNA-seq datasets annotated for sensitivity to therapy and uncovers new components of response to immune checkpoint inhibitors.
Differences in Tumor Microenvironment Dictate T Helper Lineage Polarization and Response to Immune Checkpoint Therapy
Venue: Cell

Immune checkpoint therapy (ICT) shows encouraging results in a subset of patients with metastatic castration-resistant prostate cancer (mCRPC) but still elicits a sub-optimal response among those with bone metastases. Analysis of patients' bone marrow samples revealed increased Th17 instead of Th1 subsets after ICT. To further evaluate the different tumor microenvironments, we injected mice with prostate tumor cells either subcutaneously or intraosseously. ICT in the subcutaneous CRPC model significantly increases intra-tumoral Th1 subsets and improves survival. However, ICT fails to elicit an anti-tumor response in the bone CRPC model despite an increase in the intra-tumoral CD4 T cells, which are polarized to Th17 rather than Th1 lineage. Mechanistically, tumors in the bone promote osteoclast-mediated bone resorption that releases TGF-β, which restrains Th1 lineage development. Blocking TGF-β along with ICT increases Th1 subsets and promotes clonal expansion of CD8 T cells and subsequent regression of bone CRPC and improves survival.
Mucosal Profiling of Pediatric-Onset Colitis and IBD Reveals Common Pathogenics and Therapeutic Pathways
Venue: Cell

Pediatric-onset colitis and inflammatory bowel disease (IBD) have significant effects on the growth of infants and children, but the etiopathogenesis underlying disease subtypes remains incompletely understood. Here, we report single-cell clustering, immune phenotyping, and risk gene analysis for children with undifferentiated colitis, Crohn's disease, and ulcerative colitis. We demonstrate disease-specific characteristics, as well as common pathogenesis marked by impaired cyclic AMP (cAMP)-response signaling. Specifically, infiltration of PDE4B- and TNF-expressing macrophages, decreased abundance of CD39-expressing intraepithelial T cells, and platelet aggregation and release of 5-hydroxytryptamine at the colonic mucosae were common in colitis and IBD patients. Targeting these pathways by using the phosphodiesterase inhibitor dipyridamole restored immune homeostasis and improved colitis symptoms in a pilot study. In summary, comprehensive analysis of the colonic mucosae has uncovered common pathogenesis and therapeutic targets for children with colitis and IBD.
Genetic Identification of Vagal Sensory Neurons That Control Feeding
Venue: Cell

Energy homeostasis requires precise measurement of the quantity and quality of ingested food. The vagus nerve innervates the gut and can detect diverse interoceptive cues, but the identity of the key sensory neurons and corresponding signals that regulate food intake remains unknown. Here, we use an approach for target-specific, single-cell RNA sequencing to generate a map of the vagal cell types that innervate the gastrointestinal tract. We show that unique molecular markers identify vagal neurons with distinct innervation patterns, sensory endings, and function. Surprisingly, we find that food intake is most sensitive to stimulation of mechanoreceptors in the intestine, whereas nutrient-activated mucosal afferents have no effect. Peripheral manipulations combined with central recordings reveal that intestinal mechanoreceptors, but not other cell types, potently and durably inhibit hunger-promoting AgRP neurons in the hypothalamus. These findings identify a key role for intestinal mechanoreceptors in the regulation of feeding.
Genome-Scale Identification of Essential Metabolic Processes for Targeting the Plasmodium Liver Stage
Venue: Cell

Plasmodium gene functions in mosquito and liver stages remain poorly characterized due to limitations in the throughput of phenotyping at these stages. To fill this gap, we followed more than 1,300 barcoded P. berghei mutants through the life cycle. We discover 461 genes required for efficient parasite transmission to mosquitoes through the liver stage and back into the bloodstream of mice. We analyze the screen in the context of genomic, transcriptomic, and metabolomic data by building a thermodynamic model of P. berghei liver-stage metabolism, which shows a major reprogramming of parasite metabolism to achieve rapid growth in the liver. We identify seven metabolic subsystems that become essential at the liver stages compared with asexual blood stages: type II fatty acid synthesis and elongation (FAE), tricarboxylic acid, amino sugar, heme, lipoate, and shikimate metabolism. Selected predictions from the model are individually validated in single mutants to provide future targets for drug development.
Atoms to Phenotypes: Molecular Design Principles of Cellular Energy Metabolism
Venue: Cell

We report a 100-million atom-scale model of an entire cell organelle, a photosynthetic chromatophore vesicle from a purple bacterium, that reveals the cascade of energy conversion steps culminating in the generation of ATP from sunlight. Molecular dynamics simulations of this vesicle elucidate how the integral membrane complexes influence local curvature to tune photoexcitation of pigments. Brownian dynamics of small molecules within the chromatophore probe the mechanisms of directional charge transport under various pH and salinity conditions. Reproducing phenotypic properties from atomistic details, a kinetic model evinces that low-light adaptations of the bacterium emerge as a spontaneous outcome of optimizing the balance between the chromatophore's structural integrity and robust energy conversion. Parallels are drawn with the more universal mitochondrial bioenergetic machinery, from whence molecular-scale insights into the mechanism of cellular aging are inferred. Together, our integrative method and spectroscopic experiments pave the way to first-principles modeling of whole living cells.
Global Trends in Marine Plankton Diversity across Kingdoms of Life
Venue: Cell

The ocean is home to myriad small planktonic organisms that underpin the functioning of marine ecosystems. However, their spatial patterns of diversity and the underlying drivers remain poorly known, precluding projections of their responses to global changes. Here we investigate the latitudinal gradients and global predictors of plankton diversity across archaea, bacteria, eukaryotes, and major virus clades using both molecular and imaging data from Tara Oceans. We show a decline of diversity for most planktonic groups toward the poles, mainly driven by decreasing ocean temperatures. Projections into the future suggest that severe warming of the surface ocean by the end of the 21st century could lead to tropicalization of the diversity of most planktonic groups in temperate and polar regions. These changes may have multiple consequences for marine ecosystem functioning and services and are expected to be particularly significant in key areas for carbon sequestration, fisheries, and marine conservation.
Gene Expression Changes and Community Turnover Differentially Shape the Global Ocean Metatranscriptome
Venue: Cell

Ocean microbial communities strongly influence the biogeochemistry, food webs, and climate of our planet. Despite recent advances in understanding their taxonomic and genomic compositions, little is known about how their transcriptomes vary globally. Here, we present a dataset of 187 metatranscriptomes and 370 metagenomes from 126 globally distributed sampling stations and establish a resource of 47 million genes to study community-level transcriptomes across depth layers from pole-to-pole. We examine gene expression changes and community turnover as the underlying mechanisms shaping community transcriptomes along these axes of environmental variation and show how their individual contributions differ for multiple biogeochemically relevant processes. Furthermore, we find the relative contribution of gene expression changes to be significantly lower in polar than in non-polar waters and hypothesize that in polar regions, alterations in community activity in response to ocean warming will be driven more strongly by changes in organismal composition than by gene regulatory mechanisms.
Genomes of Subaerial Zygnematophyceae Provide Insights into Land Plant Evolution
Venue: Cell

The transition to a terrestrial environment, termed terrestrialization, is generally regarded as a pivotal event in the evolution and diversification of the land plant flora that changed the surface of our planet. Through phylogenomic studies, a group of streptophyte algae, the Zygnematophyceae, have recently been recognized as the likely sister group to land plants (embryophytes). Here, we report genome sequences and analyses of two early diverging Zygnematophyceae (Spirogloea muscicola gen. nov. and Mesotaenium endlicherianum) that share the same subaerial/terrestrial habitat with the earliest-diverging embryophytes, the bryophytes. We provide evidence that genes (i.e., GRAS and PYR/PYL/RCAR) that increase resistance to biotic and abiotic stresses in land plants, in particular desiccation, originated or expanded in the common ancestor of Zygnematophyceae and embryophytes, and were gained by horizontal gene transfer (HGT) from soil bacteria. These two Zygnematophyceae genomes represent a cornerstone for future studies to understand the underlying molecular mechanism and process of plant terrestrialization.
The Role of Non-coding RNAs in Oncology
Venue: Cell

For decades, research into cancer biology focused on the involvement of protein-coding genes. Only recently was it discovered that an entire class of molecules, termed non-coding RNA (ncRNA), plays key regulatory roles in shaping cellular activity. An explosion of studies into ncRNA biology has since shown that they represent a diverse and prevalent group of RNAs, including both oncogenic molecules and those that work in a tumor suppressive manner. As a result, hundreds of cancer-focused clinical trials involving ncRNAs as novel biomarkers or therapies have begun and these are likely just the beginning.
Two- and three-dimensional de-drifting algorithms for fiducially marked image stacks.
Venue: Journal of biomechanics

Traction force microscopy has been established as the accepted method for evaluating cell-induced mechanical stresses to their microenvironments, typically using two-dimensional (2D) elastic, synthetic gel-substrates. As cells naturally experience 3D environments in vivo, traction microscopy has been adapted to 3D gels; cells can be tracked over time in 3D. Microscopy images acquired in several fields-of-view e.g. in a time series, may experience drift, which can produce artefactual results that may appear valid and lead to flawed analysis. Hence, we have developed an algorithm for 2D/3D de-drifting of cell-images on 3D gels with fiducial markers (beads) as anchor points. Both lateral and vertical de-drifting are performed using gel-internalized beads, as those used in traction microscopy experiments; this eliminates need for immobilizing beads under the gel for de-drifting, and reduces experiment time. We introduce simulations of initially grid-ordered dots (beads) that are radially displaced to experimentally observed distances, while also applying additive drift. This facilitates testing and demonstration of the de-drifting procedures in 2D/3D. We demonstrate the importance of applying de-drifting using both computer-simulated drifts and experimentally observed drifts in confocal microscopy images. We show that our de-drifting algorithm can remove lateral and/or vertical drift revealing even small, underlying signals. The 2D/3D de-drifting algorithm, crucial for accurate identification of cell-induced marker-displacement, as well as the bead simulations, will shorten traction microscopy experiments and facilitate optimization of the experimental protocols.
Multi-segment foot model reveals distal joint kinematic differences between habitual heel-toe walking and non-habitual toe walking.
Venue: Journal of biomechanics

Toe walking is observed in pathological populations including cerebral palsy, stroke, and autism spectrum disorder. To understand pathological toe walking, previous studies have analyzed non-habitual toe walking. These studies found sagittal plane deviations between heel-toe and toe walking at the hip, knee, and ankle. Further investigation is merited as toe walking may involve altered biomechanics at more distal joints, such as the midtarsal joint. The purpose of this study was to examine biomechanical differences between rearfoot strike walking (RFSW) and non-rearfoot strike walking (NRFSW) in the midfoot and ankle. We hypothesized that during NRFSW, midtarsal kinematics would diverge from those during RFSW in all three cardinal planes and ankle kinematics would display increased supination. Twenty-four healthy females walked overground with both walking patterns. Motion capture, electromyography (EMG), and force plate data were collected. A validated multi-segment foot model was used with mean difference waveform analyses to compare walking conditions during stance. Significantly different kinematics were found in all three planes for the midtarsal and ankle joint during NRFSW. The NRFSW midtarsal joint exhibited increased plantarflexion, eversion, and adduction with the largest differences occurring at initial contact and in the sagittal plane. The NRFSW ankle exhibited increased supination at initial contact and during early stance. These findings indicate that toe walking alters both distal and proximal foot joint kinematics in multiple planes. This may further the understanding of altered biomechanics during toe walking while providing a basis for future analyses of pathological gait.
A comparison of variability and gait dynamics in spatiotemporal variables between different self-paced treadmill control modes.
Venue: Journal of biomechanics

This study investigates the effects of treadmill control algorithms on spatiotemporal variables when walking on a self-paced (SP) treadmill. Ten healthy subjects walked at their preferred walking speed for 15 min under three different treadmill control modes. Stride time, stride length, and stride speed were measured using an inertial measurement unit. The mean, coefficient of variance, Poincaré descriptors, and gait dynamics were calculated for each parameter. The mean values of stride length and stride speed were significantly increased when the treadmill had a quick response speed to the user's walking behavior. The long-term variability of stride length and stride speed was significantly affected by the treadmill control algorithms. A reduced strength of long-range correlations of stride time and stride speed was found when walking on the SP treadmill with suppressed treadmill accelerations and small velocity variations. We suggest that the suppression of treadmill acceleration provides more adaptability and less constraint to the user during SP treadmill walking. Although further research is required, the present work provides a basis for interpreting the influence of treadmill control algorithms on human gait.