bluuebunny/crossref_metadata_2025_split huggingface dataset:
The history of body size evolution in termites
Authors: Mizumoto Nobuaki , Bourguignon Thomas 
Published: October 2021

AbstractTermites are social cockroaches. Because non-termite cockroaches are larger than basal termite lineages, which themselves include large termite species, it has been proposed that termites experienced a unidirectional body size reduction since they evolved eusociality. However, the validity of this hypothesis remains untested in a phylogenetic framework. Here, we reconstructed termite body size evolution using head width measurements of 1638 modern and fossil termite species. We found that the unidirectional body size reduction model was only supported by analyses excluding fossil species. Analyses including fossil species suggested that body size diversified along with speciation events and estimated that the size of the common ancestor of modern termites was comparable to that of modern species. Our analyses further revealed that body size variability among species, but not body size reduction, is associated with features attributed to advanced termite societies. Our results suggest that miniaturization took place at the origin of termites, while subsequent complexification of termite societies did not lead to further body size reduction.
Simulation-based inference of evolutionary parameters from adaptation dynamics using neural networks
Authors: Avecilla Grace , Chuong Julie N. , Li Fangfei , Sherlock Gavin , Gresham David , Ram Yoav 
Published: October 2021

ABSTRACTThe rate of adaptive evolution depends on the rate at which beneficial mutations are introduced into a population and the fitness effects of those mutations. The rate of beneficial mutations and their expected fitness effects is often difficult to empirically quantify. As these two parameters determine the pace of evolutionary change in a population, the dynamics of adaptive evolution may enable inference of their values. Copy number variants (CNVs) are a pervasive source of heritable variation that can facilitate rapid adaptive evolution. Previously, we developed a locus-specific fluorescent CNV reporter to quantify CNV dynamics in evolving populations maintained in nutrient-limiting conditions using chemostats. Here, we use the observed CNV adaptation dynamics to estimate the rate at which beneficial CNVs are introduced through de novo mutation and their fitness effects using simulation-based Bayesian likelihood-free inference approaches. We tested the suitability of two evolutionary models: a standard Wright-Fisher model and a chemostat growth model. We evaluated two likelihood-free inference algorithms: the well-established Approximate Bayesian Computation with Sequential Monte Carlo (ABC-SMC) algorithm, and the recently developed Neural Posterior Estimation (NPE) algorithm, which applies an artificial neural network to directly estimate the posterior distribution. By systematically evaluating the suitability of different inference methods and models we show that NPE has several advantages over ABC-SMC and that a Wright-Fisher evolutionary model suffices in most cases. Using our validated inference framework, we estimate the CNV formation rate at the GAP1 locus in yeast as 10−4.7 -10−4 per cell division, and a selection coefficient of 0.04 - 0.1 per generation for GAP1 CNVs in glutamine-limited chemostats. We experimentally validated our estimates using barcode lineage tracking and pairwise fitness assays. Our results are consistent with a high beneficial CNV supply rate that is 10-fold greater than the estimated rates of beneficial single-nucleotide mutations, explaining their outsized importance in rapid adaptive evolution. More generally, our study demonstrates the utility of novel simulation-based likelihood-free inference methods for inferring the rates and effects of evolutionary processes from empirical data.
Metacognition and the effect of incentive motivation in two compulsive disorders: gambling disorder and obsessive-compulsive disorder
Authors: Hoven Monja , de Boer Nina S. , Goudriaan Anna E. , Denys Damiaan , Lebreton Mael , van Holst Ruth J. , Luigjes Judy 
Published: October 2021

AbstractCompulsivity is a common phenotype amongst various psychiatric disorders, such as obsessive-compulsive disorder (OCD) and gambling disorder (GD). Deficiencies in metacognition, such as the inability to properly estimate ones’ own performance via well-calibrated confidence judgments could contribute to pathological decision-making in these psychiatric disorders. Earlier research has indeed suggested that OCD and GD patients reside at opposite ends of the confidence spectrum, with OCD patients exhibiting underconfidence, and GD patients exhibiting overconfidence. Recently, several studies established that motivational states (e.g. monetary incentives) influence metacognition, with gain (respectively loss) prospects increasing (respectively decreasing) confidence judgments. Here, we reasoned that the OCD and GD symptomatology might correspond to an exacerbation of this interaction between metacognition and motivational states. We hypothesized GD’s overconfidence to be exaggerated during gain prospects, while OCD’s underconfidence to be worsened in loss context, which we expected to see represented in ventromedial prefrontal cortex (VMPFC) blood-oxygen-level-dependent (BOLD) activity. We tested those hypotheses in a task-based functional magnetic resonance imaging (fMRI) design. Our initial analyses showed increased confidence levels for GD versus OCD patients, that could partly be explained by sex and IQ. Although our primary analyses did not support the hypothesized interaction between incentives and groups, exploratory analyses did show increased confidence in GD patients specifically in gain context. fMRI analyses confirmed a central role for VMPFC in the processing of confidence and incentives, but with no differences between the clinical samples. The trial is registered in the Dutch Trial Register (Trial NL6171, registration number: NTR6318) (https://www.trialregister.nl/trial/6171).
Ecological Stability Emerges at the Level of Strains in the Human Gut Microbiome
Authors: Wolff Richard , Shoemaker William , Garud Nandita 
Published: October 2021

AbstractThe human gut microbiome harbors substantial ecological diversity at the species level, as well as at the strain level within species. In healthy hosts, species abundance fluctuations in the microbiome are thought to be stable, and these fluctuations can be described by macroecological laws. However, it is less clear how strain abundances change over time. An open question is whether individual strains behave like species themselves, exhibiting stability and following the macroecological relationships known to hold at the species level, or whether strains have different dynamics, perhaps due to the relatively close phylogenetic relatedness of co-colonizing lineages. Here, we analyze the daily dynamics of intra-specific genetic variation in the gut microbiomes of four healthy, densely longitudinally sampled hosts. First, we find that overall genetic diversity in a large majority of species is stationary over time, despite short-term fluctuations. Next, we show that fluctuations in abundances in approximately 80% of strains analyzed can be predicted with a stochastic logistic model (SLM)—an ecological model of a population experiencing environmental fluctuations around a fixed carrying capacity which has previously been shown to capture statistical properties of species abundance fluctuations. The success of this model indicates that strain abundances typically fluctuate around a fixed carrying capacity, suggesting that most strains are dynamically stable. Finally, we find that the strain abundances follow several empirical macroecological laws known to hold at the species level. Together, our results suggest that macroecological properties of the human gut microbiome, including its stability, emerge at the level of strains.
Greater spear nosed bats commute long distances alone, rest together, but forage apart
Authors: Teague O’Mara M. , Dechmann Dina K.N. 
Published: October 2021

AbstractAnimals frequently forage in groups on ephemeral resources to profit from social information and increased efficiency. Greater spear-nosed bats (Phyllostomus hastatus) develop group-specific social calls, which are hypothesized to coordinate social foraging to feed on patchily-distributed balsa flowers. To test this, we tagged all members of three social groups ofP. hastatuson Isla Colón, Panamá, using high frequency GPS during a season when balsa had begun to flower. We found commuting distances of 20-30 km to foraging sites, more than double of what has been previously reported. In contrast to our expectations, we found that tagged individuals did not commute together, but did join group members in small foraging patches with high densities of flowering balsas on the mainland. We hypothesized that close proximity to group members would increase foraging efficiency if social foraging were used to find flower clusters, but distance between tagged individuals did not predict foraging efficiency or energy expenditure. However, decreased distance among tagged bat positively influenced time outside of the cave and increased the duration and synchrony of resting. These results suggest that social proximity seemed to be more important during resting, and indicate that factors other than increased feeding efficiency may structure social relationships of group members while foraging. It appears that, depending on the local resource landscape, these bats have an excellent map even of distant resources and may use social information only for current patch discovery. They then may no longer rely on social information during daily foraging.HighlightsUnlike in Trinidad, greater spear-nosed bats in Panamá do not commute or forage as a groupForaging distances are double of previously known and across the seaBats rest near each other, but do not forage more efficiently when closeSocial information may mainly be used for the discovery of feeding areasLocal resource landscapes may cause strong variation in social behaviour
A Biophysical Counting Mechanism for Keeping Time
Authors: Zemlianova Klavdia , Bose Amitabha , Rinzel John 
Published: October 2021

AbstractThe ability to estimate and produce appropriately timed responses is central to many behaviors including speaking, dancing, and playing a musical instrument. A classical framework for estimating or producing a time interval is the pacemaker-accumulator model in which pulses of a pacemaker are counted and compared to a stored representation. However, the neural mechanisms for how these pulses are counted remains an open question. The presence of noise and stochasticity further complicate the picture. We present a biophysical model of how to keep count of a pacemaker in the presence of various forms of stochasticity using a system of bistable Wilson-Cowan units asymmetrically connected in a one-dimensional array; all units receive the same input pulses from a central clock but only one unit is active at any point in time. With each pulse from the clock, the position of the activated unit changes thereby encoding the total number of pulses emitted by the clock. This neural architecture maps the counting problem into the spatial domain, which in turn translates count to a time estimate. We further extend the model to a hierarchical structure to be able to robustly achieve higher counts.
Role of Ring6 in the function of the E. coli MCE protein LetB
Authors: Vieni Casey , Coudray Nicolas , Isom Georgia L. , Bhabha Gira , Ekiert Damian C. 
Published: October 2021

AbstractLetB is a tunnel-forming protein found in the cell envelope of some double-membraned bacteria, and is thought to be important for the transport of lipids between the inner and outer membranes. In Escherichia coli the LetB tunnel is formed from a stack of seven rings (Ring1 - Ring7), in which each ring is composed of a homo-hexameric assembly of MCE domains. The primary sequence of each MCE domain of the LetB protein is substantially divergent from the others, making each MCE ring unique in nature. The role of each MCE domain and how it contributes to the function of LetB is not well understood. Here we probed the importance of each MCE ring for the function of LetB, using a combination of bacterial growth assays and cryo-EM. Surprisingly, we find that ΔRing3 and ΔRing6 mutants, in which Ring3 and Ring6 have been deleted, confer increased resistance to membrane perturbing agents. Specific mutations in the pore-lining loops of Ring6 similarly confer increased resistance. A cryo-EM structure of the ΔRing6 mutant shows that despite the absence of Ring6, which leads to a shorter assembly, the overall architecture is maintained, highlighting the modular nature of MCE proteins. Previous work has shown that Ring6 is dynamic and in its closed state, may restrict the passage of substrate through the tunnel. Our work suggests that removal of Ring6 may relieve this restriction. The deletion of Ring6 combined with mutations in the pore-lining loops leads to a model for the tunnel gating mechanism of LetB. Together, these results provide insight into the functional roles of individual MCE domains and pore-lining loops in the LetB protein.HighlightsDeleting MCE domains 3 or 6 from LetB confers increased resistance to membrane-perturbing agentsCryo-EM structure of ΔRing6 LetB mutant highlights the modular nature of MCE domainsMutations along LetB pore-lining loops modulate detergent resistance
EWS/FLI mediated reprogramming of 3D chromatin promotes an altered transcriptional state in Ewing sarcoma
Authors: Showpnil Iftekhar A. , Selich-Anderson Julia , Taslim Cenny , Boone Megann A. , Crow Jesse C. , Theisen Emily R. , Lessnick Stephen L. 
Published: October 2021

ABSTRACTEwing sarcoma is a prototypical fusion transcription factor-associated pediatric cancer that expresses EWS/FLI or highly related fusions. EWS/FLI dysregulates transcription to induce and maintain sarcomagenesis, but the mechanisms utilized are not fully understood. We therefore sought to define the global effects of EWS/FLI on chromatin conformation and transcription in Ewing sarcoma. We found that EWS/FLI (and EWS/ERG) genomic localization is largely conserved across multiple patient-derived Ewing sarcoma cell lines. EWS/FLI binding is primarily associated with compartment activation, establishment of topologically-associated domain (TAD) boundaries, enhancer-promoter looping that involve both intra- and inter-TAD interactions, and gene activation. Importantly, local chromatin features provide the basis for transcriptional heterogeneity in regulation of direct EWS/FLI target genes across different Ewing sarcoma cell lines. These data demonstrate a key role of EWS/FLI in mediating genome-wide changes in chromatin configuration and support the notion that fusion transcription factors serve as master regulators through three-dimensional reprogramming of chromatin.
Laminin switches terminal differentiation fate of human trophoblast stem cells under chemically defined culture conditions
Authors: Karakis Victoria , McDonald Thomas , Cordiner Abigail , Mischler Adam , Miguel Adriana San , Rao Balaji M 
Published: October 2021

AbstractHuman trophoblast stem cells (hTSCs) have emerged as a powerful tool to model early placental development in vitro. Analogous to the epithelial cytotrophoblast in the placenta, hTSCs can differentiate into cells of the extravillous trophoblast (EVT) lineage or the multinucleate syncytiotrophoblast (STB). Here we present a chemically defined culture system for STB and EVT differentiation of hTSCs. Notably, in contrast to current approaches, we do not utilize transforming growth factor-beta inhibitors or a passage step for EVT differentiation, or forskolin for STB formation. Strikingly, under these conditions, presence of a single additional extracellular cue – lam-inin-1 – switched the terminal differentiation of hTSCs from STB to the EVT lineage. Activation of the sphingosine-1 receptor 3 receptor (S1PR3) using a chemical agonist could drive EVT differentiation of hTSCs in the absence of exogenous laminin, albeit less efficiently. To illustrate the utility of a chemically defined culture system for mechanistic studies, we examined the role of protein kinase C (PKC) signaling during hTSC differentiation to the EVT lineage. Inhibition of PKCα/β signaling significantly reduced HLA-G expression and the formation of HLA-G+mesen-chymal EVTs during hTSC differentiation mediated by laminin exposure; however, it did not prevent commitment to the EVT lineage or STB differentiation. The chemically defined culture system for hTSC differentiation established herein facilitates quantitative analysis of heterogeneity that arises during hTSC differentiation, and will enable mechanistic studies in vitro.SignificanceDespite its importance to a healthy pregnancy, early human placental development remains poorly understood. Mechanistic studies are impeded by restrictions on research with human embryos and fetal tissues, and significant differences in placentation between humans and commonly used animal models. In this context, human trophoblast stem cells (hTSCs) have emerged as attractive in vitro models for the epithelial cytotrophoblast of the early gestation human placenta. Here we describe chemically defined culture conditions for differentiation of hTSCs to the two major differentiated cell types – extravillous trophoblast and syncytiotrophoblast. These culture conditions enable in vitro studies to reveal molecular mechanisms regulating hTSC differentiation.
Genetic control of the dynamic transcriptional response to immune stimuli and glucocorticoids at single cell resolution
Authors: Resztak Justyna A , Wei Julong , Zilioli Samuele , Sendler Edward , Alazizi Adnan , Mair-Meijers Henriette E , Wu Peijun , Wen Xiaoquan , Slatcher Richard B , Zhou Xiang , Luca Francesca , Pique-Regi Roger 
Published: October 2021

AbstractSynthetic glucocorticoids, such as dexamethasone, have been used as treatment for many immune conditions, such as asthma and more recently severe COVID-19. Single cell data can capture more fine-grained details on transcriptional variability and dynamics to gain a better understanding of the molecular underpinnings of inter-individual variation in drug response. Here, we used single cell RNA-seq to study the dynamics of the transcriptional response to glucocorticoids in activated Peripheral Blood Mononuclear Cells from 96 African American children. We employed novel statistical approaches to calculate a mean-independent measure of gene expression variability and a measure of transcriptional response pseudotime. Using these approaches, we demonstrated that glucocorticoids reverse the effects of immune stimulation on both gene expression mean and variability. Our novel measure of gene expression response dynamics, based on the diagonal linear discriminant analysis, separated individual cells by response status on the basis of their transcriptional profiles and allowed us to identify different dynamic patterns of gene expression along the response pseudotime. We identified genetic variants regulating gene expression mean and variability, including treatment-specific effects, and demonstrated widespread genetic regulation of the transcriptional dynamics of the gene expression response.
An Approach to Measuring Protein Turnover in Human Induced Pluripotent Stem Cell Organoids by Mass Spectrometry
Authors: Duchesne Anthony , Dong Jing , Bayne Andrew N. , Mohamed Nguyen-Vi , Yi Wei , Mathur Meghna , Fon Edward A. , Durcan Thomas M. , Trempe Jean-François 
Published: October 2021

AbstractPatient-derived organoids from induced pluripotent stem cells have emerged as a model for studying human diseases beyond conventional two-dimensional (2D) cell culture. Briefly, these three-dimensional organoids are highly complex, capable of self-organizing, recapitulate cellular architecture, and have the potential to model diseases in complex organs, such as the brain. For example, the hallmark of Parkinson’s disease - proteostatic dysfunction leading to the selective death of neurons in the substantia nigra - present a subtle distinction in cell type specificity that is simply lost in 2D cell culture models. As such, the development of robust methods to study global proteostasis and protein turnover in organoids will remain a critical need as organoid models evolve. To solve this problem, we have designed a workflow to extract proteins from organoids and measure global protein turnover using mass spectrometry and stable isotope labeling using amino acids in cell culture (SILAC). This allowed us to measure the turnover rates of 844 proteins and compare protein turnover to previously reported data in primary cell cultures and in vivo models. Taken together, this method will facilitate the study of proteostasis in organoid models of human disease and will provide an analytical and statistical framework to measure protein turnover in organoids of all cell types.
Evolutionary insights into primate skeletal gene regulation using a comparative cell culture model
Authors: Housman Genevieve , Briscoe Emilie , Gilad Yoav 
Published: October 2021

AbstractThe evolution of complex skeletal traits in primates was likely influenced by both genetic and environmental factors. Because skeletal tissues are notoriously challenging to study using functional genomic approaches, they remain poorly characterized even in humans, let alone across multiple species. The challenges involved in obtaining functional genomic data from the skeleton, combined with the difficulty of obtaining such tissues from nonhuman apes, motivated us to consider an alternative in vitro system with which to comparatively study gene regulation in skeletal cell types. Specifically, we differentiated six human and six chimpanzee induced pluripotent stem cell lines (iPSCs) into mesenchymal stem cells (MSCs) and subsequently into osteogenic cells (bone cells). We validated differentiation using standard methods and collected single-cell RNA sequencing data from over 100,000 cells across multiple samples and replicates at each stage of differentiation. While most genes that we examined display conserved patterns of expression across species, hundreds of genes are differentially expressed (DE) between humans and chimpanzees within and across stages of osteogenic differentiation. Some of these interspecific DE genes show functional enrichments relevant in skeletal tissue trait development. Moreover, topic modeling indicates that interspecific gene programs become more pronounced as cells mature. Overall, we propose that this in vitro model can be used to identify interspecific regulatory differences that may have contributed to skeletal trait differences between species.Author SummaryPrimates display a range of skeletal morphologies and susceptibilities to skeletal diseases, but the molecular basis of these phenotypic differences is unclear. Studies of gene expression variation in primate skeletal tissues are extremely restricted due to the ethical and practical challenges associated with collecting samples. Nevertheless, the ability to study gene regulation in primate skeletal tissues is crucial for understanding how the primate skeleton has evolved. We therefore developed a comparative primate skeletal cell culture model that allows us to access a spectrum of human and chimpanzee cell types as they differentiate from stem cells into bone cells. While most gene expression patterns are conserved across species, we also identified hundreds of differentially expressed genes between humans and chimpanzees within and across stages of differentiation. We also classified cells by osteogenic stage and identified additional interspecific differentially expressed genes which may contribute to skeletal trait differences. We anticipate that this model will be extremely useful for exploring questions related to gene regulation variation in primate bone biology and development.