bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuronal Activity in Dorsal Anterior Cingulate Cortex during Economic Choices under Variable Action Costs
Authors: Cai Xinying , Padoa-Schioppa Camillo 
Published: June 2021

ABSTRACTThe role of the dorsal anterior cingulate cortex (ACCd) in decision making has often been discussed but remains somewhat unclear. On the one hand, numerous studies implicated this area in decisions driven by effort or action cost. On the other hand, work on economic choices between goods (under fixed action costs) found that neurons in ACCd encoded only post-decision variables. To advance our understanding of the role played by this area in decision making, we trained monkeys to choose between different goods (juice types) offered in variable amounts and with different action costs. Importantly, the task design dissociated computation of the action cost from planning of any particular action. Neurons in ACCd encoded the chosen value and the binary choice outcome in several reference frames (chosen juice, chosen cost, chosen action). Thus, this area provided a rich representation of post-decision variables. In contrast, neurons in ACCd did not represent pre-decision variables such as individual offer values in any reference frame. Hence, ongoing decisions are unlikely guided by ACCd. Conversely, neuronal activity in this area might inform subsequent choices.
Phase-separated stress granules and processing bodies are compromised in Myotonic Dystrophy Type 1
Authors: Gulyurtlu Selma , Magon Monika S , Guest Patrick , Papavasiliou Panagiotis P , Prescott Alan R , Sleeman Judith E 
Published: June 2021

SummaryRNA regulation in mammalian cells requires complex physical compartmentalisation using structures thought to be formed by liquid-liquid phase separation. Disruption of these structures is implicated in numerous degenerative diseases. Myotonic Dystrophy Type 1 (DM1) is a multi-systemic trinucleotide repeat disorder resulting from a CTG expansion in the dystonia myotonica protein kinase gene (DMPK). The cellular hall-mark of DM1 is the formation of nuclear foci containing expanded DMPK RNA (CUGexp). We report here the deregulation of stress granules and processing bodies (P-bodies), two cytoplasmic structures key for mRNA regulation, in cell culture models of DM1. Alterations to the rates of formation and dispersal of stress granules suggest an altered ability to respond to stress associated with DM1, while changes to the structure and dynamics of stress granules and P-bodies suggest that a more widespread alteration to the biophysical properties of cellular structures may be a consequence of the presence of CUGexp RNA.
Enhancing Sampling of Water Rehydration on Ligand Binding: A Comparison of Techniques
Authors: Ge Yunhui , Wych David C. , Samways Marley L. , Wall Michael E. , Essex Jonathan W. , Mobley David L. 
Published: June 2021

1ABSTRACTWater often plays a key role in protein structure, molecular recognition, and mediating protein-ligand interactions. Thus, free energy calculations must adequately sample water motions, which often proves challenging in typical MD simulation timescales. Thus, the accuracy of methods relying on MD simulations ends up limited by slow water sampling. Particularly, as a ligand is removed or modified, bulk water may not have time to fill or rearrange in the binding site. In this work, we focus on several molecular dynamics (MD) simulation-based methods attempting to help rehydrate buried water sites: BLUES, using nonequilibrium candidate Monte Carlo (NCMC); grand, using grand canonical Monte Carlo (GCMC); and normal MD. We assess the accuracy and efficiency of these methods in rehydrating target water sites. We selected a range of systems with varying numbers of waters in the binding site, as well as those where water occupancy is coupled to the identity or binding mode of the ligand. We analyzed rehydration of buried water sites in binding pockets using both clustering of trajectories and direct analysis of electron density maps. Our results suggest both BLUES and grand enhance water sampling relative to normal MD and grand is more robust than BLUES, but also that water sampling remains a major challenge for all of the methods tested. The lessons we learned for these methods and systems are discussed.
Deep learning trained on H&E tumor ROIs predicts HER2 status and Trastuzumab treatment response in HER2+ breast cancer
Authors: Farahmand Saman , Fernandez Aileen I , Ahmed Fahad Shabbir , Rimm David L. , Chuang Jeffrey H. , Reisenbichler Emily , Zarringhalam Kourosh 
Published: June 2021

AbstractThe current standard of care for many patients with HER2-positive breast cancer is neoadjuvant chemotherapy in combination with anti-HER2 agents, based on HER2 amplification as detected by in situ hybridization (ISH) or protein immunohistochemistry (IHC). However, hematoxylin & eosin (H&E) tumor stains are more commonly available, and accurate prediction of HER2 status and anti-HER2 treatment response from H&E would reduce costs and increase the speed of treatment selection. Computational algorithms for H&E have been effective in predicting a variety of cancer features and clinical outcomes, including moderate success in predicting HER2 status. In this work, we present a novel convolutional neural network (CNN) approach able to predict HER2 status with increased accuracy over prior methods. We trained a CNN classifier on 188 H&E whole slide images (WSIs) manually annotated for tumor regions of interest (ROIs) by our pathology team. Our classifier achieved an area under the curve (AUC) of 0.90 in cross-validation of slide-level HER2 status and 0.81 on an independent TCGA test set. Within slides, we observed strong agreement between pathologist annotated ROIs and blinded computational predictions of tumor regions / HER2 status. Moreover, we trained our classifier on pre-treatment samples from 187 HER2+ patients that subsequently received trastuzumab therapy. Our classifier achieved an AUC of 0.80 in a five-fold cross validation. Our work provides an H&E-based algorithm that can predict HER2 status and trastuzumab response in breast cancer at an accuracy that is better than IHC and may benefit clinical evaluations.
Practical observations on the use of fluorescent reporter systems in C. difficile
Authors: Oliveira Paiva Ana M. , Friggen Annemieke H. , Douwes Roxanne , Wittekoek Bert , Smits Wiep Klaas 
Published: June 2021

AbstractObjectivesFluorescence microscopy is a valuable tool to study a broad variety of bacterial cell components and dynamics thereof. For Clostridioides difficile, the fluorescent proteins CFPopt, mCherryOpt and phiLOV2.1, and the self-labelling tags SNAPCd and HaloTag, hereafter collectively referred as fluorescent systems, have been described to explore different cellular pathways. In this study, we sought to characterize previously used fluorescent systems in C. difficile cells.MethodsWe performed single cell analyses using fluorescence microscopy of exponentially growing C. difficile cells harbouring different fluorescent systems, either expressing these separately in the cytosol or fused to the C-terminus of HupA, under defined conditions.ResultsWe show that the intrinsic fluorescence of C. difficile cells increases during growth, independent from sigB or spo0A. However, when C. difficile cells are exposed to environmental oxygen autofluorescence is enhanced.Cytosolic overexpression of the different fluorescent systems alone, using the same expression signals, showed heterogeneous expression of the fluorescent systems. High levels of mCherryOpt were toxic for C. difficile cells limiting the applicability of this fluorophore as a transcriptional reporter. When fused to HupA, C. difficile histone-like protein, the fluorescent systems behaved similarly and did not affect the HupA overproduction phenotype.ConclusionsThe present study compares several commonly used fluorescent systems for application as transcriptional or translational reporters in microscopy and summarizes the limitations and key challenges for live-cell imaging of C. difficile. Due to independence of molecular oxygen and fluorescent signal, SNAPCd appears the most suitable candidate for live-cell imaging in C. difficile to date.Abstract Figure
Oscillations and variability in neuronal systems: interplay of autonomous transient dynamics and fast deterministic fluctuations
Authors: Pena Rodrigo F. O. , Rotstein Horacio G. 
Published: June 2021

AbstractNeuronal systems are subject to rapid fluctuations both intrinsically and externally. These fluctuations can be disruptive or constructive. We investigate the dynamic mechanisms underlying the interactions between rapidly fluctuating signals and the intrinsic properties of the target cells to produce variable and/or coherent responses. We use linearized and non-linear conductance-based models and piecewise constant (PWC) inputs with short duration pieces. The amplitude distributions of the constant pieces consist of arbitrary permutations of a baseline PWC function. In each trial within a given protocol we use one of these permutations and each protocol consists of a subset of all possible permutations, which is the only source of uncertainty in the protocol. We show that sustained oscillatory behavior can be generated in response to various forms of PWC inputs independently of whether the stable equilibria of the corresponding unperturbed systems are foci or nodes. The oscillatory voltage responses are amplified by the model nonlinearities and attenuated for conductance-based PWC inputs as compared to current-based PWC inputs, consistent with previous theoretical and experimental work. In addition, the voltage responses to PWC inputs exhibited variability across trials, which is reminiscent of the variability generated by stochastic noise (e.g., Gaussian white noise). Our analysis demonstrates that both oscillations and variability are the result of the interaction between the PWC input and the target cell’s autonomous transient dynamics with little to no contribution from the dynamics in vicinities of the steady-state, and do not require input stochasticity.
Nutrient-dependent allometric plasticity in a male-diphenic mite
Authors: Rhebergen Flor T. , Stewart Kathryn A. , Smallegange Isabel M. 
Published: June 2021

AbstractMale secondary sexual traits often scale allometrically with body size. These allometries can be variable within species, and may shift depending on environmental conditions such as food quality. Such allometric plasticity has been hypothesized to initiate local adaptation and evolutionary diversification of scaling relationships, but is under-recorded, and its eco- evolutionary effects are not well understood. Here, we test for allometric plasticity in the bulb mite (Rhizoglyphus robini) in which large males tend to develop as armed adult fighters with thickened third legs, while small males become adult scramblers without thickened legs. We first examined the ontogenetic timing for size- and growth-dependent male morph determination, using experimentally amplified fluctuations in growth rate throughout juvenile development. Having established that somatic growth and body size determine male morph expression immediately before metamorphosis, we examined whether the relationship between adult male morph and size at metamorphosis shifts with food quality. We found that the threshold body size for male morph expression shifts towards lower values with deteriorating food quality, confirming food-dependent allometric plasticity. Such allometric plasticity may allow populations to track prevailing nutritional conditions, potentially facilitating rapid evolution of allometric scaling relationships.
Functional regulatory variants implicate distinct transcriptional networks in dementia
Authors: Cooper Yonatan A. , Davis Jessica E. , Kosuri Sriram , Coppola Giovanni , Geschwind Daniel H. 
Published: June 2021

AbstractPredicting functionality of noncoding variation is one of the major challenges in modern genetics. We employed massively parallel reporter assays to screen 5,706 variants from genome-wide association studies for both Alzheimer’s disease (AD) and Progressive Supranuclear Palsy (PSP). We identified 320 functional regulatory polymorphisms (SigVars) comprising 27 of 34 unique tested loci, including multiple independent signals across the complex 17q21.31 region. We identify novel risk genes includingPLEKHM1in PSP andAPOC1in AD, and perform gene-editing to validate four distinct causal loci, confirming complement 4 (C4A) as a novel genetic risk factor for AD. Moreover, functional variants preferentially disrupt transcription factor binding sites that converge on enhancers with differential cell-type specific activity in PSP and AD, implicating a neuronalSP1-driven regulatory network in PSP pathogenesis. These analyses support a novel mechanism underlying noncoding genetic risk, whereby common genetic variants drive disease risk via their aggregate activity on specific transcriptional programs.One Sentence SummaryHigh-throughput functional analysis of GWAS loci reveals cell-type specific regulatory networks that mediate genetic risk for dementia.
Distinct gene expression dynamics in developing and regenerating limbs
Authors: Sinigaglia Chiara , Almazán Alba , Sémon Marie , Gillet Benjamin , Hughes Sandrine , Edsinger Eric , Averof Michalis , Paris Mathilde 
Published: June 2021

ABSTRACTRegenerating animals have the ability to reproduce organs that were originally generated in the embryo and subsequently lost due to injury. Understanding whether the process of regeneration mirrors development is an open question in most regenerative species. Here we take a transcriptomics approach to examine to what extent leg regeneration shows the same temporal patterns of gene expression as leg development in the embryo, in the crustacean Parhyale hawaiensis. We find that leg development in the embryo shows stereotypic temporal patterns of gene expression. In contrast, global patterns of gene expression during leg regeneration show a high degree of variation, related to the physiology of individual animals. A major driver of this variation is the molting cycle. After dissecting the transcriptional signals of individual physiology from regeneration, we obtain temporal signals that mark distinct phases of leg regeneration. Comparing the transcriptional dynamics of development and regeneration we find that, although both processes use largely the same genes, the temporal patterns in which these gene sets are deployed are different and cannot be systematically aligned.HIGHLIGHTSSingle-limb data on transcriptional dynamics of leg development and regenerationDeveloping embryonic legs show stereotypic transcriptional profilesRegenerating leg transcriptomes show a high degree on individual variationRegenerating leg transcriptomes are influenced by adult physiology, especially moltingRegenerating leg transcriptomes reveal distinct phases of leg regenerationLeg development and regeneration use overlapping sets of genes in different temporal patterns
MetA is a ‘thermal fuse’ that arrests growth and protects Escherichia coli at elevated temperatures
Authors: Schink Severin , Gough Zara , Biselli Elena , Huiman Mariel Garcia , Chang Yu-Fang , Basan Markus , Gerland Ulrich 
Published: June 2021

AbstractAdaptive stress resistance in microbes is mostly attributed to the expression of stress response genes, such as heat shock proteins, which prevent deterioration of cellular material. Here, we report a novel response of E. coli to heat stress: induction of a growth-arrested state, caused by degradation of an enzyme in the methionine biosynthesis pathway (MetA). While MetA degradation is detrimental for proliferation, we show that the resulting growth arrest has a direct benefit for survival at high temperatures; it protects cells when temperatures rise beyond 50°C, increasing the survival chances by over 1000-fold. Using a combination of experiments and mathematical modelling, we show that degradation of MetA leads to the coexistence of growing and non-growing cells, allowing microbes to bet-hedge between continued growth if conditions remain bearable and survival if conditions worsen. We test our model experimentally and verify quantitatively how protein expression, degradation rates and environmental stresses affect the partitioning between growing and non-growing cells. Because growth arrest can be abolished with simple mutations, such as point mutations of MetA and knock-outs of proteases, we interpret the breakdown of methionine synthesis as a system that has evolved to disintegrate at high temperature and shut off growth, analogous to ‘thermal fuses’ used in engineering to shut off electricity when the device could be damaged by overheating.
Distributional reinforcement learning in prefrontal cortex
Authors: Muller Timothy H. , Butler James L. , Veselic Sebastijan , Miranda Bruno , Behrens Timothy E.J. , Kurth-Nelson Zeb , Kennerley Steven W. 
Published: June 2021

AbstractPrefrontal cortex is crucial for learning and decision-making. Classic reinforcement learning (RL) theories centre on learning the expectation of potential rewarding outcomes and explain a wealth of neural data in prefrontal cortex. Distributional RL, on the other hand, learns the full distribution of rewarding outcomes and better explains dopamine responses. Here we show distributional RL also better explains prefrontal cortical responses, suggesting it is a ubiquitous mechanism for reward-guided learning.
Targeting a proteolytic neo-epitope of CUB-domain containing protein 1 in RAS-driven cancer
Authors: Lim Shion A. , Zhou Jie , Martinko Alexander J. , Wang Yung-Hua , Filippova Ekaterina V. , Steri Veronica , Wang Donghui , Remesh Soumya G. , Liu Jia , Hann Byron , Kossiakoff Anthony A. , Evans Michael J. , Leung Kevin K. , Wells James A. 
Published: June 2021

AbstractA central challenge for any therapeutic is targeting diseased over normal cells. Proteolysis is frequently upregulated in disease and can generate proteoforms with unique neo-epitopes. We hypothesize that targeting proteolytic neo-epitopes can enable more effective and safer treatments, reflecting a conditional layer of disease-specific regulation. Here, we characterized the precise proteolytic isoforms of CUB domain containing protein 1 (CDCP1), a protein overexpressed and specifically cleaved in RAS-driven cancers. We validated that the N-terminal and C-terminal fragments of CDCP1 remain associated after proteolysis in vitro and on the surface of pancreatic cancer cells. Using a differential phage display strategy, we generated exquisitely selective recombinant antibodies that target cells harboring cleaved CDCP1 and not the full-length form using antibody-drug conjugates or a bi-specific T-cell engagers. We show tumor-specific localization and anti-tumor activity in a syngeneic pancreatic tumor model having superior safety profiles compared to a pan-CDCP1-targeting antibody. Our studies show proteolytic neo-epitopes can provide an orthogonal “AND” gate for disease-specific targeting.One-Sentence SummaryAntibody-based targeting of neo-epitopes generated by disease-associated proteolysis improves the therapeutic index
FlyPhoneDB: An integrated web-based resource for cell-cell communication prediction in Drosophila
Authors: Liu Yifang , Hu Yanhui , Li Joshua Shing Shun , Rodiger Jonathan , Comjean Aram , Attrill Helen , Antonazzo Giulia , Brown Nicholas H. , Perrimon Norbert 
Published: June 2021

ABSTRACTMulticellular organisms rely on cell-cell communication to exchange information necessary for developmental processes and metabolic homeostasis. Cell-cell communication pathways can be inferred from transcriptomic datasets based on ligand-receptor (L-R) expression. Recently, data generated from single cell RNA sequencing (scRNA-seq) have enabled L-R interaction predictions at an unprecedented resolution. While computational methods are available to infer cell-cell communication in vertebrates such a tool does not yet exist for Drosophila. Here, we generated a high confidence list of L-R pairs for the major fly signaling pathways and developed FlyPhoneDB, a quantification algorithm that calculates interaction scores to predict L-R interactions between cells. At the FlyPhoneDB user interface, results are presented in a variety of tabular and graphical formats to facilitate biological interpretation. To demonstrate that FlyPhoneDB can effectively identify active ligands and receptors to uncover cell-cell communication events, we applied FlyPhoneDB to Drosophila scRNA-seq data sets from adult midgut, abdomen, and blood, and demonstrate that FlyPhoneDB can readily identify previously characterized cell-cell communication pathways. Altogether, FlyPhoneDB is an easy-to-use framework that can be used to predict cell-cell communication between cell types from scRNA-seq data in Drosophila.
A functional network signature in the developing cerebellum: evidence from a preclinical model of autism
Authors: Soria-Ortiz María Berenice , Martínez-Torres Ataúlfo , Reyes-Haro Daniel 
Published: June 2021

AbstractAutism spectrum disorders (ASD) are pervasive neurodevelopmental conditions detected during childhood when delayed language onset and social deficits are observed. Children diagnosed with ASD frequently display sensorimotor deficits associated with the cerebellum, suggesting a dysfunction of synaptic circuits. Astroglia are part of the tripartite synapses and postmortem studies reported an increased expression of the glial fibrillary acidic protein (GFAP) in the cerebellum of ASD patients. Astroglia respond to neuronal activity with calcium transients that propagate to neighboring cells, resulting in a functional network response known as a calcium wave. This form of intercellular signaling is implicated in proliferation, migration, and differentiation of neural precursors. Prenatal exposure to valproate (VPA) is a preclinical model of ASD in which premature migration and excess of apoptosis occur in the internal granular layer (IGL) of the cerebellum during the early postnatal period. In this study we tested calcium wave propagation in the IGL of mice prenatally exposed to VPA. Sensorimotor and social deficits were observed and IGL depolarization evoked a calcium wave with astrocyte recruitment. The calcium wave propagation, initial cell recruitment, and mean amplitude of the calcium transients increased significantly in VPA-exposed mice compared to the control group. Astrocyte recruitment was significantly increased in the VPA model, but the mean amplitude of the calcium transients was unchanged. Western blot and histological studies revealed an increased expression of GFAP and higher astroglial density. We conclude that the functional network of the IGL is remarkably augmented in the preclinical model of autism.