bluuebunny/crossref_metadata_2025_split huggingface dataset:
Only the fastest corticospinal fibers contribute to beta corticomuscular coherence
Authors: Ibáñez J. , Del Vecchio A. , Rothwell J. C. , Baker S. N. , Farina D. 
Published: November 2020

ABSTRACTA common way to study human corticospinal transmission is with transcranial magnetic stimulation. However, this is biased to activity in the fastest conducting axons. It is unclear whether conclusions obtained in this context are representative of volitional activity in mild-to-moderate contractions. A possible alternative to overcome this limitation is to study the corticospinal transmission of endogenously generated brain activity. Here we study the transmission speeds of cortical beta rhythms travelling to the muscles during steady contractions. To do this, we introduce new methods to improve delay estimates in the corticomuscular transmission of beta rhythms, and which we validate both in simulations and experimentally. Applying these approaches to experimental data from humans, we show that corticomuscular beta transmission delays are only 1-2ms longer than expected from the fastest corticospinal pathway. Simulations using realistic distributions of the conduction velocities for descending axons projecting to lower motoneurons suggest two scenarios that can explain these results: either a very small fraction of only the fastest corticospinal axons selectively transmit beta activity, or else the entire pool does. The implications that these two scenarios have for our understanding of corticomuscular interactions are discussed in the final part of this manuscript.SIGNIFICANCEWe present and validate an improved methodology to measure the delay in the transmission of cortical beta activity to tonically active muscles. The estimated corticomuscular beta transmission delays which this yields are remarkably similar to those expected from transmission in the fastest corticospinal axons. A simulation of beta transmission along a pool of corticospinal axons using a realistic distribution of fiber diameters suggests two possible mechanisms by which fast corticomuscular transmission is achieved: either a very small fraction of descending axons transmits beta activity to the muscles or, alternatively, the entire population does and natural cancellation of slow channels occurs due to the distribution of axon diameters in the corticospinal tract.
Patterns of MHC-dependent sexual selection in a free-living population of sheep
Authors: Huang Wei , Pilkington Jill G. , Pemberton Josephine M. 
Published: November 2020

AbstractThe MHC is one of the most polymorphic gene clusters in vertebrates and play an essential role in adaptive immunity. Apart from pathogen-mediated selection, sexual selection can also contribute to the maintenance of MHC diversity. MHC-dependent sexual selection could occur via several mechanisms but at present there is no consensus as to which of these mechanisms are involved and their importance. Previous studies have often suffered from limited genetic and behavioural data and small sample size, and were rarely able to examine all the mechanisms together, determine whether signatures of MHC-based non-random mating are independent of genomic effects or differentiate whether MHC-dependent sexual selection takes place at the pre- or post-copulatory stage. In this study, we use Monte Carlo simulation to investigate evidence for non-random MHC-dependent mating patterns by all three mechanisms in a free-living population of Soay sheep. Using 1710 sheep diplotyped at the MHC class IIa region and genome-wide SNPs, together with field observations of consorts, we found sexual selection against a particular haplotype in males at the pre-copulatory stage and sexual selection against female MHC heterozygosity during the rut. We also found MHC-dependent disassortative mating at the post-copulatory stage, along with strong evidence of inbreeding avoidance at both stages. However, results from generalized linear mixed models suggest that the pattern of MHC-dependent disassortative mating could be a by-product of inbreeding avoidance. Our results therefore suggest that while multiple apparent mechanisms of non-random mating with respect to the MHC may occur, some of them have alternative explanations.
Deletion ofLetmd1leads to the disruption of mitochondrial function in brown adipose tissue
Authors: Song Runjie , Du Yaqi , Li Peng , Liu Huijiao , Zheng Han , Lu Xiaohui , Wang Shenghong , Zhou Lijun , Rahman Nafis A , Wołczyński Sławomir , Kretowski Adam , Ren Fazheng , Li Xiru , Li Xiangdong 
Published: November 2020

AbstractHuman cervical cancer oncogene (HCCR-1), also named as LETMD1, is a LETM-domain containing outer mitochondrial membrane protein which plays an important role in the carcinogenesis of cancers. Surprisingly, we found that loss ofLetmd1in mice leads to multiply severe abnormities, such as the brown adipose tissue (BAT) whitening, disruption of thermogenesis, cold-induced death, diet-induced obesity, hyperglycinemia and insulin resistance. Mechanistically, deletion ofLetmd1in BAT causes the reduction of mitochondrial calcium ion, which in turn results in the suppressed fission of mitochondria, and ultimately leads to the depletion ofUcp1-mediated BAT heat production. This study indicates that LETMD1 plays a crucial role in controlling BAT thermogenesis and energy homeostasis by regulating mitochondrial structures and functions, and also provides a novel insight for the clinical biomarker and therapeutical target of oncogene for the metabolic disorders.HighlightsLetmd1is an oncogene and also highly expressed in brown adipose tissue (BAT) of human and mice.Loss ofLetmd1leads to BAT whitening, diet-induced obesity, hyperglycemia and insulin resistant.Letmd1knockout causes the disruption of thermogenesis and death at 4°C exposure.Deletion ofLetmd1results in mitochondrial calcium homeostasis disorders.Graphic abstract
Computing the Orientational-Average of Diffusion-Weighted MRI Signals: A Comparison of Different Techniques
Authors: Afzali Maryam , Knutsson Hans , Özarslan Evren , Jones Derek K 
Published: November 2020

ABSTRACTNumerous applications in diffusion MRI, from multi-compartment modeling to power-law analyses, involves computing the orientationally-averaged diffusion-weighted signal. Most approaches implicitly assume, for a given b-value, that the gradient sampling vectors are uniformly distributed on a sphere (or ‘shell’), computing the orientationally-averaged signal through simple arithmetic averaging. One challenge with this approach is that not all acquisition schemes have gradient sampling vectors distributed over perfect spheres (either by design, or due to gradient non-linearities). To ameliorate this challenge, alternative averaging methods include: weighted signal averaging; spherical harmonic representation of the signal in each shell; and using Mean Apparent Propagator MRI (MAP-MRI) to derive a three-dimensional signal representation and estimate its ‘isotropic part’. This latter approach can be applied to all q-space sampling schemes, making it suitable for multi-shell acquisitions when unwanted gradient non-linearities are present.Here, these different methods are compared under different signal-to-noise (SNR) realizations. With sufficiently dense sampling points (61points per shell), and isotropically-distributed sampling vectors, all methods give comparable results, (accuracy of MAP-MRI-based estimates being slightly higher albeit with slightly elevated bias as b-value increases). As the SNR and number of data points per shell are reduced, MAP-MRI-based approaches give pronounced improvements in accuracy over the other methods.
Cell cycle lengths of stem cells and their lineage from cellular demography
Authors: Gadre Purna , Nitsure Nitin , Mazumdar Debasmita , Gupta Samir , Ray Krishanu 
Published: November 2020

AbstractAdult stem cells and their transit-amplifying (TA) progeny dynamically alter their proliferation rates to maintain tissue homeostasis. To test how the division rates of stem cell and TA cells affect tissue growth and differentiation, we developed a computation strategy which estimates the average cell cycle lengths/lifespans of germline stem cells (GSCs) and their TA progeny from cellular demography. Analysis of the wild-type data fromDrosophilatestis using this method indicated anomalous changes in lifespans during the germline transit-amplification with a nearly 1.3-fold increase after the first division and about a 2-fold decrease in the subsequent stage. Genetic perturbations altering the cell cycle rates of GSC and its immediate daughter, the gonialblast (GB), proportionately changed the rates of subsequent TA divisions. Notably, a nearly 2-fold increase or decrease in the total TA duration did not alter the induction of meiosis after four mitotic cycles. Altogether, these results suggest that the rates of GSC and GB divisions can adjust the rates of subsequent divisions and the onset of differentiation.Significance StatementDynamic regulation of the proliferation rate of stem cells and their transit-amplifying daughters maintains tissue homeostasis in different conditions such as tissue regeneration, aging, and hormonal imbalance. Previous studies suggested that a molecular clock in the stem cell progeny determines the timing of differentiation. This work shows that alterations of the rates of stem cell divisions, as well as that of its progeny, could override the differentiation clock in theDrosophilatestis, and highlights a possible mechanism of fine-tuning the transit-amplification program under different conditions such as tissue damage, aging, and hormonal inputs. Also, the method developed for this study could be adapted to estimate lineage expansion plasticity from demographic changes in other systems.HighlightsDetermination of cellular lifespan during transit-amplification from demographyLifespans of Drosophila male germline cells changes anomalously during the TALifespan changes of germline stem cells readjust that of the progeny cellsAnomalous lifespan expansion midway through TA precedes the Bam onset
Spatial structure of natural boxwood and the invasive box tree moth can promote coexistence
Authors: Ledru Léo , Garnier Jimmy , Gallet Christiane , Noûs Camille , Ibanez Sébastien 
Published: November 2020

AbstractIn the absence of top-down and bottom-up controls, herbivores eventually drive themselves to extinction by ex-hausting their host plants. Poorly mobile herbivores may experiment only local disappearance, because they can recolonize intact plant patches elsewhere, leaving time to previously over-exploited patches to regrow. However most herbivores such as winged insects are highly mobile, which may prevent the formation of spatial heterogeneity.We test if long-distance dispersal can preclude coexistence using the invasion of box tree moth (Cydalima perspectalis) in Europe as a model system. We build a lattice model and estimate the parameters with a combination of field measurements, experimental data and literature sources. Space corresponds either to a realistic boxwood landscape in the Alps, or to theoretical landscapes of various sizes.We find that both species persist under a large range of realistic parameter values, despite a severe reduction in boxwood biomass, with an alternation of outbreaks and near-to-extinction moth densities. Large landscapes are necessary for coexistence, allowing the formation of spatial structure. Slow plant regrowth combined with long-distance dispersal could drive moths to extinction, because of resources depletion at the global scale even without a complete synchronization of the local dynamics. The spatial dynamics leads to formation of small plant patches evenly distributed in the landscape, because of a combination of local plant dispersal and global indirect competition between plants through their positive effect on moth population size. Coexistence is favored by such heterogeneous landscapes, because empty patches increase moth mortality during dispersal: the system thus creates its own stability conditions.
A neural turning point - the EEG P3 component tracks unfolding changes of mind
Authors: Parés-Pujolràs Elisabeth , Hatchuel Jeremy , Haggard Patrick 
Published: November 2020

AbstractThe ability to change one’s mind is a key feature of human cognition. Yet, the neural mechanisms underpinning our capacity to change our minds remain poorly understood. Here, we investigated the neural correlates of evidence accumulation and changes of mind in a two-step sequential sampling task. Participants provided a first, quick guess regarding the relative frequencies of target letters in a visual stream, followed by a slower, more deliberate decision. We found that the P3 amplitude evoked by successive target letters tracks an internal signed decision variable and predicts choices on a single-trial level. Moreover, this neural decision variable offers new insights into the dynamics of changes of mind. In particular, we show that the start of evidence accumulation after the early decision constitutes a neural turning point: the P3 evoked by the first letter contrary to the initial decision can be used to predict subsequent changes of mind. Our results highlight a critical interaction between the processing of external evidence and endogenous modulations of decisional parameters that facilitate reversing an original decision.
A short course of Tofacitinib sustains the immunoregulatory effect of CTLA4-Ig in presence of inflammatory cytokines and promotes long-term survival of murine cardiac allografts
Authors: Iglesias Marcos , Khalifian Saami , Oh Byoung Chol , Zhang Yichuan , Miller Devin , Beck Sarah , Brandacher Gerald , Raimondi Giorgio 
Published: November 2020

AbstractCostimulation blockade-based regimens are a promising strategy for management of transplant recipients. However, maintenance immunosuppression via CTLA4-Ig monotherapy is characterized by high frequency of rejection episodes. Recent evidence suggests that inflammatory cytokines contribute to alloreactive T cell activation in a CD28-independent manner, a reasonable contributor to the limited efficacy of CTLA4-Ig. In this study, we investigated the possible synergism of a combined short-term inhibition of cytokine signaling and CD28 engagement on the modulation of rejection. Our results demonstrate that the JAK/STAT inhibitor Tofacitinib restored the immunomodulatory effect of CTLA4-Ig on mouse alloreactive T cells in presence of inflammatory cytokines. Tofacitinib exposure conferred dendritic cells with a tolerogenic phenotype reducing their cytokine secretion and costimulatory molecules expression. JAK inhibition also directly affected T cell activation. In vivo, the combination of CTLA4-Ig and Tofacitinib induced long-term survival of heart allografts and, importantly, it was equally effective when using grafts subjected to prolonged ischemia. Transplant survival correlated with a reduction in effector T cells and intragraft accumulation of regulatory T cells. Collectively, our studies demonstrate a powerful synergism between CTLA4-Ig and Tofacitinib and suggest their combined use is a promising strategy for improved management of transplanted patients.
No preference for prosocial ‘helping’ behavior in rats with concurrent social interaction opportunities
Authors: Heslin Kelsey A. , Brown Michael F. 
Published: November 2020

Abstract‘Helping behavior’ tasks are proposed to assess prosocial or ‘empathic’ behavior in rodents. This paradigm characterizes the behavior of subject animals presented with the opportunity to release a conspecific from a distressing situation. Previous studies found a preference in rats for releasing restrained or distressed conspecifics over other controls (e.g., empty restrainers or inanimate objects). An empathy account was offered to explain the observed behaviors, claiming subjects were motivated to reduce the distress of others based on a rodent homologue of empathy. An opposing account attributes all previous results to subjects seeking social-contact. To dissociate these two accounts for helping behavior, we presented subject rats with three simultaneous choice alternatives: releasing a restrained conspecific, engaging a non-restrained conspecific, or not socializing. Subjects showed an initial preference for socializing with the non-restrained conspecific, and no preference for helping. This result contradicts the empathy account, but is consistent with the social-contact account of helping behavior.
Identification of high confidence human poly(A) RNA isoform scaffolds using nanopore sequencing
Authors: Mulroney Logan , Wulf Madalee G. , Schildkraut Ira , Tzertzinis George , Buswell John , Jain Miten , Olsen Hugh , Diekhans Mark , Corrêa Ivan R. , Akeson Mark , Ettwiller Laurence 
Published: November 2020

ABSTRACTNanopore sequencing devices read individual RNA strands directly. This facilitates identification of exon linkages and nucleotide modifications; however, using conventional methods the 5′ and 3′ ends of poly(A) RNA cannot be identified unambiguously. This is due in part to the architecture of the nanopore/enzyme-motor complex, and in part to RNA degradation in vivo and in vitro that can obscure transcription start and end sites. In this study, we aimed to identify individual full-length human RNA isoform scaffolds among ∼4 million nanopore poly(A)-selected RNA reads. First, to identify RNA strands bearing 5′ m7G caps, we exchanged the biological cap for a modified cap attached to a 45-nucleotide oligomer. This oligomer adaptation method improved 5′ end sequencing and ensured correct identification of the 5′ m7G capped ends. Second, among these 5′-capped nanopore reads, we screened for ionic current signatures consistent with a 3′ polyadenylation site. Combining these two steps, we identified 294,107 individual high-confidence full-length RNA scaffolds, most of which (257,721) aligned to protein-coding genes. Of these, 4,876 scaffolds indicated unannotated isoforms that were often internal to longer, previously identified RNA isoforms. Orthogonal data confirmed the validity of these high-confidence RNA scaffolds.
Efficient and precise single-cell reference atlas mapping with Symphony
Authors: Kang Joyce B. , Nathan Aparna , Zhang Fan , Millard Nghia , Rumker Laurie , Moody D. Branch , Korsunsky Ilya , Raychaudhuri Soumya 
Published: November 2020

AbstractRecent advances in single-cell technologies and integration algorithms make it possible to construct comprehensive reference atlases encompassing many donors, studies, disease states, and sequencing platforms. Much like mapping sequencing reads to a reference genome, it is essential to be able to map query cells onto complex, multimillion-cell reference atlases to rapidly identify relevant cell states and phenotypes. We present Symphony (https://github.com/immunogenomics/symphony), an algorithm for building integrated reference atlases of millions of cells in a convenient, portable format that enables efficient query mapping within seconds. Symphony localizes query cells within a stable low-dimensional reference embedding, facilitating reproducible downstream transfer of reference-defined annotations to the query. We demonstrate the power of Symphony by (1) mapping a multi-donor, multi-species query to predict pancreatic cell types, (2) localizing query cells along a developmental trajectory of human fetal liver hematopoiesis, and (3) inferring surface protein expression with a multimodal CITE-seq atlas of memory T cells.
Deep Learning-based Ligand Design using Shared Latent Implicit Fingerprints from Collaborative Filtering
Authors: Srinivas Raghuram , Verma Niraj , Kraka Elfi , Larson Eric C. 
Published: November 2020

AbstractIn their previous work, Srinivas et al.1 have shown that implicit fingerprints capture ligands and proteins in a shared latent space, typically for the purposes of virtual screening with collaborative filtering models applied on known bioactivity data. In this work, we extend these implicit fingerprints/descriptors using deep learning techniques to translate latent descriptors into discrete representations of molecules (SMILES), without explicitly optimizing for chemical properties. This allows the design of new compounds based upon the latent representation of nearby proteins, thereby encoding drug-like properties including binding affinities to known proteins. The implicit descriptor method does not require any fingerprint similarity search, which makes the method free of any bias arising from the empirical nature of the fingerprint models. 1 We evaluate the properties of the novel drugs generated by our approach using physical properties of drug-like molecules and chemical complexity. Additionally, we analyze the reliability of the biological activity of the new compounds generated using this method by employing models of protein ligand interaction, which assists in assessing the potential binding affinity of the designed compounds. We find that the generated compounds exhibit properties of chemically feasible compounds and are likely to be excellent binders to known proteins. Furthermore, we also analyze the diversity of compounds created using the Tanimoto distance and conclude that there is a wide diversity in the generated compounds.Graphical TOC Entry
A conserved ubiquitin- and ESCRT-dependent pathway to regulate human lysosomal membrane proteins
Authors: Zhang Weichao , Yang Xi , Chen Liang , Liu Yun-Yu , Venkatarangan Varsha , Reist Lucas , Hanson Phyllis , Xu Haoxing , Wang Yanzhuang , Li Ming 
Published: November 2020

AbstractThe lysosome is an essential organelle to recycle cellular materials and maintain nutrient homeostasis, but the mechanism to down-regulate lysosomal membrane proteins is poorly understood. In this study, we developed a cycloheximide chase assay to measure the half-lives of ~30 human lysosomal membrane proteins, and identified RNF152 as a short-lived protein. The degradation of RNF152 depends on ubiquitin and the endosomal sorting complexes required for transport (ESCRT) machinery. Ubiquitinated RNF152 is sorted and internalized by the ESCRT machinery into the lysosomal lumen for degradation. Strikingly, when expressed in budding yeast, human RNF152 is also degraded by the vacuole (yeast lysosome) in an ESCRT-dependent manner. Thus, our study uncovered a conserved mechanism to down-regulate lysosome membrane proteins.
A modified fluctuation test for elucidating drug resistance in microbial and cancer cells
Authors: Bokes Pavol , Singh Abhyudai 
Published: November 2020

AbstractClonal populations of microbial and cancer cells are often driven into a drug-tolerant persister state in response to drug therapy, and these persisters can subsequently adapt to the new drug environment via genetic and epigenetic mechanisms. Estimating the frequency with which drug-tolerance states arise, and its transition to drug-resistance, is critical for designing efficient treatment schedules. Here we study a stochastic model of cell proliferation where drug-tolerant persister cells transform into a drug-resistant state with a certain adaptation rate, and the resistant cells can then proliferate in the presence of the drug. Assuming a random number of persisters to begin with, we derive an exact analytical expression for the statistical moments and the distribution of the total cell count (i.e., colony size) over time. Interestingly, for Poisson initial conditions the noise in the colony size (as quantified by the Fano factor) becomes independent of the initial condition and only depends on the adaptation rate. Thus, experimentally quantifying the fluctuations in the colony sizes provides an estimate of the adaptation rate, which then can be used to infer the starting persister numbers from the mean colony size. Overall, our analysis introduces a modification of the classical Luria–Delbrück experiment, also called the “Fluctuation Test”, providing a valuable tool to quantify the emergence of drug resistance in cell populations.