bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptomes and metabolism define mouse and human MAIT cell heterogeneity
Authors: Chandra Shilpi , Ascui Gabriel , Riffelmacher Thomas , Chawla Ashu , Ramirez-Suastegui Ciro , Castelan Viankail Cedillo , Seumois Gregory , Simon Hayley , Murray Mallory Paynich , Seo Goo-Young , Premlal Ashmitaa Logandha Ramamoorthy , Verstichel Greet , Li Yingcong , Lin Chia-Hao , Greenbaum Jason , Lamberti John , Murthy Raghav , Nigro John , Cheroutre Hilde , Ottensmeier Christian H. , Hedrick Stephen M. , Lu Li-Fan , Vijayanand Pandurangan , Kronenberg Mitchell 
Published: December 2021

AbstractMucosal-associated invariant T (MAIT) cells are a subpopulation of T lymphocytes that respond to microbial metabolites. We performed single-cell RNA sequencing and metabolic analyses of MAIT cell subsets in thymus and peripheral tissues from mice and humans to define the heterogeneity and developmental pathway of these innate-like lymphocytes. We show that the predominant mouse subset, which produces IL-17 (MAIT17), and the subset that produces IFNγ (MAIT1), have greatly different transcriptomes and metabolic states in the thymus and periphery. A splenic MAIT subset has a transcriptome similar to circulating lymphocytes, and in mice these also are found in recent thymic emigrants, suggesting partially mature cells emigrate from the thymus. Human MAIT cells are predominantly MAIT1 cells, but have a different metabolism from their mouse counterparts with increased fatty acid uptake and storage. Although mouse and human subsets are similar in thymus, in the periphery they diverge, likely reflecting environmental influences.
The origins and functional effects of postzygotic mutations throughout the human lifespan
Authors: Rockweiler Nicole B. , Ramu Avinash , Nagirnaja Liina , Wong Wing H. , Noordam Michiel J. , Drubin Casey W. , Huang Ni , Miller Brian , Todres Ellen Z. , Vigh-Conrad Katinka A. , Zito Antonino , Small Kerrin S. , Ardlie Kristin G. , Cohen Barak A. , Conrad Donald F. 
Published: December 2021

AbstractPostzygotic mutations (PZMs) begin to accrue in the human genome immediately after fertilization, but how and when PZMs affect development and lifetime health remains unclear. To study the origins and functional consequences of PZMs, we generated a multi-tissue atlas of PZMs from 948 donors using the final major release of the Genotype-Tissue Expression (GTEx) project. Nearly half the variation in mutation burden among tissue samples can be explained by measured technical and biological effects, while 9% can be attributed to donor-specific effects. Through phylogenetic reconstruction of PZMs, we find that their type and predicted functional impact varies during prenatal development, across tissues, and the germ cell lifecycle. Remarkably, a class of prenatal mutations was predicted to be more deleterious than any other category of genetic variation investigated and under positive selection as strong as somatic mutations in cancers. In total, the data indicate that PZMs can contribute to phenotypic variation throughout the human lifespan, and, to better understand the relationship between genotype and phenotype, we must broaden the long-held assumption of one genome per individual to multiple, dynamic genomes per individual.One-Sentence SummaryThe predicted rates, functional effects and selection pressure of postzygotic mutations vary through the human lifecycle.
Estimating human mobility in Holocene Western Eurasia with large-scale ancient genomic data
Authors: Schmid Clemens , Schiffels Stephan 
Published: December 2021

AbstractThe recent increase in openly available ancient human DNA samples allows for new, large-scale meta analysis applications. Trans-generational past human mobility is one of the key aspects that ancient genomics can contribute to, since changes in ancestry – unlike cultural changes seen in the archaeological record – necessarily reflect movements of people. Here we present a new algorithm to quantify past human mobility from large ancient genomic datasets. The key idea of the method is for each individual to compare a hypothetical genetic “origin” point with its actual burial point in space. This is achieved by first creating an interpolated ancestry field through space and time based on Multidimensional scaling and Gaussian process regression, and then using this field to map the ancient individuals into space according to their genetic profile. We apply this new algorithm to a dataset of 3191 aDNA samples with genome-wide data from Western Eurasia in the last 10,000 years and derive a diachronic measure of mobility for subregions in Western, Central, Southern and Eastern Europe. For regions and periods with sufficient data coverage, our mobility estimates show general concordance with previous results, but also reveal new signals of movements beyond the well-known key events.Significance StatementAncient human DNA (aDNA) extracted from archaeological contexts (e.g. burials) allows to reconstruct past population movements. Relevant methods work by calculating proportions of shared ancestry among individuals or groups in order to answer specific, regional research questions. Here, we propose a largescale algorithm to quantify human mobility through time and space using bulk aDNA data. The algorithm has two core components: i) Interpolation of the spatio-temporal distribution of genetic ancestry to obtain a continuous ancestry information field and ii) estimation of the spatial origin of each input sample by projecting its ancestry into this field. We apply this to thousands of published genomic samples in the last 10,000 years to trace diachronic mobility patterns across Western Eurasia.
Integrated view and comparative analysis of baseline protein expression in mouse and rat tissues
Authors: Wang Shengbo , García-Seisdedos David , Prakash Ananth , Kundu Deepti Jaiswal , Collins Andrew , George Nancy , Fexova Silvie , Moreno Pablo , Papatheodorou Irene , Jones Andrew R. , Vizcaíno Juan Antonio 
Published: December 2021

AbstractThe increasingly large amount of proteomics data in the public domain enables, among other applications, the combined analyses of datasets to create comparative protein expression maps covering different organisms and different biological conditions. Here we have reanalysed public proteomics datasets from mouse and rat tissues (14 and 9 datasets, respectively), to assess baseline protein abundance. Overall, the aggregated dataset contained 23 individual datasets, including a total of 211 samples coming from 34 different tissues across 14 organs, comprising 9 mouse and 3 rat strains, respectively.In all cases, we studied the distribution of canonical proteins between the different organs. The number of canonical proteins per dataset ranged from 273 (tendon) and 9,715 (liver) in mouse, and from 101 (tendon) and 6,130 (kidney) in rat. Then, we studied how protein abundances compared across different datasets and organs for both species. As a key point we carried out a comparative analysis of protein expression between mouse, rat and human tissues. We observed a high level of correlation of protein expression among orthologs between all three species in brain, kidney, heart and liver samples, whereas the correlation of protein expression was generally slightly lower between organs within the same species. Protein expression results have been integrated into the resource Expression Atlas for widespread dissemination.Author summaryWe have reanalysed 23 baseline mass spectrometry-based public proteomics datasets stored in the PRIDE database. Overall, the aggregated dataset contained 211 samples, coming from 34 different tissues across 14 organs, comprising 9 mouse and 3 rat strains, respectively. We analysed the distribution of protein expression across organs in both species. We also studied how protein abundances compared across different datasets and organs for both species. Then we performed gene ontology and pathway enrichment analyses to identify enriched biological processes and pathways across organs. We also carried out a comparative analysis of baseline protein expression across mouse, rat and human tissues, observing a high level of expression correlation among orthologs in all three species, in brain, kidney, heart and liver samples. To disseminate these findings, we have integrated the protein expression results into the resource Expression Atlas.
Therapeutic potential of methylxanthine drug on alpha synuclein protein in Parkinson’s disease
Authors: Rana Nishant Kumar , Srivastava Neha , Kumar Bhupendra , Pathak Abhishek , Mishra Vijay Nath 
Published: December 2021

AbstractParkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer. It exists in sporadic (90 to 95%) and familial (5 to 10%) form. Its pathogenesis is due to oxidative stress, glutamate excitotoxicity, protein aggregation, neuroinflammation and neurodegeneration. There is currently no cure for this disease. The protein-protein interaction and gene ontology/functional enrichment analysis have been performed to find out the prominent interactor protein and shared common biological pathways, especially PD pathway. Further in silico docking analysis was performed on target protein to investigate the prominent drug molecule for PD. Through computational molecular virtual screening of small molecules from selected twelve natural compounds, and among these compounds methylxanthine was shown to be prominent inhibitor to SNCA protein that ultimately prevent PD. The interaction of methylxanthine compound with the target protein SNCA suggested that, it interacted with prominent binding site with good docking score and might be involved in blocking the binding of neuroinducing substances like: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to SNCA protein. Thus methylxanthine compounds can be explored as promising drugs for the prevention of Parkinson’s disease.
BESFA: Bioinformatics based Evolutionary, Structural & Functional Analysis of Prostrate, Placenta, Ovary, Testis, and Embryo (POTE) Paralogs
Authors: Qazi Sahar , Jit Bimal Prasad , Das Abhishek , Karthikeyan Muthukumarasamy , Saxena Amit , Ray M.D , Singh Angel Rajan , Raza Khalid , Jayaram B. , Sharma Ashok 
Published: December 2021

AbstractThe POTE family comprises 14 paralogues and is primarily expressed in Prostrate, Placenta, Ovary, Testis, Embryo (POTE), and cancerous cells. The prospective function of the POTE protein family under physiological conditions is less understood. We systematically analyzed their cellular localization and molecular docking analysis to elucidate POTE proteins’ structure, function, and Adaptive Divergence. Our result discerns that group three POTE paralogs (POTEE, POTEF, POTEI, POTEJ, and POTEKP (a pseudogene)) exhibits significant variation among other members could be because of their Adaptive Divergence. Furthermore, our molecular docking studies on POTE protein revealed the highest binding affinity with NCI-approved anticancer compounds. Additionally, POTEE, POTEF, POTEI, and POTEJ were subject to an explicit molecular dynamic simulation for 50ns. MM-GBSA and other essential electrostatics were calculated that showcased that only POTEE and POTEF have absolute binding affinities with minimum energy exploitation. Thus, this study’s outcomes are expected to drive cancer research to successful utilization of POTE genes family as a new biomarker, which could pave the way for the discovery of new therapies.
Revisiting the number of self-incompatibility alleles in finite populations: from old models to new results
Authors: Czuppon Peter , Billiard Sylvain 
Published: December 2021

AbstractUnder gametophytic self-incompatibility (GSI), plants are heterozygous at the self-incompatibility locus (S-locus) and can only be fertilized by pollen with a different allele at that locus. The last century has seen a heated debate about the correct way of modeling the allele diversity in a GSI population that was never formally resolved. Starting from an individual-based model, we derive the deterministic dynamics as proposed by Fisher (1958), and compute the stationary S-allele frequency distribution. We find that the stationary distribution proposed by Wright (1964) is close to our theoretical prediction, in line with earlier numerical confirmation. Additionally, we approximate the invasion probability of a new S-allele, which scales inversely with the number of resident S-alleles. Lastly, we use the stationary allele frequency distribution to estimate the population size of a plant population from an empirically obtained allele frequency spectrum, which complements the existing estimator of the number of S-alleles. Our expression of the stationary distribution resolves the long-standing debate about the correct approximation of the number of S-alleles and paves the way to new statistical developments for the estimation of the plant population size based on S-allele frequencies.
TreeKnit: Inferring Ancestral Reassortment Graphs of influenza viruses
Authors: Barrat-Charlaix Pierre , Vaughan Timothy G. , Neher Richard A. 
Published: December 2021

AbstractWhen two influenza viruses co-infect the same cell, they can exchange genome segments in a process known as reassortment. Reassortment is an important source of genetic diversity and is known to have been involved in the emergence of most pandemic influenza strains. However, because of the difficulty in identifying reassortments events from viral sequence data, little is known about its role in the evolution of the seasonal influenza viruses. Here we introduce TreeKnit, a method that infers ancestral reassortment graphs (ARG) from two segment trees. It is based on topological differences between trees, and proceeds in a greedy fashion by finding regions that are compatible in the two trees. Using simulated genealogies with reassortments, we show that TreeKnit performs well in a wide range of settings and that it is as accurate as a more principled bayesian method, while being orders of magnitude faster. Finally, we show that it is possible to use the inferred ARG to better resolve segment trees and to construct more informative visualizations of reassortments.
Δ9-tetrahydrocannabinol (THC) vapor exposure produces conditioned place preference in male and female rats
Authors: Moore Catherine F. , Davis Catherine M. , Sempio Cristina , Klawitter Jost , Christians Uwe , Weerts Elise M. 
Published: December 2021

AbstractBackgroundThe use of place conditioning procedures and drug vapor exposure models can increase our understanding of the rewarding and aversive effects of vaped cannabis products. Currently there are limited data on the conditioned rewarding effects of vaporized Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis in rats, and no studies to date examining sex differences.MethodsMale and female Sprague-Dawley rats (N=96; 12 per sex/group) underwent place conditioning sessions immediately after exposure to THC or vehicle (propylene glycol, PG) vapor. Locomotor activity was measured by beam breaks during conditioning sessions. THC vapor-conditioned rats received one of three THC vapor exposure amounts (low: 5 puffs of 100 mg/ml THC, medium: 5 puffs of 200 mg/ml THC, or high: 10 puffs of 200 mg/ml THC) and matched vehicle vapor (PG) exposure on alternate days for 16 daily sessions. A ‘no THC’ control group of vehicle-conditioned rats received only PG vapor exposure each day. After the 8th and 16th conditioning sessions, untreated rats were tested for conditioned place preference (CPP) or avoidance (CPA). Next, extinction tests and a THC vapor-primed reinstatement test were conducted.ResultsTHC vapor produced CPP and locomotor effects in an exposure dependent manner, and some sex differences were observed. Low THC vapor exposure did not produce CPP in males or females. Medium THC vapor exposure produced CPP in males, but not females. High THC vapor exposure produced CPP in both males and females. Medium and high THC vapor exposure amounts produced hyperactivity in female rats, but not male rats. CPP was more resistant to extinction in females than males. THC vapor re-exposure (i.e., drug-prime) after extinction did not result in reinstatement of CPP for either sex.ConclusionThis study demonstrates conditioned rewarding effects of THC vapor in both male and female rats and provides evidence for sex differences in amounts of THC vapor that produce CPP and in time to extinction. CPA was not observed at any of the THC vapor exposure amounts tested. These data provide a foundation for future exploration of the conditioned effects of cannabis constituents and extracts using vapor exposure models.
Effectiveness and relationship between biased and unbiased measures of dopamine release and clearance
Authors: Everett Anna C. , Graul Ben E. , Robinson J. Kayden , Watts Daniel B. , España Rodrigo A. , Siciliano Cody A. , Yorgason Jordan T. 
Published: December 2021

AbstractFast-scan cyclic voltammetry (FSCV) is an effective tool for measuring dopamine (DA) release and clearance throughout the brain, including the ventral and dorsal striatum. Striatal DA terminals are abundant with signals heavily regulated by release machinery and the dopamine transporter (DAT). Peak height is a common method for measuring release but can be affected by changes in clearance. The Michaelis-Menten model has been a standard in measuring DA clearance, but requires experimenter fitted modeling subject to experimenter bias. The current study presents the use of the first derivative (velocity) of evoked DA signals as an alternative approach for measuring dopamine release and clearance and can be used to distinguish the two measures. Maximal upwards velocity predicts reductions in DA peak height due to D2 and GABAB receptor stimulation and by alterations in calcium concentrations. The Michaelis-Menten maximal velocity (Vmax) measure, an approximation for DAT numbers, predicted maximal downward velocity in slices and in vivo. Dopamine peak height and upward velocity were similar between wildtype C57 (WT) and DAT knock out (DATKO) mice. In contrast, downward velocity was considerably reduced and exponential decay (tau) was increased in DATKO mice, supporting use of both measures for changes in DAT activity. In slices, the competitive DAT inhibitors cocaine, PTT and WF23 increased peak height and upward velocity differentially across increasing concentrations, with PTT and cocaine reducing these measures at high concentrations. Downward velocity and tau values decreased and increased respectively across concentrations, with greater potency and efficacy observed with WF23 and PTT. In vivo recordings demonstrated similar effects of WF23 and PTT on measures of release and clearance. Tau was a more sensitive measure at low concentrations, supporting its use as a surrogate for the Michaelis-Menten measure of apparent affinity (Km). Together, these results inform on the use of these measures for DA release and clearance.
Delivery of CAR-T Cells in a Transient Injectable Stimulatory Hydrogel Niche Improves Treatment of Solid Tumors
Authors: Grosskopf Abigail K. , Labanieh Louai , Klysz Dorota D. , Roth Gillie A. , Xu Peng , Adebowale Omokolade , Gale Emily C. , Jons Carolyn K. , Klich John H. , Yan Jerry , Maikawa Caitlin L. , Correa Santiago , Ou Ben S. , d’Aquino Andrea I. , Cochran Jennifer R. , Chaudhuri Ovijit , Mackall Crystal L. , Appel Eric A. 
Published: December 2021

AbstractAdoptive cell therapy (ACT) has proven to be highly effective in treating blood cancers such as B cell malignancies, but traditional approaches to ACT are poorly effective in treating the multifarious solid tumors observed clinically. Locoregional cell delivery methods have shown promising results in treating solid tumors compared to standard intravenous delivery methods, but the approaches that have been described to date have several critical drawbacks ranging from complex manufacturing and poor modularity to challenging adminstration. In this work, we develop a simple-to-implement self-assembled and injectable hydrogel material for the controlled co-delivery of CAR-T cells and stimulatory cytokines that improves treatment of solid tumors. We evaluate a range of hydrogel formulations to optimize the creation of a transient inflammatory niche that affords sustained exposure of CAR-T cells and cytokines. This facile approach yields increased CAR-T cell expansion, induces a more tumor-reactive CAR-T phenotype, and improves efficacy in treating solid tumors in mice.
ORA47 is a transcriptional regulator of a general stress response hub
Authors: Zeng Liping , Chen Hao , Wang Yaqi , Hicks Derrick , Ke Haiyan , Pruneda-Paz Jose , Dehesh Katayoon 
Published: December 2021

AbstractTranscriptional regulators of general stress response (GSR) reprogram expression of selected genes to transduce informational signals into cellular events, ultimately manifested in plant’s ability to cope with environmental challenges. Identification of the core GSR regulatory proteins will uncover the principal modules and their mode of action in the establishment of adaptive responses. To define the GSR regulatory components, we employed a yeast-one-hybrid assay to identify the protein(s) that binds to the previously established functional GSR motif, coined Rapid Stress Response Element (RSRE). This led to the isolation of ORA47 (octadecanoid-responsive AP2/ERF-domain transcription factor 47), a Methyl jasmonate (MeJA) inducible protein. Subsequently, the ORA47 transcriptional activity was confirmed using RSRE-driven Luciferase (LUC) activity assay performed in the ORA47 loss- and gain-of-function lines introgressed into the 4xRSRE::Luc background. In addition, the prime contribution of CALMODULIN-BINDING TRANSCRIPTIONAL ACTIVATOR3 (CAMTA3) protein in induction of RSRE was reaffirmed by genetic studies. Moreover, exogenous application of MeJA led to enhanced levels of ORA47 and CAMTA3 transcripts, and the induction of RSRE::LUC activity. Metabolic analyses illustrated the reciprocal functional inputs of ORA47 and CAMTA3 in increasing JA levels. Lastly, transient assays identified JASMONATE ZIM-domain1 (JAZ1) as a repressor of RSRE::LUC activity.Collectively, the report provides a fresh insight into the initial mechanistic features of transducing the informational signals into adaptive responses in part via the complex functional interplay between JA biosynthesis/signaling cascade and the transcriptional reprogramming necessary for potentiation of GSR, while offering a window into the role of intraorganellar communication in the establishment of adaptive responses.SignificanceThe work unmasks the initial mechanistic features of adaptive responses that include tight cooperativity between JA biosynthesis and signaling cascade and the nuclear transcriptional machinery comprised of two activators (CAMTA3 and ORA47) and a suppressor JAZ1). The work further identifies CAMTA3 as a functional link between JA signaling and activation of a general stress transcriptional hub.
Structural flexibility of the SARS-CoV-2 genome relevant to variation, replication, pathogenicity, and immune evasion
Authors: Patarca Roberto , Haseltine William A. 
Published: December 2021

AbstractThe SARS-CoV-2 pandemic continues to be driven by viral variants. Most research has focused on structural proteins and on site-specific mutations. Here, we describe recombination events involving genomic terminal sequences in SARS-CoV-2 and related viruses leading to structural rearrangements in terminal and coding regions and discuss their potential contributions to viral variation, replication, pathogenicity, and immune evasion.