bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gait Abnormalities and Aberrant D2 Receptor Expression and Signaling in a Mouse Model of the Human Pathogenic Mutation DRD2I212F
Authors: Rodriguez-Contreras Dayana , Gong Sheng , Lebowitz Joseph J , Fedorov Lev M , Asad Naeem , Dore Timothy M , Ford Christopher P , Williams John T , Neve Kim A 
Published: June 2022

AbstractA dopamine D2 receptor mutation was recently identified in a family with a novel hyperkinetic movement disorder (Mov Disord 36: 729-739, 2021). That allelic variant D2-I212F is a constitutively active and G protein-biased receptor. We now describe mice engineered to carry the D2-I212F variant, Drd2I212F. The mice exhibited gait abnormalities resembling those in other mouse models of chorea and/or dystonia, and had decreased striatal D2 receptor expression. Electrically evoked IPSCs in midbrain dopamine neurons and striatum from Drd2I212F mice exhibited slow onset and decay compared to wild type mice. In the presence of dopamine, current decay initiated by photolytic release of sulpiride from CyHQ-sulpiride was slower in midbrain slices from Drd2I212F mice than Drd2+/+ mice. Furthermore, in contrast to wild type mice in which dopamine is more potent at neurons in the nucleus accumbens than in the dorsal striatum, reflecting activation of Gαo vs. Gαi1, dopamine had similar potencies in those two brain regions of Drd2I212F mice. Repeated cocaine treatment, which decreases dopamine potency in the nucleus accumbens of wild type mice, had no effect on dopamine potency in Drd2I212F mice. The results demonstrate the utility of this mouse model for investigating the role of pathogenic DRD2 variants in early-onset hyperkinetic movement disorders.
Fine temporal brain network structure modularizes and localizes differently in men and women: Insights from a novel explainability framework
Authors: Lewis Noah , Miller Robyn , Gazula Harshvardhan , Calhoun Vince 
Published: June 2022

AbstractDeep learning has become an effective tool for classifying biological sex based on functional magnetic resonance imaging (fMRI), but research on what features within the brain are most relevant to this classification is still lacking. Model interpretability has become a powerful way to understand “black box” deep-learning models and select features within the input data that are most relevant to the correct classification. However, very little work has been done employing these methods to understand the relationship between the temporal dimension of functional imaging signals and classification of biological sex, nor has there been attention paid to rectifying problems and limitations associated with feature explanation models, e.g. underspecification and instability. We provide a methodology to limit the impact of underspecification on the stability of the measured feature importance, and then, using intrinsic connectivity networks (ICNs) from fMRI data, we provide a deep exploration of sex differences among functional brain networks. We report numerous conclusions, including activity differences in the visual and cognitive domains, as well as major connectivity differences.
Single-cell transcriptomics identifies regulation of invasive behavior in Drosophila follicle cells with polarity loss
Authors: Chatterjee Deeptiman , Wang Xian-Feng , Jevitt Allison , Machado Costa Caique Almeida , Huang Yi- Chun , Deng Wu-Min 
Published: June 2022

ABSTRACTApicobasal cell-polarity loss is a founding event in Epithelial-Mesenchymal Transition (EMT) and epithelial tumorigenesis, yet how pathological polarity loss induces plasticity changes remains largely unknown. To understand the mechanisms and mediators regulating plasticity upon polarity loss, we performed single-cell (sc) RNA sequencing of Drosophila ovaries, where inducing polarity-gene l(2)gl knockdown (Lgl-KD) causes invasive delamination of the follicular epithelia. Integrating Lgl-KD with the corresponding wild-type sc-transcriptome, we discovered clusters specific to various discernible phenotype-specific cell types and further characterized the regulons active in those cells. A genetic requirement of Keap1-Nrf2 signaling in promoting multilayer formation of Lgl-KD cells was further identified. Elevated expression of Keap1 increased the volume of delaminated follicle cells that undergo enhanced collective invasion via cytoskeletal remodeling. Overall, our findings describe the comprehensive transcriptome of the follicle-cell tumor model at the single-cell resolution and identify a previously unappreciated link between stress signaling and cell plasticity in early tumorigenesis.
Prediction of HLA genotypes from single-cell transcriptome data
Authors: Solomon Benjamin D , Zheng Hong , Dillon Laura W , Goldman Jason D. , Hourigan Christopher S , Heath James R. , Khatri Purvesh 
Published: June 2022

ABSTRACTThe human leukocyte antigen (HLA) locus plays a central role in adaptive immune function and has significant clinical implications for tissue transplant compatibility and allelic disease associations. Studies using bulk-cell RNA sequencing have demonstrated that HLA transcription may be regulated in an allele-specific manner and single-cell RNA sequencing (scRNA-seq) has the potential to better characterize these expression patterns. However, quantification of allele-specific expression (ASE) for HLA loci requires sample-specific reference genotyping due to extensive polymorphism. While genotype prediction from bulk RNA sequencing is well described, the feasibility of predicting HLA genotypes directly from single-cell data is unknown. Here we evaluate and expand upon several computational HLA genotyping tools by comparing predictions from human single-cell data to gold-standard, molecular genotyping. The highest 2-field accuracy averaged across all loci was 76% by arcasHLA and increased to 86% using a composite model of multiple genotyping tools. We also developed a highly accurate model (AUC 0.93) for predicting HLA-DRB345 copy number in order to improve genotyping accuracy of the HLA-DRB locus. Genotyping accuracy improved with read depth and was reproducible at repeat sampling. Using a metanalytic approach, we also show that HLA genotypes from PHLAT and OptiType can generate ASE ratios that are highly correlated (R2 = 0.8 and 0.94, respectively) with those derived from gold-standard genotyping.Highlights-Benchmarking of HLA genotype prediction accuracy from 5’- and 3’-based single-cell RNA-seq data compared to molecular HLA genotyping-Quantification of transcript coverage by 5’- and 3’-based single cell sequencing methods-Accurate prediction of complex HLA-DRB345 copy numbers using supervised learning-Balancing accuracy and performance through composite HLA genotyping-Meta-analytic approach to summarizing allele-specific expression of HLA genotypes at single-cell level
The evolutionary history of class I aminoacyl-tRNA synthetases indicates early statistical translation
Authors: Jabłońska Jagoda , Chun-Chen Yao , Longo Liam M. , Tawfik Dan S. , Gruic-Sovulj Ita 
Published: June 2022

AbstractHow protein translation evolved from a simple beginning to its complex and accurate contemporary state is unknown. Aminoacyl-tRNA synthetases (AARSs) define the genetic code by activating amino acids and loading them onto cognate tRNAs. As such, their evolutionary history can shed light on early translation. Using structure-based alignments of the conserved core of Class I AARSs, we reconstructed their phylogenetic tree and ancestral states. Unexpectedly, AARSs charging amino acids that are assumed to have emerged later – such as TrpRS and TyrRS or LysRS and CysRS – appear as the earliest splits in the tree; conversely, those AARSs charging abiotic, early-emerging amino acids, e.g. ValRS, seem to have diverged most recently. Furthermore, the inferred Class I ancestor (excluding TrpRS and TyrRS) lacks the residues that mediate selectivity in contemporary AARSs, and appears to be a generalist that could charge a wide range of amino acids. This ancestor subsequently diverged to two clades: “charged” (which gave rise to ArgRS, GluRS, and GlnRS) and “hydrophobics”, which includes CysRS and LysRS as its outgroups. The ancestors of both clades maintain a wide-accepting pocket that could readily diverge to the contemporary, specialized families. Overall, our findings suggest a “generalist-maintaining” model of class I AARS evolution, in which early statistical translation was kept active by a generalist AARS while the evolution of a specialized, accurate translation system took place.SignificanceAminoacyl-tRNA synthetases (AARS) define the genetic code by linking amino acids with their cognate tRNAs. While contemporary AARSs leverage exquisite molecular recognition and proofreading to ensure translational fidelity, early translation was likely less stringent and operated on a different pool of amino acids. The co-emergence of translational fidelity and the amino acid alphabet, however, is poorly understood. By inferring the evolutionary history of Class I AARSs we found seemingly conflicting signals: Namely, the oldest AARSs apparently operate on the youngest amino acids. We also observed that the early ancestors had broad amino acid specificities, consistent with a model of statistical translation. Our data suggests that a generalist AARS was actively maintained until complete specialization, thereby resolving the age paradox.
Increased paternal corticosterone exposure preconception shifts offspring social behaviours and expression of urinary pheromones
Authors: Hoffmann Lucas B. , McVicar Evangeline A. , Harris Rebekah V. , Collar-Fernández Coralina , Clark Michael B. , Hannan Anthony J. , Pang Terence Y. 
Published: June 2022

AbstractStudies have shown that paternal stress prior to conception can influence the innate behaviours of their offspring. The evolutionary impacts of such intergenerational effects are therefore of considerable interest. Our group previously showed that glucocorticoid treatment of adult male mouse breeders prior to conception leads to increased anxiety-related behaviours in male offspring. Here, we aimed to understand the transgenerational effects of paternal stress exposure on the social behaviour of progeny and its potential influence on reproductive success. We assessed social parameters including social reward, male attractiveness and social dominance, in the offspring (F1) and grand-offspring (F2). We report that paternal corticosterone-treatment was associated with increased display of subordination towards other male mice. Those mice were unexpectedly more attractive to female mice while expressing reduced levels of the key rodent pheromone Darcin, contrary to its conventional purpose. We investigated the epigenetic regulation of major urinary protein (Mup) expression by performing the first Oxford Nanopore direct methylation of sperm DNA in a mouse model of stress, but found no differences inMupgenes that could be attributed to corticosterone-treatment. Furthermore, no overt differences of the prefrontal cortex transcriptome were found in F1offspring, implying that peripheral mechanisms are likely contributing to the phenotypic differences. Interestingly, no phenotypic differences were observed in the F2grand-offspring. Overall, our findings highlight the potential of moderate paternal stress to affect intergenerational (mal)adaptive responses, informing future studies of adaptiveness in rodents, humans and other species.
Mathematical Modeling of Fluconazole Resistance in the Ergosterol Pathway of Candida albicans
Authors: Yu Paul K. , Moron Llewelyn S. , Lao Angelyn R. 
Published: June 2022

AbstractCandidiasis is reported as the most common fungal infection in the critical care setting. The causative agent of this infection is a commensal pathogen belonging to the genus Candida, most common species of which is the Candida albicans. The ergosterol pathway in yeast is a common target by many antifungal agents since ergosterol is an essential component of the cell membrane. The current antifungal agent of choice for the treatment of Candidiasis is fluconazole, which is classified under the azole antifungals. In recent years, the significant increase of fluconazole-resistant C. albicans in clinical samples calls for a need to search for other possible drug targets. In this study, we constructed a mathematical model of the ergosterol pathway of C. albicans using ordinary differential equations with mass action kinetics. From the model simulations, we found the following results: (1) a partial inhibition of the sterol-methyltransferase enzyme yields a fair amount of fluconazole resistance, (2) an overexpression of the ERG6 gene, leading to increased sterol-methyltransferase enzyme, is a good target of antifungals as an adjunct to fluconazole, (3) a partial inhibition of lanosterol yields a fair amount of fluconazole resistance, (4) the C5-desaturase enzyme is not a good target of antifungals as an adjunct to fluconazole, (5) the C14α-demethylase enzyme is confirmed to be a good target of fluconazole, and (6) the dose-dependent effect of fluconazole is confirmed. This study hopes to aid experimenters narrow down the possible drug targets prior to doing costly and time-consuming experiments, and to serve as a cross-validation tool for experimental data.
Reconstruction of visual images from mouse retinal ganglion cell spiking activity using convolutional neural networks
Authors: Benster Tyler , Babino Darwin , Thickstun John , Hunt Matthew , Liu Xiyang , Harchaoui Zaid , Oh Sewoong , Van Gelder Russell N. 
Published: June 2022

ABSTRACTAll visual information in mammals is encoded in the aggregate pattern of retinal ganglion cell (RGC) firing. How this information is decoded to yield percepts remains incompletely understood. We have trained convolutional neural networks with multielectrode array-recorded murine RGC responses to projected images. The trained model accurately reconstructed novel facial images solely from RGC firing data. In this model, subpopulations of cells with faster firing rates are largely sufficient for accurate reconstruction, and ON- and OFF-cells contribute complementary and overlapping information to image reconstruction. Information content for reconstruction correlates with overall firing rate, and locality of information contributing to reconstruction varies substantially across the image and retina. This model demonstrates that artificial neural networks are capable of learning multicellular sensory neural encoding, and provides a viable model for understanding visual information encoding.Significance StatementConvolutional neural networks can be trained on high-density neuronal firing data from the optic nerve to reconstruct complicated images within a defined image space.
Formal Recognition and Classification of Gene Transfer Agents as Viriforms
Authors: Kogay Roman , Koppenhöfer Sonja , Beatty J. Thomas , Kuhn Jens H. , Lang Andrew S. , Zhaxybayeva Olga 
Published: June 2022

ABSTRACTMorphological and genetic features strongly suggest that gene transfer agents (GTAs) are caudoviricete-derived entities that have evolved in concert with cellular genomes to such a degree that they should not be considered viruses. Indeed, GTA particles resemble caudoviricete virions but, in contrast to caudoviricetes (or any viruses), GTAs can encapsidate at best only part of their own genomes, are induced solely in small subpopulations of prokaryotic host cells and are transmitted vertically as part of cellular genomes during replication and division. Therefore, the lifecycles of GTAs are analogous to virus-derived entities found in parasitoid wasps, which have recently been recognized as non-virus entities and therefore reclassified as viriforms. We evaluated three distinct, independently exapted GTA groups for which the genetic basis for GTA particle production has been established. Based on the evidence, we outline a classification scheme for these viriforms.
Galantamine Attenuates Autoinflammation in a Mouse Model of Familial Mediterranean Fever
Authors: Mughrabi Ibrahim T. , Ochani Mahendar , Tanovic Mirza , Wang Ping , Diamond Betty , Sherry Barbara , Pavlov Valentin A. , Ozen Seza , Kastner Daniel L. , Chae Jae Jin , Al-Abed Yousef 
Published: June 2022

AbstractAutoinflammatory diseases, a diverse group of inherited conditions characterized by excessive innate immune activation, have limited therapeutic options. Neuroimmune circuits of the inflammatory reflex control innate immune overactivation and can be stimulated to treat disease using the acetylcholinesterase inhibitor galantamine. Here, we tested the efficacy of galantamine in a rodent model of the prototypical autoinflammatory disease familial Mediterranean fever (FMF). Long-term treatment with galantamine attenuated the associated splenomegaly, amyloidosis, and anemia that are characteristic features of this disease. Further, treatment reduced inflammatory cell infiltration into affected organs and a subcutaneous air pouch. These findings suggest that galantamine attenuates chronic inflammation in this mouse model of FMF. Further research is warranted to explore the therapeutic potential of galantamine in FMF and other autoinflammatory diseases.
Identification, expression, and purification of DNA cytosine 5-methyltransferases with short recognition sequences
Authors: Miura Fumihito , Miura Miki , Shibata Yukiko , Furuta Yoshikazu , Miyamura Keisuke , Ino Yuki , Bayoumi Asmaa M.A. , Oba Utako , Ito Takashi 
Published: June 2022

ABSTRACTBackgroundDNA methyltransferases (MTases) are enzymes that induce methylation, one of the representative epigenetic modifications of DNA, and are also useful tools for analyzing epigenomes. However, regarding DNA cytosine 5-methylation, MTases identified so far have drawbacks in that their recognition sequences overlap with those for intrinsic DNA methylation in mammalian cells and/or that the recognition sequence is too long for fine epigenetic mapping. To identify MTases with short recognition sequences that never overlap with the CG dinucleotide, we systematically investigated the 25 candidate enzymes identified using a database search, which showed high similarity to known cytosine 5-MTases recognizing short sequences.ResultsWe identified MTases with six new recognition sequences, including TCTG, CC, CNG, TCG, GCY, and GGCA. Because the recognition sequence never overlapped with the CG dinucleotide, MTases recognizing the CC dinucleotide were promising.ConclusionsIn the current study, we established a procedure for producing active CC-methylating MTases and applied it to nucleosome occupancy and methylome sequencing to prove the usefulness of the enzyme for fine epigenetic mapping. MTases that never overlap with CG dinucleotides would allow us to profile multiple epigenomes simultaneously.
Structural basis for tunable affinity and specificity of LxCxE-dependent protein interactions with the retinoblastoma protein family
Authors: Putta Sivasankar , Alvarez Lucia , Lüdtke Stephan , Sehr Peter , Müller Gerd A. , Fernandez Samantha M. , Tripathi Sarvind , Lewis Joe , Gibson Toby J. , Chemes Lucia B. , Rubin Seth M. 
Published: June 2022

AbstractThe retinoblastoma protein (Rb) and its homologs p107 and p130 are critical regulators of gene expression during the cell cycle. Functional inactivation of Rb family proteins leads to loss of cell-cycle control and promotes genome instability and proliferation, which are hallmarks of cancer. Rb proteins share a structural domain, known as the “pocket domain”, which mediates association with a large number of cellular proteins. A cleft in the pocket domain binds an LxCxE sequence motif in these proteins, many of which function with Rb proteins to co-regulate transcription during quiescence and G1. Proteins from oncogenic DNA viruses also bind this cleft to inactivate Rb family proteins, and the E7 protein from the human papillomavirus has been used as the primary model for understanding LxCxE motif interactions. Evidence presented previously and here demonstrates that the E7 sequence binds tighter and competes with cellular proteins for the LxCxE site, but the molecular basis for the relatively weak affinities of the cellular proteins has been poorly understood. Here, we present binding data and a series of crystal structures of the p107 pocket domain in complex with LxCxE peptides derived from the transcriptional co-repressor proteins HDAC1, ARI4DA, and EID1. The structures reveal determinants of protein binding beyond the L-C-E core that include the N and C-terminal sides of the LxCxE motif and the x (wild card) residues. Our results explain how differences in these interactions outside the L-C-E core result in weaker affinities of pocket protein for cellular LxCxE proteins compared to E7 and result in differences in Rb and p107 affinities for some LxCxE-containing sequences. Our study provides new insights into how Rb proteins bind their myriad of cell partners and lays the foundation for structure-based design of peptides that inhibit oncogenic viral protein interactions.
Metabolic control of histone acetylation for precise and timely regulation of minor ZGA in early mammalian embryos
Authors: Li Jingyu , Zhang Jiaming , Hou Weibo , Yang Xu , Liu Xiaoyu , Zhang Yan , Gao Meiling , Zong Ming , Dong Zhixiong , Liu Zhonghua , Shen Jingling , Cong Weitao , Ding Chunming , Gao Shaorong , Huang Guoning , Kong Qingran 
Published: June 2022

AbstractMetabolism feeds into the regulation of epigenetics via metabolic enzymes and metabolites. However, metabolic features, and their impact on epigenetic remodeling during mammalian pre-implantation development, remain poorly understood. In this study, we established the metabolic landscape of mouse pre-implantation embryos from zygote to blastocyst, and quantified some absolute carbohydrate metabolites. We integrated these data with transcriptomic and proteomic data, and discovered the metabolic characteristics of the development process, including the activation of methionine cycle from 8-cell embryo to blastocyst, high glutaminolysis metabolism at blastocyst stage, enhanced TCA cycle activity from the 8-cell embryo stage, and active glycolysis in the blastocyst. We further demonstrated that oxidized nicotinamide adenine dinucleotide (NAD+) synthesis is indispensable for mouse pre-implantation development. Mechanistically, in part, NAD+ is required for the exit of minor zygotic gene activation (ZGA) by cooperating with SIRT1 to remove zygotic H3K27ac. In human, NAD+ supplement can promote the removal of zygotic H3K27ac and benefit pre-implantation development. Our findings demonstrate that precise and timely regulation of minor ZGA is controlled by metabolic dynamics, and enhance our understanding of the metabolism of mammalian early embryos.HighlightsWe identified the metabolic features of mouse pre-implantation embryo development.NAD+ synthesis is indispensable for mouse embryo pre-implantation development.NAD+-mediated erasure of zygotic H3K27ac is required for the exit of minor ZGA.NAD+ supplement promotes the removal of zygotic H3K27ac and benefits preimplantation development of human embryos.