bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of the cleaved-protamine 2 domain leads to incomplete histone-to-protamine exchange and infertility in mice
Authors: Arévalo Lena , Merges Gina Esther , Schneider Simon , Oben Franka Enow , Neumann Isabelle , Schorle Hubert 
Published: October 2021

AbstractProtamines are unique sperm-specific proteins that package and protect paternal chromatin until fertilization. A subset of mammalian species expresses two protamines (PRM1 and PRM2), while in others PRM1 is sufficient for sperm chromatin packaging. Alterations of the species-specific ratio between PRM1 and PRM2 are associated with infertility. Unlike PRM1, PRM2 is generated as a precursor protein consisting of a highly conserved N-terminal domain, termed cleaved PRM2 (cP2), which is consecutively trimmed off during chromatin condensation. The carboxyterminal part, called mature PRM2 (mP2), interacts with DNA and together with PRM1, mediates chromatin-hypercondensation. The removal of the cP2 domain is believed to be imperative for proper chromatin condensation, yet, the role of cP2 is not yet understood. We generated mice lacking the cP2 domain while the mP2 is still expressed. We show that the cP2 domain is indispensable for complete sperm chromatin protamination and male mouse fertility. cP2 deficient sperm show incomplete PRM2 incorporation, resulting in a severely altered protamine ratio, retention of transition proteins and aberrant retention of the testis specific histone variant H2A.L.2. During epididymal transit, cP2 deficient sperm seem to undergo ROS mediated degradation leading to complete DNA fragmentation. The cP2 domain therefore seems to be a key aspect in the complex crosstalk between histones, transition proteins and protamines during sperm chromatin condensation. Overall, we present the first step towards understanding the role of the cP2 domain in paternal chromatin packaging and open up avenues for further research.
The organization of individually mapped structural and functional semantic networks in aging adults
Authors: Ketchabaw W. Tyler , DeMarco Andrew T. , Paul Sachi , Dvorak Elizabeth , van der Stelt Candace , Turkeltaub Peter E. 
Published: October 2021

AbstractLanguage function in the brain, once thought to be highly localized, is now appreciated as relying on a connected but distributed network. The semantic system is of particular interest in the language domain because of its hypothesized integration of information across multiple cortical regions. Previous work in healthy individuals has focused on group-level functional connectivity (FC) analyses of the semantic system, which may obscure interindividual differences driving variance in performance. These studies also overlook the contributions of white matter networks to semantic function. Here, we identified semantic network nodes with a semantic decision fMRI task in 53 typically-aging adults, characterized network organization using structural connectivity (SC), and quantified the segregation and integration of the network using FC. Hub regions were identified in left inferior frontal gyrus. The individualized semantic network was composed of three interacting modules: 1) default-mode module characterized by bilateral medial prefrontal and posterior cingulate regions and also including right-hemisphere homotopes of language regions; 2) left frontal module extending dorsally from inferior frontal gyrus to pre-motor area; and 3) left temporoparietal module extending from temporal pole to inferior parietal lobule. FC within Module3 and integration of the entire network related to a semantic verbal fluency task, but not a matched phonological task. These results support and extend the tri-network semantic model (Xu et al., 2017) and the controlled semantic cognition model (Chiou et al., 2018) of semantic function.
Gaussian Network Model Revisited: Effects of Mutation and Ligand Binding on Protein Behavior
Authors: Erman Burak 
Published: October 2021

AbstractThe coarse-grained Gaussian Network model, GNM, considers only the alpha carbons of the folded protein. Therefore it is not directly applicable to the study of mutation or ligand binding problems where atomic detail is required. This shortcoming is improved by including the local effect of heavy atoms in the neighborhood of each alpha carbon into the Kirchoff Adjacency Matrix. The presence of other atoms in the coordination shell of each alpha carbon diminishes the magnitude of fluctuations of that alpha carbon. But more importantly, it changes the graph-like connectivity structure, i.e., the Kirchoff Adjacency Matrix of the whole system which introduces amino acid specific and position specific information into the classical coarse-grained GNM which was originally modelled in analogy with phantom network theory of rubber elasticity. With this modification, it is now possible to make predictions on the effects of mutation and ligand binding on residue fluctuations and their pair-correlations. We refer to the new model as ‘all-atom GNM’. Using examples from published data we show that the all-atom GNM applied to in silico mutated proteins and to their laboratory mutated structures gives similar results. Thus, loss and gain of correlations, which may be related to loss and gain of function, may be studied by using simple in silico mutations only.
PEAK2VEC ENABLES INFERRENCE OF TRANSCRIPTIONAL REGULATION FROM ATAC-SEQ
Authors: Liang Lifan , Lu Xinghua , Lu Songjian 
Published: October 2021

ABSTRACTTranscription factor (TF) binding sites in ATAC-seq are typically determined by footprint analysis. However, the performance of footprint analysis remains unsatisfying and most TFs do not exhibit footprint patterns. In this study, we modified the convolutional neural network to project sequences into an embedding space. Sequences with similar nucleotide patterns will stay close together in the embedding. The dimensionality of this embedding space represents binding specificities of various TFs. In the simulation experiment, peak2vec accurately distinguished the three TFs in the embedding space while conventional deep learning cannot. When applied to the ATAC-seq profiles of hepatitis carcinoma, peak2vec recovered multiple motifs curated in database, while significant portion of sequences corresponding to the TF are located at the promoter region of its regulated genes.
A model screening pipeline for bile acid converting anti-Clostridioides difficile bacteria reveals unique biotherapeutic potential of Peptacetobacter hiranonis
Authors: Vinithakumari Akhil A. , Hernandez Belen G. , Ghimire Sudeep , Adams Seidu , Stokes Caroline , Jepsen Isaac , Brezina Caleb , Sahin Orhan , Li Ganwu , Tangudu Chandra , Andreasen Claire , Philips Gregory J. , Wannemuehler Michael , Jergens Albert E. , Scaria Joy , Sponseller Brett , Mooyottu Shankumar 
Published: October 2021

AbstractClostridioides difficile is an antibiotic-resistant bacterium that causes serious, toxin-mediated enteric disease in humans and animals. Gut dysbiosis and resultant alterations in the intestinal bile acid profile play an important role in the pathogenesis of C. difficile infection (CDI). Restoration of the gut microbiota and re-establishment of bacterial bile acid metabolism using fecal microbiota transplantation (FMT) has been established as a promising strategy against this disease, although this method has several limitations. Thus, a more defined and precise microbiota-based approach using bacteria that biotransform primary bile acids into secondary bile acids could effectively overcome these limitations and control CDI. Therefore, a screening pipeline was developed to isolate bile acid converting bacteria from fecal samples. Dogs were selected as a model CDI-resistant microbiota donor for this pipeline, which yielded a novel Peptacetobacter hiranonis strain that possesses unique anti-C. difficile properties, and both bile acid deconjugation and 7-α dehydroxylating activities to perform bile acid conversion. The screening pipeline included a set of in vitro tests along with a precision in vivo gut colonization and bile acid conversion test using altered Schadler flora (ASF) colonized mice. In addition, this pipeline also provided essential information on the growth requirements for screening and cultivating the candidate bacterium, its survival in a CDI predisposing environment, and potential pathogenicity. The model pipeline documented here yielded multiple bile acid converting bacteria, including a P. hiranonis isolate with unique anti-C. difficile biotherapeutic potential, which can be further tested in subsequent preclinical and human clinical trials.
ReadZS detects cell type-specific and developmentally regulated RNA processing programs in single-cell RNA-seq
Authors: Meyer Elisabeth , Chaung Kaitlin , Dehghannasiri Roozbeh , Salzman Julia 
Published: October 2021

AbstractRNA processing (RNAP), including splicing and alternative polyadenylation, is crucial to gene function and regulation, but methods to detect RNAP from single-cell RNA sequencing data are limited by reliance on pre-existing annotations, peak-calling heuristics, and collapsing measurements by cell type. We introduce ReadZS, the first annotation-free statistical approach to identify regulated RNAP in single cells. ReadZS discovers cell type-specific RNAP in the human lung and conserved, developmentally regulated RNAP in mammalian spermatogenesis - including global 3’ UTR shortening in human spermatogenesis. ReadZS also discovers global 3’ UTR lengthening in Arabidopsis root development, highlighting the usefulness of this method in under-annotated transcriptomes.
Fibroblast-derived HGF integrates muscle and nerve development during morphogenesis of the mammalian diaphragm
Authors: Sefton Elizabeth M. , Gallardo Mirialys , Tobin Claire E. , Colasanto Mary P. , Kardon Gabrielle 
Published: October 2021

AbstractThe diaphragm is a domed muscle between the thorax and abdomen essential for breathing in mammals. Diaphragm development requires the coordinated development of muscle, connective tissue, and nerve, which are derived from different embryonic sources. Defects in diaphragm development cause the common and often lethal birth defect, Congenital Diaphragmatic Hernias (CDH). HGF/MET signaling is required for diaphragm muscularization, but the source of HGF and the specific functions of this pathway in muscle progenitors or potentially the phrenic nerve have not been explicitly tested. Using conditional mutagenesis and pharmacological inhibition of MET, we demonstrate that the pleuroperitoneal folds (PPFs), transient embryonic structures that give rise to the connective tissue, are the source of HGF critical for diaphragm muscularization and phrenic nerve primary branching. HGF not only is required for recruitment of muscle progenitors to the diaphragm, but is continuously required for maintenance and motility of the pool of progenitors to enable full muscularization. Thus, the connective tissue fibroblasts and HGF coordinately regulate diaphragm muscularization and innervation. Defects in PPF-derived HGF result in muscleless regions that are susceptible to CDH.Summary StatementFibroblast-derived HGF signals to Met+ muscle progenitors and nerve to control the expansion of diaphragm muscle and primary branching of phrenic nerve axons - structures critical for breathing in mammals.
Intravital imaging of cerebral microinfarct reveals an astrocyte reaction led to glial scar
Authors: Lee Jingu , Kim Joon-Goon , Hong Sujung , Kim Young Seo , Ahn Soyeon , Kim Ryul , Chun Heejung , Park Ki Duk , Jeong Yong , Kim Dong-Eog , Lee C. Justin , Ku Taeyun , Kim Pilhan 
Published: October 2021

AbstractCerebral microinfarct increases the risk of dementia. But how microscopic cerebrovascular disruption affects the brain tissue in cellular-level are mostly unknown. Herein, with a longitudinal intravital imaging, we serially visualized in vivo dynamic cellular-level changes in astrocyte, pericyte and neuron as well as microvascular integrity after the induction of cerebral microinfarction for 1 month in mice. At day 2-3, it revealed a localized edema with acute astrocyte loss, neuronal death, impaired pericyte-vessel coverage and extravascular leakage indicating blood-brain barrier (BBB) dysfunction. At day 5, edema disappeared with recovery of pericyte-vessel coverage and BBB integrity. But brain tissue continued to shrink with persisted loss of astrocyte and neuron in microinfarct until 30 days, resulting in a collagen-rich fibrous scar surrounding the microinfarct. Notably, reactive astrocytes appeared at the peri-infarct area early at day 2 and thereafter accumulated in the peri-infarct. Oral administration of a reversible monoamine oxidase B inhibitor significantly decreased the astrocyte reactivity and fibrous scar formation. Our result suggests that astrocyte reactivity may be a key target to alleviate the impact of microinfarction.
DOMINANT AWN INHIBITORencodes the ALOG protein originating from gene duplication and inhibits awn elongation by suppressing cell proliferation and elongation in sorghum
Authors: Takanashi Hideki , Kajiya-Kanegae Hiromi , Nishimura Asuka , Yamada Junko , Ishimori Motoyuki , Kobayashi Masaaki , Yano Kentaro , Iwata Hiroyoshi , Tsutsumi Nobuhiro , Sakamoto Wataru 
Published: October 2021

AbstractThe awn, a needle-like structure extending from the tip of the lemma in grass species, plays a role in environmental adaptation and fitness. In some crops, awns appear to have been eliminated during domestication. Although numerous genes involved in awn development have been identified, several dominant genes that eliminate awns are also known to exist. For example, in sorghum (Sorghum bicolor), the dominant awn inhibiting gene has been known since 1921; however, its molecular features remain uncharacterized. In this study, we conducted quantitative trait locus analysis and a genome-wide association study of awn-related traits in sorghum and identifiedDOMINANT AWN INHIBITOR(DAI), which encodes the ALOG family protein on chromosome 3.DAIappeared to be present in most awnless sorghum cultivars, likely because of its effectiveness. Detailed analysis of the ALOG protein family in cereals revealed thatDAIoriginated from duplication of its twin paralog (DAIori) on chromosome 10. Observations of immature awns in near-isogenic lines revealed that DAI inhibits awn elongation by suppressing both cell proliferation and elongation. We also found that onlyDAIgained a novel function to inhibit awn elongation through an awn-specific expression pattern distinct from that ofDAIori. Interestingly, heterologous expression ofDAIwith its own promoter in rice inhibited awn elongation in the awned cultivar Kasalath. We found thatDAIoriginated from gene duplication, providing an interesting example of gain-of-function that occurs only in sorghum but shares its functionality with rice and sorghum.
SARS-CoV-2 Beta variant infection elicits potent lineage-specific and cross-reactive antibodies
Authors: Reincke S Momsen , Yuan Meng , Kornau Hans-Christian , Corman Victor M , van Hoof Scott , Sánchez-Sendin Elisa , Ramberger Melanie , Yu Wenli , Hua Yuanzi , Tien Henry , Schmidt Marie Luisa , Schwarz Tatjana , Jeworowski Lara Maria , Brandl Sarah E , Rasmussen Helle Foverskov , Homeyer Marie A , Stöffler Laura , Barner Martin , Kunkel Désirée , Huo Shufan , Horler Johannes , von Wardenburg Niels , Kroidl Inge , Eser Tabea M , Wieser Andreas , Geldmacher Christof , Hoelscher Michael , Gänzer Hannes , Weiss Günter , Schmitz Dietmar , Drosten Christian , Prüss Harald , Wilson Ian A. , Kreye Jakob 
Published: October 2021

AbstractSARS-CoV-2 Beta variant of concern (VOC) resists neutralization by major classes of antibodies from non-VOC COVID-19 patients and vaccinated individuals. Here, serum of Beta variant infected patients revealed reduced cross-neutralization of non-VOC virus. From these patients, we isolated Beta-specific and cross-reactive receptor-binding domain (RBD) antibodies. The Beta-specificity results from recruitment of novel VOC-specific clonotypes and accommodation of VOC-defining amino acids into a major non-VOC antibody class that is normally sensitive to these mutations. The Beta-elicited cross-reactive antibodies share genetic and structural features with non-VOC-elicited antibodies, including a public VH1-58 clonotype targeting the RBD ridge independent of VOC mutations. These findings advance our understanding of the antibody response to SARS-CoV-2 shaped by antigenic drift with implications for design of next-generation vaccines and therapeutics.One sentence summarySARS-CoV-2 Beta variant elicits lineage-specific antibodies and antibodies with neutralizing breadth against wild-type virus and VOCs.
Juvenile hormones direct primordial germ cell migration to the embryonic gonad
Authors: Lacy J Barton , Justina Sanny , Emily P Dawson , Marcela Nouzova , Fernando Gabriel Noriega , Matthias Stadtfeld , Ruth Lehmann 
Published: October 2021

SummaryGerm cells are essential to sexual reproduction. Across the animal kingdom, extracellular signaling isoprenoids, such as retinoic acids (RAs) in vertebrates and juvenile hormones (JHs) in invertebrates, facilitate multiple processes in the germline lifecycle. Here we investigated the role of these potent signaling molecules in embryonic germ cell migration, using JHs inDrosophila melanogasteras a model system. In contrast to their established endocrine roles during larval and adult germline development, we found that JH signaling acts locally during embryonic development. Using anin vivobiosensor, we found JH signaling is first active near primordial germ cells (PGCs) as they migrate to the developing somatic gonad. Throughin vivoandin vitroassays, we found that JHs are both necessary and sufficient for PGC migration. Analysis into the mechanisms of this newly uncovered paracrine JH function revealed that PGC migration was compromised when JHs were reduced or increased, suggesting that specific titers or spatiotemporal JH dynamics are required for robust PGC colonization to the gonad. Compromised PGC migration can impair fertility and cause germ cell tumors in many species, including humans. In mammals, retinoids, a JH-related family of signaling isoprenoids, has many roles in development and reproduction. We found that retinoic acid, like JH, was sufficient to impact PGC migrationin vitro. Together, our study reveals a previously unanticipated role of isoprenoids as local effectors of pre-gonadal PGC development and suggests a broadly shared mechanism in PGC migration.HighlightsJuvenile hormones (JH) are necessary & sufficient for Primordial Germ Cell (PGC) migration.JH signaling acts directly in and around migrating PGCs prior to its endocrine function.Compensatory feedback sensitive to JH receptor function maintains JH homeostasis.JH-like retinoic acids may have similar roles during mammalian germ cell migration.
Hypoxia-directed tumor targeting of CRISPR/Cas9 and HSV-TK suicide gene therapy using lipid nanoparticles
Authors: Davis Alicia , Morris Kevin V. , Shevchenko Galina 
Published: October 2021

AbstractHypoxia is a characteristic feature of solid tumors that contributes to tumor aggressiveness and is associated with resistance to cancer therapy. The hypoxia inducible factor-1 (HIF-1) transcription factor complex mediates hypoxia-specific gene expression by binding to hypoxia responsive element (HRE) sequences within the promoter of target genes. HRE driven expression of therapeutic cargo has been widely explored as a strategy to achieve cancer-specific gene expression. By utilizing this system, we achieve hypoxia-specific expression of two therapeutically relevant cargo elements: the Herpes Simplex Virus thymidine kinase (HSV-tk) suicide gene and the CRISPR/Cas9 nuclease. Using an expression vector containing five copies of the HRE derived from the vascular endothelial growth factor gene, we are able to show high transgene expression in cells in a hypoxic environment, similar to levels achieved using the CMV and CBh promoters. Furthermore, we are able to deliver our therapeutic cargo to tumor cells with high efficiency using plasmid packaged lipid nanoparticles (LNPs) to achieve specific killing of tumor cells in hypoxic conditions, while maintaining tight regulation with no significant changes to cell viability in normoxia.
Comprehensive simulation and interpretation of single nucleotide substitutions in GJB2 reveals the genetic and phenotypic landscape of GJB2-related hearing loss
Authors: Xiang Jiale , Sun Xiangzhong , Song Nana , Chen Lisha , Ramaswamy Sathishkumar , Tayoun Ahmad Abou , Peng Zhiyu 
Published: October 2021

AbstractGenetic variants in the GJB2 gene are the most frequent causes of congenital and childhood hearing loss worldwide. In addition to nonsyndromic hearing loss, GJB2 pathogenic variants are also correlated with syndromic phenotypes, showing high genetic and phenotypic heterogeneity. To comprehensively delineate the genetic and phenotypic landscape of GJB2 variants, we interpreted and manually curated all the 2043 possible single-nucleotide substitution (SNS) coding variants in this gene following the hearing loss-specific ACMG/AMP guidelines. As a result, 61 (3.0%), 188 (9.2%), 1487 (72.8%), 301 (14.7%) and 6 (0.3%) variants were classified as pathogenic, likely pathogenic, variant of uncertain significance, likely benign and benign, respectively. Interestingly, 54% (84/156) of pathogenic/likely pathogenic missense variants were not recorded in ClinVar. Further analysis showed that the second transmembrane domain (TM2) and the 310 helix are highly enriched for pathogenic missense variants. The N-terminal tail and the extracellular loop (E1) showed a high density of variants that are associated with syndromic or dominant nonsyndromic hearing loss. On the other hand, the intracellular loops (CL and CT) were extremely tolerant to variation. Based on this new information, we propose refinements of the guidelines for variant interpretation in GJB2. In summary, our study interpreted all possible SNS variants in the coding region of the GJB2 gene, characterized novel clinically significant (N = 249) and benign or likely benign (N = 307) in this gene, and revealed significant genotype-phenotype correlations at this common hearing loss locus. The interpretation of GJB2 SNS variants in the coding region provides a prototype for genes with similarly high genetic and phenotypic heterogeneity.
Astrocytic extracellular vesicles modulate neuronal calcium homeostasis via transglutaminase-2
Authors: Tonoli Elisa , Verduci Ivan , Prada Ilaria , Gabrielli Martina , Forcaia Greta , Coveney Clare , Savoca Maria Pia , Boocock David J. , Sancini Giulio , Mazzanti Michele , Verderio Claudia , Verderio Elisabetta A.M. 
Published: October 2021

AbstractWe have uncovered a novel role for astrocytes-derived extracellular vesicles (EVs) in controlling intraneuronal Ca2+concentration ([Ca2+]i) and identified transglutaminase-2 (TG2) as a surface-cargo of astrocytes-derived EVs. Incubation of hippocampal neurons with primed astrocyte-derived EVs have led to an increase in [Ca2+]i, unlike EVs from TG2-knockout astrocytes. Exposure of neurons or brain slices to extracellular TG2 promoted a [Ca2+]irise, which was reversible upon TG2 removal and was dependent on Ca2+influx through the plasma membrane. Patch-clamp and calcium imaging recordings revealed TG2-dependent neuronal membrane depolarisation and activation of inward currents, due to the opening of L-type-VOCCs and to Na+/Ca2+-exchanger (NCX) operation in the reverse mode, as indicated by VOCCs/NCX pharmacological inhibitors. A subunit of Na+/K+-ATPase was selected by comparative proteomics and identified as being functionally inhibited by extracellular TG2, implicating Na+/K+-ATPase inhibition in NCX reverse mode-switching leading to Ca2+influx and higher basal [Ca2+]i. These data suggest that reactive astrocytes control intraneuronal [Ca2+]ithrough release of EVs with TG2 as responsible cargo, which could have a significant impact on synaptic activity in brain inflammation.