bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential co-expression network analysis with DCoNA reveals isomiR targeting aberrations in prostate cancer
Authors: Zhiyanov Anton , Engibaryan Narek , Nersisya Stepan , Shkurnikov Maxim , Tonevitsky Alexander 
Published: July 2022

AbstractWe developed DCoNA – a statistical tool that allows one to identify pair interactions, which correlation significantly changes between two conditions. Comparing DCoNA with the state-of-the-art analog, we showed that DCoNA is a faster, more accurate, and less memory-consuming tool. We applied DCoNA to prostate mRNA/miRNA-seq data collected from The Cancer Genome Atlas (TCGA) and compared predicted regulatory interactions of miRNA isoforms (isomiRs) and their target mRNAs between normal and cancer samples. As a result, almost all highly expressed isomiRs lost negative correlation with their targets in prostate cancer samples compared to ones without the pathology. One exception to this trend was the canonical isomiR of hsa-miR-93-5p acquiring cancerspecific targets. Further analysis showed that cancer aggresiveness increased with the expression of this isomiR in both TCGA primary tumor samples and 153 blood plasma samples of own patients’ cohort analyzed by miRNA microarrays.
Analysis of nucleus and cytoplasm-specific RNA fractions demonstrates that a significant proportion of the genetic regulation of gene expression across the human brain occurs post-transcriptionally
Authors: D’Sa Karishma , Guelfi Sebastian , Vandrovcova Jana , Reynolds Regina H. , Zhang David , Hardy John , Botía Juan A. , Weale Michael E. , Gagliano Taliun Sarah A. , Small Kerrin S. , Ryten Mina 
Published: July 2022

ABSTRACTGaining insight into the genetic regulation of gene expression in human brain is key to the interpretation of genome-wide association studies for major neurological and neuropsychiatric diseases. Expression quantitative trait loci (eQTL) analyses have largely been used to achieve this, providing valuable insights into the genetic regulation of steady-state RNA in human brain, but not distinguishing between molecular processes regulating transcription and stability. RNA quantification within cellular fractions can disentangle these processes in cell types and tissues which are challenging to model in vitro. We investigated the underlying molecular processes driving the genetic regulation of gene expression specific to a cellular fraction using allele-specific expression (ASE). Applying ASE analysis to genomic and transcriptomic data from paired nuclear and cytoplasmic fractions of anterior prefrontal cortex, cerebellar cortex and putamen tissues from 4 post-mortem neuropathologically-confirmed control human brains, we demonstrate that a significant proportion of genetic regulation of gene expression occurs post-transcriptionally in the cytoplasm, with genes undergoing this form of regulation more likely to be synaptic. These findings have implications for understanding the structure of gene expression regulation in human brain, and importantly the interpretation of rapidly growing single-nucleus brain RNA-sequencing and eQTL datasets, where cytoplasm-specific regulatory events could be missed.
Deficit in observational learning in experimental epilepsy
Authors: Doublet Thomas , Ghestem Antoine , Bernard Christophe 
Published: July 2022

AbstractIndividuals use the observation of a conspecific to learn new behaviors and skills in many species. Whether observational learning is affected in epilepsy is not known. Using the pilocarpine rat model of epilepsy, we assessed learning by observation in a spatial task.The task involves a naïve animal observing a demonstrator animal seeking a reward at a specific spatial location. After five observational sessions, the observer is allowed to explore the rewarded space and look for the reward.Although control observer rats succeed in finding the reward when allowed to explore the rewarded space, epileptic animals fail. However, epileptic animals are able to successfully learn the location of the reward through their own experience after several trial sessions.Thus, epileptic animals show a clear deficit in learning by observation. This result may be clinically relevant, in particular in children who strongly rely on observational learning.
Losartan controls immune checkpoint blocker-induced edema and improves survival in glioblastoma
Authors: Datta Meenal , Chatterjee Sampurna , Perez Elizabeth M. , Gritsch Simon , Roberge Sylvie , Duquette Mark , Chen Ivy X. , Naxerova Kamila , Kumar Ashwin S. , Ghosh Mitrajit , Emblem Kyrre E. , Ng Mei R. , Ho William W. , Kumar Pragya , Krishnan Shanmugarajan , Dong Xinyue , Speranza Maria C. , Neagu Martha R. , Reardon David A. , Sharpe Arlene H. , Freeman Gordon J. , Suvà Mario L. , Xu Lei , Jain Rakesh K. 
Published: July 2022

AbstractImmune checkpoint blockers (ICBs) have failed in all Phase III glioblastoma trials. Here, we found that ICBs induce cerebral edema in some patients and mice with glioblastoma. Through single-cell RNA sequencing, intravital imaging, and T cell blocking studies in mice, we demonstrated that this edema results from an inflammatory response following anti-PD1 antibody treatment that disrupts the blood-tumor-barrier. Used in lieu of immunosuppressive corticosteroids, the angiotensin receptor blocker losartan prevented this ICB-induced edema and reprogrammed the tumor microenvironment, curing 20% of mice which increased to 40% in combination with standard of care treatment. Using a bihemispheric tumor model, we identified a “hot” tumor immune signature prior to losartan+anti-PD1 therapy that predicted long-term survival. Our findings provide the rationale and associated biomarkers to test losartan with ICBs in glioblastoma patients.One-Sentence SummaryLosartan prevents immunotherapy-associated edema and enhances the outcome of immunotherapy in glioblastoma.
Regulatory divergence as a mechanism for X-autosome incompatibilities in Caenorhabditis nematodes
Authors: Viswanath Athmaja , Cutter Asher D. 
Published: July 2022

ABSTRACTThe world’s astounding biodiversity results from speciation, the process of formation of distinct species. Hybrids between species often have reduced fitness due to negative epistatic interactions between divergent genetic factors, as each lineage accumulated substitutions independently in their evolutionary history. Such negative genetic interactions can manifest as gene misexpression due to divergence in gene regulatory controls from mutations in cis-regulatory elements and trans-acting factors. Gene misexpression due to differences in regulatory controls can ultimately contribute to incompatibility within hybrids through developmental defects such as sterility and inviability. We sought to quantify the contributions of regulatory divergence to post-zygotic reproductive isolation using sterile interspecies hybrids of two Caenorhabditis nematodes: C. briggsae and C. nigoni. We analysed previous transcriptome profiles for two introgression lines with distinct homozygous X-linked fragments from C. briggsae in a C. nigoni genomic background that confers male sterility, owing to defects in spermatogenesis (Li et al. 2016). Our analysis identified hundreds of genes that show distinct classes of non-additive expression inheritance and regulatory divergence. We find that these non-overlapping introgressions affect many of the same genes in the same way and demonstrate that the preponderance of transgressive gene expression is due to regulatory divergence involving compensatory and joint effects of cis- and trans-acting factors. The similar transcriptomic responses to non-overlapping genetic perturbations of the X-chromosome implicate multiway incompatibilities as an important feature contributing to hybrid male sterility in this system.Significance statementThe genetic causes of intrinsic post-zygotic reproductive isolation can arise from hybrids experiencing negative gene regulatory interactions. In Caenorhabditis nematodes, hybrid male sterility involves X-autosome incompatibilities that affect small-RNA regulatory pathways. We sought to understand the role of gene regulatory divergence as a related contributor to hybrid misexpression by analyzing transcriptomes of sterile males from two hybrid introgression lines, each containing distinct X-linked fragments from C. briggsae in a C. nigoni genomic background. We show that gene misexpression occurs due to extensive joint divergence of cis- and trans-acting regulatory factors and provide evidence for multiway incompatibilities as an important feature of this system.
IL-15 superagonist N-803 enhances IFNγ production and alters the trafficking of MAIT cells in SIV+ macaques
Authors: Ellis-Connell Amy L. , Balgeman Alexis J. , Kannal Nadean M. , Chaimson Karigynn Hansen , Batchenkova Anna , Safrit Jeffrey T. , O’Connor Shelby L. 
Published: July 2022

AbstractMucosal Associated Invariant T cells (MAIT cells) are innate T cells that recognize bacterial metabolites and secrete cytokines and cytolytic enzymes to destroy infected target cells. This makes MAIT cells promising targets for immunotherapy to combat bacterial infections. Here, we analyzed the effects of an immunotherapeutic agent, the IL-15 superagonist N-803, on MAIT cell activation, trafficking, and cytolytic function in macaques. We found that N-803 could activate MAIT cells in vitro and increase their ability to produce IFNγ in response to bacterial stimulation. To expand upon this, we examined the phenotypes and function of MAIT cells present in samples collected from PBMC, airways (BAL), and lymph nodes (LN) from rhesus macaques that were treated in vivo with N-803. N-803 treatment led to a transient 6-7 fold decrease in the total number of MAIT cells in the peripheral blood relative to pre N-803 timepoints. Concurrent with the decrease in cells in the peripheral blood, we observed a rapid decline in the frequency of CXCR3+CCR6+ MAITs. This corresponded with an increase in the frequency of CCR6+ MAITs in BAL, and higher frequencies of ki-67+ and granzyme B+ MAITs in blood, LN, and BAL. Finally, N-803 improved the ability of MAIT cells collected from PBMC and airways to produce IFNγ in response to bacterial stimulation. Overall, N-803 shows the potential to transiently alter the trafficking and enhance the antibacterial activity of MAIT cells which could be combined with other strategies to combat bacterial infections.
Accountable Prediction of Drug ADMET Properties with Molecular Descriptors
Authors: Boral Nilavo , Ghosh Promita , Goswami Adhish , Bhattacharyya Malay 
Published: July 2022

AbstractDrugs are chemical substances of low molecular weights that require to travel from the site of administration to the site of action. For safety and effective permeability, drugs are required to exhibit ideal absorption, distribution, metabolism, excretion and toxicity (ADMET) properties. Given the Simplified Molecular Input Line Entry System (SMILES) representation of drugs, we aim to predict their ADMET properties. By feeding molecular descriptors (as global features) to traditional machine learning models, we show that ADMET properties of drug molecules can be predicted with an accuracy competitive with the state-of-the-art deep learning models. We demonstrate that the proposed approach with only 31 molecular descriptors beats the state-of-the-art for 3 datasets. Moreover, it stands the second best for 2 other datasets, where none of the best provides a statistically significant improvement. We also demonstrate that two-dimensional descriptors can better represent absorption, distribution and excretion properties than the fingerprints widely used in the literature. However, they fail to distinguish metabolism and toxicity properties.
Annotation of Phage Genomes with Multiple Genetic Codes
Authors: Pfennig Aaron , Lomsadze Alexandre , Borodovsky Mark 
Published: July 2022

AbstractSome of recently discovered in human gut microbiome highly divergent crAssphages were reported to use multiple genetic codes. Opal or amber stop codon reassignments were present in parts of the genomes, while the standard genetic code was used in the remaining genome sections. Essentially, the phage genomes were divided into distinct blocks where one or another code was used. We have developed a tool, Mgcod, that identifies blocks with specific genetic codes and annotates protein-coding regions. We used Mgcod to scan a large set of human metagenomic contigs. As a result, we identified hundreds of contigs of viral origin with the standard genetic code used in some parts while genetic codes with opal or amber stop codon reassignments were used in others. Many of these contigs originated from known crAssphages. Further investigation revealed that while the genes in one genomic block could be translated by a distinct genetic code, translation of genes by either of the two genetic codes genes in an adjacent block would produce proteins with little difference from each other. The dual-coded genes were enriched with early-stage phage genes, while a single code was used for the late-stage genes. The code-block structure expands the phage’s ability to infect bacteria whose genomes employ the standard genetic code. The new tool provides means for accurate annotation of unusual genomes of these phages.
Paracrine signaling by pancreatic δ cells determines the glycemic set point in mice
Authors: Huang Jessica L , Lee Sharon , Pourhosseinzadeh Mohammad S , Krämer Niels , Guillen Jaresley V , Cinque Naomi H , Aniceto Paola A , Koike Shinichiro , Huising Mark O 
Published: July 2022

SUMMARYPancreatic islets contain several endocrine cell types that coordinate to maintain blood glucose homeostasis. While β and α cells are thought to be the main drivers of glucose homeostasis through insulin and glucagon secretion respectively, the contribution of δ cells and somatostatin (SST) secretion to establishing the glycemic set point remains unresolved. Here we remove local SST signaling from δ cells within the pancreatic islet to investigate their contribution to the glycemic set point. Our data demonstrate that ablating δ cells or SST leads to a sustained decrease in the glycemic set point. This coincides with a decreased glucose threshold for insulin response from β cells, leading to increased insulin secretion to the same glucose challenge. In contrast, α cell ablation had no effect on glycemic set point. Collectively, these data establish the physiological role of δ cells in determining the glycemic set point through their interaction with β cells.
Presynaptic Rac1 controls synaptic strength through the regulation of synaptic vesicle priming
Authors: Keine Christian , Al-Yaari Mohammed , Radulovic Tamara , Thomas Connon I. , Ramos Paula Valino , Guerrero-Given Debbie , Ranjan Mrinalini , Taschenberger Holger , Kamasawa Naomi , Young Samuel M. 
Published: July 2022

AbstractSynapses contain a limited number of synaptic vesicles (SVs) that are released in response to action potentials (APs). Therefore, sustaining synaptic transmission over a wide range of AP firing rates and timescales depends on SV release and replenishment. Although actin dynamics impact synaptic transmission, how presynaptic regulators of actin signaling cascades control SV release and replenishment remains unresolved. Rac1, a Rho GTPase, regulates actin signaling cascades that control synaptogenesis, neuronal development, and postsynaptic function. However, the presynaptic role of Rac1 in regulating synaptic transmission is unclear. To unravel Rac1’s roles in controlling transmitter release, we performed selective presynaptic ablation of Rac1 at the mature mouse calyx of Held synapse. Loss of Rac1 increased synaptic strength, accelerated EPSC recovery after conditioning stimulus trains, and augmented spontaneous SV release with no change in presynaptic morphology or AZ ultrastructure. Analyses with constrained short-term plasticity models revealed faster SV priming kinetics and, depending on model assumptions, elevated SV release probability or higher abundance of tightly docked fusion-competent SVs in Rac1-deficient synapses. We conclude that presynaptic Rac1 is a key regulator of synaptic transmission and plasticity mainly by regulating the dynamics of SV priming and potentially SV release probability.
tinyRNA: precision analysis of small RNA-seq data with user-defined hierarchical selection rules
Authors: Tate Alex J. , Brown Kristen C. , Montgomery Taiowa A. 
Published: July 2022

ABSTRACTSummarytinyRNA performs precision analysis of small RNAs, including miRNAs, piRNAs, and siRNAs, from high-throughput sequencing experiments. At the core of tinyRNA is a highly flexible counting utility, tiny-count, that allows for hierarchical assignment of small RNA reads to features based on positional information, extent of feature overlap, 5’ nucleotide, length, and strandedness. tinyRNA provides an all-in-one solution for small RNA-seq data analysis, with documentation and statistics generated at each step for accurate, reproducible results.Availability and ImplementationtinyRNA tools are implemented in Python and R, and the pipeline workflow is coordinated with CWL. tinyRNA is free and open-source software distributed under the GPLv3 license. tinyRNA is available at https://github.com/MontgomeryLab/tinyRNA.Contacttai.montgomery@colostate.eduSupplementary informationReference data, including genome sequences and features tables, for certain species can be found at https://www.MontgomeryLab.org.
Molecular characteristics of phages located in Carbapenemase-Producing Escherichia coli clinical isolates: New Phage-Like Plasmids
Authors: Lopez-Diaz Maria , Bleriot Ines , Pacios Olga , Fernandez-Garcia Laura , Blasco Lucia , Ambroa Anton , Ortiz-Cartagena Concha , Woodford Neil , Ellington Matthew J. , Tomas Maria 
Published: July 2022

ABSTRACTEscherichia coli normally inhabits the gastrointestinal tract of humans and animals. Most E. coli bacteria do not cause problems, but the acquisition of different resistance and virulence genes encoded by mobile plasmids or phages by different bacterial isolates has been associated with the appearance of successful high-risk clones of multidrug-resistant (MDR) E. coli such as ST131 or ST405. In the present study, 50 temperate bacteriophages present in 21 clinical isolates of carbapenemase-producing E. coli of sequence types (STs) ST38, ST131, ST167, ST405 and ST410 were analysed. These phages were classified in the three families of the order Caudovirales: 24 within the family Siphoviridae, 23 in Myoviridae and 3 in Podoviridae. The size of the phages studied ranged from 11 to 95 Kb. Phylogenetic analysis of the terminase large subunit allowed us to classify these phages into different groups showing similarity with the phage sequences deposited in the Microbe Versus Phage (MVP) database and which belonged to clusters 229, 604, 2503 and 2725. On the other hand, bioinformatic study revealed that most of the identified proteins exerted a structural function (26.73%) but also functions involved in lysis/lysogeny (6.70%) or regulation (5.20%) among others. In addition, the ParA-ParB partitioning system and the type II toxin-antitoxin Phd-Doc system were also found in two of the phages studied, which could indicate the presence of plasmid-prophages. Host range testing revealed that two isolates were more susceptible to infection than the other isolates.IMPORTANCEEscherichia coli is one of the pathogens that causes most problems in human health, as it presents multiple resistances to different antibiotics. The study of bacteriophages located in different isolates of this species is important for the development of new anti-infective therapies. Currently, antibiotic resistance is a major problem, but more and more studies are pointing to experimental treatments with bacteriophages as a possible solution.
Reconstituted depolarization-induced Ca2+release platform for skeletal muscle disease mutation validation and drug discovery
Authors: Murayama Takashi , Kurebayashi Nagomi , Numaga-Tomita Takuro , Kobayashi Takuya , Okazaki Satoru , Yamashiro Kyosuke , Nakada Tsutomu , Mori Shuichi , Ishida Ryosuke , Kagechika Hiroyuki , Yamada Mitsuhiko , Sakurai Takashi 
Published: July 2022

AbstractIn skeletal muscle excitation-contraction (E-C) coupling, depolarization of the plasma membrane triggers Ca2+release from the sarcoplasmic reticulum (SR), referred to as depolarization-induced Ca2+release (DICR). DICR occurs via the type 1 ryanodine receptor (RyR1), which physically interacts with the dihydropyridine receptor Cav1.1 subunit in specific machinery formed with additional essential components including β1a, Stac3 adaptor protein and junctophilins. Exome sequencing has accelerated the discovery of many novel mutations in genes encoding DICR machinery in various skeletal muscle diseases. However, functional validation is time-consuming because it must be performed in a skeletal muscle environment. In this study, we established a platform of the reconstituted DICR in HEK293 cells. The essential components were effectively transduced into HEK293 cells expressing RyR1 using baculovirus vectors, and Ca2+release was quantitatively measured with R-CEPIA1er, a fluorescent ER Ca2+indicator, without contaminant of extracellular Ca2+influx. In these cells, [K+]-dependent Ca2+release was triggered by chemical depolarization with the aid of inward rectifying potassium channel, indicating a successful reconstitution of DICR. Using the platform, we evaluated several Cav1.1 mutations that are implicated in malignant hyperthermia and myopathy. We also tested several RyR1 inhibitors; whereas dantrolene and Cpd1 inhibited DICR, procaine had no effect. Furthermore, twitch potentiators such as perchlorate and thiocyanate shifted the voltage dependence of DICR to more negative potentials without affecting Ca2+-induced Ca2+release. These results well reproduced the findings with the muscle fibers and the cultured myotubes. Since the procedure is simple and reproducible, the reconstituted DICR platform will be highly useful for validation of mutations and drug discovery for skeletal muscle diseases.SummaryMutations in essential components for depolarization-induced Ca2+release (DICR) are implicated into various skeletal muscle diseases. Murayama et al. establish a reconstituted DICR platform in nonmuscle cells for evaluation of disease-causing mutations and drug discovery.
Scaling pattern of the carnivoran forelimb: Locomotor types, differential scaling and thoughts on a dying similarity
Authors: Gálvez-López Eloy , Casinos Adrià 
Published: July 2022

AbstractThe scaling pattern of the forelimb in Carnivora was determined using a sample of 30 variables measured on the scapula, humerus, radius, ulna, and third metacarpal, of 429 specimens belonging to 137 species of Carnivora. Standardized major axis regressions on body mass were calculated for all variables, using both traditional regression methods and phylogenetically independent contrasts (PIC). In agreement with previous studies on the scaling of the appendicular skeleton, conformity to either the geometric similarity hypothesis or the elastic similarity hypothesis was low. The scaling pattern of several phyletic lines and locomotor types within Carnivora was also determined, and significant deviations from the scaling pattern of the order were found in some of these subsamples. Furthermore, significant evidence for differential scaling was found for several variables, both in the whole sample and in various phylogenetic and locomotor subsamples. Contrary to previous studies, significant differences were found between the allometric exponents obtained with traditional and PIC regression methods, emphasizing the need to take into account phylogenetic relatedness in scaling studies. In light of these and previous results, we conclude that similarity hypotheses are too simplistic to describe scaling patterns in the carnivoran appendicular skeleton, and thus we propose that scaling hypotheses should be built from similarities in the scaling patterns of phylogenetically narrow samples of species with similar locomotor requirements. The present work is a first step in the study of those samples.