bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase 1 Study of Novel Antiplatelet Agent to Overcome Pharmacogenomic Limitations of Clopidogrel
Authors: Pareek Anil , Chandurkar Nitin , Raut Vivek , Naidu Kumar 
Published: March 2024

AbstractBackgroundClopidogrel is the most commonly prescribed thienopyridine as part of dual antiplatelet therapy for the treatment of cardiovascular diseases. However, Clopidogrel responsiveness shows variability based on CYP2C19 polymorphism. Therefore, we planned a study with an objective of evaluating safety, tolerability, pharmacodynamics and pharmacokinetics of a novel thienopyridine antiplatelet agent AT-10 in healthy Indian subjects in comparison with standard dosage regimen of Clopidogrel based on their CYP2C19 genotyping.MethodsTwo CYP2C19 genotype based groups were identified i.e., Poor Metabolizer and Extensive Metabolizers with 20 subjects in each group (N=40) for participating in a randomized, two period, cross-over study. Each study period lasted 6 days including administration of loading and maintenance doses of AT-10 (40mg/10mg) or Clopidogrel (300mg/75mg). The pharmacokinetics and pharmacodynamics were assessed on day 1 and day 6 at several time intervals.ResultsOverall result of pharmacodynamic parameters showed that, mean % Inhibition of Platelet Aggregation between AT-10 and Clopidogrel in all subjects at Post-dose 6hr (loading dose) (AT-10: Clopidogrel; 73.30% vs. 18.53%) and Post-dose 6 hr on Day 6 (maintenance dose) (AT-10: Clopidogrel; 83.41% vs. 51.19 %) obtained from the AT-10 group was significantly higher than the Clopidogrel group. Further, %inhibition of platelet aggregation from AT-10 treatment in poor metabolizer group was significantly higher than the Clopidogrel treatments in extensive metabolizer group.Overall pharmacokinetic comparison in all subjects indicates that AT-10 gives greater exposure to active Metabolite MP-H4 than Clopidogrel.ConclusionAT-10 may emerge as a promising anti-platelet drug and can be further developed in clinical studies for the unmet medical needs of cardiovascular diseases. CTRI Registration: CTRI/2021/03/032206Clinical PerspectivesAT-10 (2-oxo-Clopidogrel) is a novel thienopyridine P2Y12 inhibitor under clinical development in India.It is a Clopidogrel derivative that is metabolically converted to produce the active thiol metabolite similar to Clopidogrel.The response to AT-10 was found unaffected by genetic CYP2C19 polymorphisms to the extent of its influence in Clopidogrel, thus eliminating the need for characterization of Clopidogrel responsiveness and thereby maintaining effectiveness in all patients, including those patients who are identified as CYP2C19 poor and intermediate metabolizers.Further studies are required to investigate the influence of CYP2C19 functional polymorphisms on the response to AT-10 dose in diverse clinical settings, and especially on the risk of recurrent thrombotic events during AT-10 treatment as compared to Clopidogrel therapy.
Novel assay for endangered Hong Kong grouper (Epinephelus akaara) to assess eDNA shedding, decay, and population status
Authors: Chung Arthur , Kam Y.C. , Schunter Celia 
Published: March 2024

AbstractOverexploitation is a major threat to marine ecosystems, causing collapse of numerous fisheries since the 19thcentury. The Hong Kong Grouper (Epinephelus akaara) is a commercial fish species that suffered at least 50-80% population declines in the past 40 years throughout its distribution range. Yet there has been minimal research or specific management, resulting in insufficient data on abundance, reproduction and habitat utilization. Here we aim to develop a novel species-specific quantitative PCR (qPCR) assay to detect potential occurrence ofE. akaarathrough non-invasive environmental water samples. We developed a qPCR assay amplifying 71 bps of the mitochondrial ND2 gene which offers high sensitivity and specificity. To quantify theE. akaarapopulation with the emerging environmental DNA (eDNA) tool, however, species-specific shedding and decay rates are crucial. The decay rate ofE. akaarawas similar to that of reported values of other marine fish species. However, the shedding rate ofE. akaarawas found to be few orders of magnitude lower which may be related to the relatively low activity and energy use from solitary and sedentary behavior of groupers. This highlights the importance of empirically determining species or taxon-specific shedding and decay rates to inform accurate abundance estimates with modelling tools for eDNA concentrations. Only 6 out of 88 water samples (6.81%) collected across 4 sampling seasons and 11 sites around Hong Kong showed positive signals at a concentration below limit of detection of the assay, implying its rarity in Hong Kong nowadays. Overall, we demonstrate that eDNA with our qPCR assay is efficient and sensitive in detecting the target species and is a promising tool in documenting endangered species for species management and conservation.
ComprehensiveInvitroandInsilicoAnalysis of Secondary Metabolites fromDatura metel: Promising Anti-Alzheimer’s Therapeutics
Authors: Sharma Meenakshi , Jain Mukul , Patil Nil , Barnwal Abhishek , Tayade Sumeet , Delta Anil Kumar , Kole Chittaranjan , Kaushik Prashant 
Published: March 2024

AbstractThis research investigates secondary metabolites fromDatura metelas potential anti-Alzheimer’s therapies. In vitro techniques isolated extracts for AD pathology targeting, with in silico analysis identifying gene targets for prevention. Apigenin, Luteolin, and Withanolide A were studied, each with 300 potential gene targets and core gene counts of 54, 52, and 58 respectively. Lipinski’s Rule assessed their pharmacological properties, showing good absorption but limited blood-brain barrier penetration. Protein interaction mapping revealed shared targets among the compounds. GO enrichment and KEGG pathway analysis highlighted their impact on biological processes and pathways, suggesting their anti-Alzheimer’s potential. Luteolin notably reduced Aβ1–42 levels by up to 35.2% (*p<0.05) in SH-SY5Y cells, positioning it and Withanolide A as promising multi-functional Alzheimer’s medications. These findings underscore the significance of Datura phytochemicals in AD prevention and treatment.
Characterization of Genome-wide Phylogenetic Conflict Uncovers Evolutionary Modes of Carnivorous Fungi
Authors: Zhang Weiwei , Fan Yani , Deng Wei , Chen Yue , Wang Shunxian , Kang Seogchan , Steenwyk Jacob Lucas , Xiang Meichun , Liu Xingzhong 
Published: March 2024

AbstractMass extinction has often paved the way for rapid evolutionary radiation, resulting in the emergence of diverse taxa within specific lineages. While the emergence and diversification of carnivorous nematode-trapping fungi (NTF) in Ascomycota has been linked to the Permian-Triassic (PT) extinction, the processes underlying NTF radiation remain unclear. Here, we conducted phylogenomic analyses using 23 genomes spanning three NTF lineages, each employing distinct nematode traps — mechanical traps (Drechslerellaspp.), three-dimensional (3-D) adhesive traps (Arthrobotrysspp.), and two-dimensional (2-D) adhesive traps (Dactylellinaspp.), and one non-NTF species as the outgroup. This analysis revealed how diverse mechanisms contributed to the tempo of NTF evolution and rapid radiation. The genome-scale species tree of NTFs suggested thatDrechslerellaemerged earlier thanArthrobotrysandDactylellina. Extensive genome-wide phylogenetic discordance was observed, mainly due to incomplete lineage sorting (ILS) between lineages (∼81.3%). Modes of non-vertical evolution (i.e., introgression and horizontal gene transfer) also contributed to phylogenetic discordance. The ILS genes that are associated with hyphal growth and trap morphogenesis (e.g., those associated with the cell membrane system and cellular polarity division) exhibited signs of positive selection.
Circadian control in the timing of critical periods duringDrosophilalarval neuronal development
Authors: Doran Sarah , Bradlaugh Adam A. , Corke Jack , Baines Richard A. 
Published: March 2024

AbstractCritical periods (CPs) of development are temporal windows of heightened neural plasticity. Activity perturbation during CPs can produce significant, and permanent, alterations to the development of neural circuits. In this study we report a circadian mechanism underlying the timing of CPs inDrosophilaembryonic and larval development. These CPs occur at ∼24 hr intervals and are open to manipulation through blue light (BL)-activation of the circadian regulator Cryptochrome (CRY). This manipulation is sufficient to destabilize the larval CNS, evidenced by an induced seizure phenotype when tested at third instar (L3). In addition to CRY nulls, genetic ablation of theperiodgene also mitigates the BL exposure seizure phenotype and, moreover, alleles ofperiodthat affect circadian timing alter the timing of the CPs. Our analysis shows a clear role for the main clock neuropeptide, pigment dispersing factor (PDF), to transduce the output of these CPs. Targeted PDF receptor knockdown, in either GABAergic or CRY-positive neurons, is sufficient to prevent the CRY-mediated seizure phenotype. This study is a first demonstration of a circadian mechanism inDrosophilalarvae, and whilst this alone is of major significance, our results highlight the potential of usingDrosophilalarvae as a model to investigate the impact of circadian rhythms on early neuronal development in higher organisms, which remains experimentally challenging.Significance StatementWhilst the role of the biological clock is well understood in adult organisms, the same is not true for embryonic development. How the maternal clock impacts the mammalian fetus remains poorly understood. Given that many expectant mothers experience altered circadian rhythms, largely due to nightshift working, it is important to address these concerns. Here we identify clock-mediated periods in neural development of the embryonic Drosophila which can be manipulated by light. These findings provide an experimental opportunity to better understand the role of the circadian clock in early development.
Deep learning to decode sites of RNA translation in normal and cancerous tissues
Authors: Clauwaert Jim , McVey Zahra , Gupta Ramneek , Yannuzzi Ian , Menschaert Gerben , Prensner John R. 
Published: March 2024

AbstractThe biological process of RNA translation is fundamental to cellular life and has wide-ranging implications for human disease. Yet, accurately delineating the variation in RNA translation represents a significant challenge. Here, we develop RiboTIE, a transformer model-based approach to map global RNA translation. We find that RiboTIE offers unparalleled precision and sensitivity for ribosome profiling data. Application of RiboTIE to normal brain and medulloblastoma cancer samples enables high-resolution insights into disease regulation of RNA translation.
GeneSqueeze: A Novel Lossless, Reference-Free Compression Algorithm for FASTQ/A Files
Authors: Nazari Foad , Patel Sneh , LaRocca Melissa , Czarny Ryan , Schena Giana , Murray Emma K. 
Published: March 2024

AbstractAs sequencing becomes more accessible, there is an acute need for novel compression methods to efficiently store this data. Omics technologies can enhance biomedical research and individualize patient care, but they demand immense storage capabilities, especially when applied to longitudinal studies. Addressing the storage challenges posed by these technologies is crucial for omics technologies to achieve their full potential. We present a novel lossless, reference-free compression algorithm, GeneSqueeze, that leverages the patterns inherent in the underlying components of FASTQ files (i.e., nucleotide sequences, quality scores and read identifiers). GeneSqueeze provides several benefits, including an auto-tuning compression protocol based on each sample’s distribution, lossless preservation of IUPAC nucleotides and read identifiers, and unrestricted FASTQ/A file attributes (i.e., read length, read depth, or read identifier format). We compared GeneSqueeze to the general-purpose compressor, gzip, and to the domain-specific compressor, SPRING. GeneSqueeze achieved up to three times higher compression ratios as compared to gzip, regardless of read length, read depth, or file size. GeneSqueeze achieved 100% lossless compression, with the original and decompressed files perfectly matching for all tested samples, preserving read identifiers, quality scores, and IUPAC nucleotides, in contrast to SPRING. Overall, GeneSqueeze represents a competitive and specialized compression method optimized for FASTQ/A files containing nucleotide sequences that has the potential to significantly reduce the storage and transmission costs associated with large omics datasets without sacrificing data integrity.
Analysis of the limitedM. tuberculosisaccessory genome reveals potential pitfalls of pan-genome analysis approaches
Authors: Marin Maximillian G. , Wippel Christoph , Quinones-Olvera Natalia , Behruznia Mahboobeh , Jeffrey Brendan M. , Harris Michael , Mann Brendon C. , Rosenthal Alex , Jacobson Karen R. , Warren Robin M. , Li Heng , Meehan Conor J. , Farhat Maha R. 
Published: March 2024

AbstractPan-genome analysis is a fundamental tool for studying bacterial genome evolution; however, the variety of methods used to define and measure the pan-genome poses challenges to the interpretation and reliability of results. To quantify sources of bias and error related to common pan-genome analysis approaches, we evaluated different approaches applied to curated collection of 151Mycobacterium tuberculosis(Mtb) isolates.Mtbis characterized by its clonal evolution, absence of horizontal gene transfer, and limited accessory genome, making it an ideal test case for this study. Using a state-of-the-art graph-genome approach, we found that a majority of the structural variation observed inMtboriginates from rearrangement, deletion, and duplication of redundant nucleotide sequences. In contrast, we found that pan-genome analyses that focus on comparison of coding sequences (at the amino acid level) can yield surprisingly variable results, driven by differences in assembly quality and the softwares used. Upon closer inspection, we found that coding sequence annotation discrepancies were a major contributor to inflatedMtbaccessory genome estimates. To address this, we developed panqc, a software that detects annotation discrepancies and collapses nucleotide redundancy in pan-genome estimates. When applied toMtbandE. colipan-genomes, panqc exposed distinct biases influenced by the genomic diversity of the population studied. Our findings underscore the need for careful methodological selection and quality control to accurately map the evolutionary dynamics of a bacterial species.
A chromosome-level genome assembly of the Hispid cotton rat (Sigmodon hispidus), a model for human pathogenic virus infections
Authors: Lilue Jingtao , Corvelo André , Gómez-Garrido Jèssica , Yang Fengtang , Akagi Keiko , Green Gia , Ng Bee Ling , Fu Beiyuan , Chorostecki Uciel Pablo , Warner Sarah , Marcet-Houben Marina , Keane Thomas , Mullikin James C. , Alioto Tyler , Gabaldón Toni , Hubert Benjamin , Symer David E. , Niewiesk Stefan 
Published: March 2024

ABSTRACTBackgroundThe cotton rat (Sigmodon hispidus), a rodent species native to the Americas, has emerged as a valuable laboratory model of infections by numerous human pathogens including poliovirus and respiratory syncytial virus (RSV).ResultsHere we report the first reference assembly of the cotton rat genome organized at a chromosomal level, providing annotation of 24,878 protein-coding genes. Data from PCR-free whole genome sequencing, linked-read sequencing and RNA sequencing from pooled cotton rat tissues were analyzed to assemble and annotate this novel genome sequence. Spectral karyotyping data using fluorescent probes derived from mouse chromosomes facilitated the assignment of cotton rat orthologs to syntenic chromosomes, comprising 25 autosomes and a sex chromosome in the haploid genome. Comparative phylome analysis revealed both gains and losses of numerous genes including immune defense genes against pathogens. We identified thousands of recently retrotransposed L1 and SINE B2 elements, revealing widespread genetic innovations unique to this species.ConclusionsWe anticipate that annotation and characterization of the first chromosome-level cotton rat genome assembly as described here will enable and accelerate ongoing investigations into its host defenses against viral and other pathogens, genome biology and mammalian evolution.
Transcriptional landscape of the dorsal raphe serotonin neurons rendering stress resiliency
Authors: Andoh Chihiro , Otani Suzuka , Noguchi Takuma , Hagiwara Masako , Nishitani Naoya , Kawai Hiroyuki , Fukui Yuto , Koda Masashi , Morishita Hinako , Nomura Kento , Oki Moeka , Hori Harune , Shirakawa Hisashi , Kaneko Shuji , Nagayasu Kazuki 
Published: March 2024

AbstractMajor depressive disorder (MDD) is a serious and large social problem, yet the pathophysiology of MDD and the action mechanism of antidepressants are still poorly understood. A number of studies have reported that activation and inactivation of serotonin neurons in the dorsal raphe nucleus (DRN) cause antidepressant-like effects and depressive-like behaviors, respectively. Also, their physiological neural activities are increased when mice were chronically administered an SSRI and decreased in mice exposed to chronic social defeat stress (CSDS), a mouse model of depression. However, the molecular mechanism underlying these neural activity changes in DRN serotonin neurons remains unclear. In this study, we performed a DRN serotonin neuron-specific comprehensive gene expression analysis by using Translating Ribosome Affinity Purification (TRAP) technology in both chronic SSRI-treated mice as a model of antidepressant treatment and CSDS mice as a model of depression. It revealed that many gene expression changes were the opposite between SSRI-treated mice and CSDS-susceptible mice. Among these, we identified S100a10 as a prodepressive gene in DRN serotonin neurons, and we found that Interleukin-4 (IL-4) – Signal Transducer and Activator of Transcription 6 (STAT6) pathway and 5-HT1Breceptor were the upstream and downstream molecules of S100a10, respectively. Our findings provide insights into molecular mechanisms underlying the action of antidepressants and stress resiliency.
Association between Paediatric Mild Traumatic Brain Injury and Two-Year Psychiatric Outcomes Largely Explained by Pre-Existing Mental Health Problems
Authors: Revill Grace , Poole Norman , Carlisi Christina , David Anthony S. , Bell Vaughan 
Published: March 2024

AbstractBackgroundEvidence that mild traumatic brain injury (mTBI) causes psychiatric problems in children has been mixed. Investigating this issue has been difficult due to the lack of representative longitudinal data on child mTBI that includes adequate measures of subsequent mental health symptoms and service use in young people.MethodsWe used data from the ABCD longitudinal cohort study to examine the association between mTBI and psychiatric diagnoses, symptoms, and psychiatric service use in over 11,000 children aged 9-10 at i) baseline, and ii) with new cases of mTBI since baseline and psychiatric outcomes and service use at two-year follow-up. We also compared mTBI cases to a comparison group of participants with orthopaedic injury but without mTBI. Mixed-effects models were used and adjusted for demographic and social covariates, with missing data imputed using random forest multiple imputation. To account for baseline mental health outcomes, we used propensity-score matching to identify a comparison sample matched on potential confounding variables and baseline outcome measures.ResultsWhen examined without adjustment for baseline mental health, both lifetime mTBI at baseline, and new occurrence of mTBI at two-year follow-up, were reliably associated with an increased risk of DSM-5 anxiety and behavioural disorders, mental health symptom scores measured psychometrically, and increased psychiatric service use. These associations were not present, or occasionally only minimally present, in the orthopaedic injury comparison group. However, controlling for baseline mental health using propensity-score matching resulted in no association between new incidence mTBI and psychiatric symptoms, diagnoses and service use, with the exception of parent-reported anxiety and conduct symptom scores in supplementary analyses.ConclusionThe association between childhood mTBI and subsequent psychiatric problems and service use may be largely explained by pre-existing mental health problems.
CITE-seq analysis reveals human cytomegalovirus and diabetes-associated adaptive NK cell alterations in cardiovascular disease
Authors: Armstrong Sujit Silas , Chen Daniel G. , Kumar Sunil , Heath James R. , Feinstein Matthew J. , Greenland John R. , Calabrese Daniel R. , Lanier Lewis L. , Ley Klaus , Shemesh Avishai 
Published: March 2024

AbstractCoronary artery disease (CAD) is a leading cause of mortality worldwide with Diabetes and human cyto-megalovirus (HCMV) infection as risk factors. CAD’s influence on human NK cells is not well characterized. CITE-seq analysis of a CAD cohort of 61 patients revealed distinctly higher NK cellSPON2expression and lowerIFNGexpression in severe CAD patients. Interestingly, HCMV+patients displayed lowerSPON2ex-pression while diabetes status reversed the HCMV effect. Diabetes led to diminished adaptive FcεRIγ−/lowNK cell frequencies and was associated with a higher PBMCIL15/TGFBtranscript ratio, while TGFB in-creased in severe CAD.SPON2expression corresponded to changes in conventional vs. adaptive NK cell frequencies, andSPON2/IFNGratio decreased in inflamed plaque tissue with an increased adaptive NK cell gene signature and was increased in severe CAD patients. Our results indicate that theSPON2/IFNGra-tio and adaptive NK cell gene signature associated with stenosis severity or inflammation in CAD.
High-resolution scRNA-seq reveals genomic determinants of antigen expression hierarchy in African Trypanosomes
Authors: McWilliam Kirsty R. , Keneskhanova Zhibek , Cosentino Raúl O. , Dobrynin Atai , Smith Jaclyn E. , Subota Ines , Mugnier Monica R. , Colomé-Tatché Maria , Siegel T. Nicolai 
Published: March 2024

AbstractAntigenic variation is an immune evasion strategy used by many different pathogens. It involves the periodic, non-random switch in the expression of different antigens throughout an infection. How the observed hierarchy in antigen expression is achieved has remained a mystery. A key challenge in uncovering this process has been the inability to track transcriptome changes and potential genomic rearrangements in individual cells during a switch event. Here, we report the establishment of a highly sensitive single-cell RNA-seq (scRNA-seq) approach for the model protozoan parasiteTrypanosoma brucei. This approach has revealed genomic rearrangements that occur in individual cells during a switch event. Our data show that following a double-strand break (DSB) in the transcribed antigen-coding gene – an important trigger for antigen switching – the type of repair mechanism and the resultant antigen expression depend on the availability of a homologous repair template in the genome. When such a template was available, repair proceeded through segmental gene conversion, creating new, mosaic antigen-coding genes. Conversely, in the absence of a suitable template, a telomere-adjacent antigen-coding gene from a different part of the genome was activated by break-induced replication. Our results reveal the critical role of available repair sequence in the antigen selection mechanism. Additionally, our study demonstrates the power of highly sensitive scRNA-seq methods in detecting genomic rearrangements that drive transcriptional changes at the single-cell level.