bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluating the Sick Quitting Hypothesis for Frailty Status and Reducing Alcohol Use Among People With HIV in a Longitudinal Clinical Cohort Study
Authors: Ruderman Stephanie A. , Drumright Lydia N. , Delaney Joseph A. C. , Webel Allison R. , Fitzpatrick Annette L. , Whitney Bridget M. , Nance Robin M. , Hahn Andrew W. , Ma Jimmy , Mixson L. Sarah , Eltonsy Sherif , Willig Amanda L. , Mayer Kenneth H. , Napravnik Sonia , Greene Meredith , McCaul Mary , Cachay Edward , Kritchevsky Stephen B. , Austad Steven N. , Landay Alan , Saag Michael S. , Kitahata Mari M. , Lau Bryan , Lesko Catherine , Chander Geetanjali , Crane Heidi M. , Odden Michelle C. 
Published: December 2023

Abstract“Sick quitting,” a phenomenon describing reductions in alcohol consumption following poor health, may explain observations that alcohol appears protective for frailty risk. We examined associations between frailty and reductions in drinking frequency among people with HIV (PWH). At six Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) sites between January 2012 and August 2021, we assessed whether frailty, measured through validated modified frailty phenotype, precedes reductions in drinking frequency. We associated time-updated frailty with quitting and reducing frequency of any drinking and heavy episodic drinking (HED), adjusted for demographic and clinical characteristics in Cox models. Among 5,654 PWH reporting drinking, 60% reported >monthly drinking and 18% reported ≥monthly HED. Over an average of 5.4 years, frail PWH had greater probabilities of quitting (HR: 1.56, 95% confidence interval [95% CI] [1.13–2.15]) and reducing (HR: 1.35, 95% CI [1.13–1.62]) drinking frequency, as well as reducing HED frequency (HR: 1.58, 95% CI [1.20–2.09]) versus robust PWH. Sick quitting likely confounds the association between alcohol use and frailty risk, requiring investigation for control.
Comparison of Patient’s Procedural Tolerance of EBUS-TBNA Performed Through Nasal Versus Oral Route
Authors: Mishra Mayank , Chowdhury Nilotpal , Krishnadas Padmanabhan Ajeesh , Banerjee Saikat , Kumar Saini Lokesh , Sharma Prakhar , Agrawal Shruti , Sindhwani Girish 
Published: December 2023

Background:
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a commonly performed procedure by the bronchoscopist for the evaluation of mediastinal lesions. However, evidence directly comparing the nasal and oral routes to guide the choice of an optimal insertion approach is scanty.

Methods:
In this prospective, parallel-group, open-label randomized clinical trial, adults posted for a linear EBUS-TBNA examination under conscious sedation were randomized to undergo the procedure via the nasal or oral route. The primary objective was to assess the equivalence of subject-rated tolerance of EBUS-TBNA procedure in the 2 groups. Key secondary objectives were to assess the equivalence of subject-rated overall experience, willingness for a repeat procedure, operator-rated subject’s tolerance, and operator-rated ease of performing the procedure.

Results:
One hundred and eighty subjects were randomized in a 1:1 ratio to the nasal (n=98) or oral (n=82) group. Outcome measures were assessed by both per-protocol (PP) and intention-to-treat (ITT) analysis. Subject-rated procedural tolerance, overall satisfaction and operator’s ease of performing the procedure were found to be equivalent in the 2 groups (P<0.05 in all cases for PP and ITT analysis). The operator-rated subject’s tolerance was, however, nonequivalent (P=0.0596, 0.1286 for PP and ITT, respectively). Subject’s willingness to undergo a repeat procedure was similar in both groups [90% CI of difference in proportions: (−0.023, 0.121) in PP and (−0.028, 0.115) in ITT analysis].

Conclusion:
Nasal route for EBUS-TBNA could be considered where it is feasible and preferable for the patient as well as the operator.
DNA replication in early mammalian embryos is patterned, predisposing lamina-associated regions to fragility
Authors: Xu Shuangyi , Wang Ning , Zuccaro Michael V. , Gerhardt Jeannine , Baslan Timour , Koren Amnon , Egli Dieter 
Published: December 2023

AbstractDNA replication in differentiated cells follows a defined program, but when and how it is established during mammalian development is not known. Here we show using single-cell sequencing, that both bovine and mouse cleavage stage embryos progress through S-phase in a defined pattern. Late replicating regions are associated with the nuclear lamina from the first cell cycle after fertilization, and contain few active origins, and few but long genes. Chromosome breaks, which form spontaneously in bovine embryos at sites concordant with human embryos, preferentially locate to late replicating regions. In mice, late replicating regions show enhanced fragility due to a sparsity of dormant origins that can be activated under conditions of replication stress. This pattern predisposes regions with long neuronal genes to fragility and genetic change prior to segregation of soma and germ line. Our studies show that the formation of early and late replicating regions is among the first layers of epigenetic regulation established on the mammalian genome after fertilization.
CryoVirusDB: A Labeled Cryo-EM Image Dataset for AI-Driven Virus Particle Picking
Authors: Gyawali Rajan , Dhakal Ashwin , Wang Liguo , Cheng Jianlin 
Published: December 2023

AbstractWith the advancements in instrumentation, image processing algorithms, and computational capabilities, single-particle electron cryo-microscopy (cryo-EM) has achieved nearly atomic resolution in determining the 3D structures of viruses. The virus structures play a crucial role in studying their biological function and advancing the development of antiviral vaccines and treatments. Despite the effectiveness of artificial intelligence (AI) in general image processing, its development for identifying and extracting virus particles from cryo-EM micrographs (images) has been hindered by the lack of manually labelled high-quality datasets. To fill the gap, we introduce CryoVirusDB, a labeled dataset containing the coordinates of expert-picked virus particles in cryo-EM micrographs. CryoVirusDB comprises 9,941 micrographs of 9 different viruses along with the coordinates of 339,398 labeled virus particles. It can be used to train and test AI and machine learning (e.g., deep learning) methods to accurately identify virus particles in cryo-EM micrographs for building atomic 3D structural models for viruses.
CRISPRmap: Sequencing-free optical pooled screens mapping multi-omic phenotypes in cells and tissue
Authors: Gu Jiacheng , Iyer Abhishek , Wesley Ben , Taglialatela Angelo , Leuzzi Giuseppe , Hangai Sho , Decker Aubrianna , Gu Ruoyu , Klickstein Naomi , Shuai Yuanlong , Jankovic Kristina , Parker-Burns Lucy , Jin Yinuo , Zhang Jia Yi , Hong Justin , Niu Steve , Chou Jacqueline , Landau Dan A. , Azizi Elham , Chan Edmond M. , Ciccia Alberto , Gaublomme Jellert T. 
Published: December 2023

AbstractPooled genetic screens are powerful tools to study gene function in a high-throughput manner. Typically, sequencing-based screens require cell lysis, which limits the examination of critical phenotypes such as cell morphology, protein subcellular localization, and cell-cell/tissue interactions. In contrast, emerging optical pooled screening methods enable the investigation of these spatial phenotypes in response to targeted CRISPR perturbations. In this study, we report a multi-omic optical pooled CRISPR screening method, which we have named CRISPRmap. Our method combines a novel in situ CRISPR guide identifying barcode readout approach with concurrent multiplexed immunofluorescence and in situ RNA detection. CRISPRmap barcodes are detected and read out through combinatorial hybridization of DNA oligos, enhancing barcode detection efficiency, while reducing both dependency on third party proprietary sequencing reagents and assay cost. Notably, we conducted a multi-omic base-editing screen in a breast cancer cell line on core DNA damage repair genes involved in the homologous recombination and Fanconi anemia pathways investigating how nucleotide variants in those genes influence DNA damage signaling and cell cycle regulation following treatment with ionizing radiation or DNA damaging agents commonly used for cancer therapy. Approximately a million cells were profiled with our multi-omic approach, providing a comprehensive phenotypic assessment of the functional consequences of the studied variants. CRISPRmap enabled us to pinpoint likely-pathogenic patient-derived mutations that were previously classified as variants of unknown clinical significance. Furthermore, our approach effectively distinguished barcodes of a pooled library in tumor tissue, and we coupled it with cell-type and molecular phenotyping by cyclic immunofluorescence. Multi-omic spatial analysis of how CRISPR-perturbed cells respond to various environmental cues in the tissue context offers the potential to significantly expand our understanding of tissue biology in both health and disease.
Ribosome Quality Control Mechanism Mitigates the Cytotoxic Impacts of Ribosome Collisions Induced by 5-Fluorouracil
Authors: Chatterjee Susanta , Naeli Parisa , Simms Nicole , Garzia Aitor , Hackett Angela , Coyle Kelsey , Snell Patric Harris , McGirr Tom , Sawant Tanvi Nitin , Dang Kexin , Stoichkova Zornitsa V. , Alain Tommy , Tuschl Thomas , McDade Simon S. , Longley Daniel B. , Gkogkas Christos G. , Adrain Colin , Knight John R.P. , Jafarnejad Seyed Mehdi 
Published: December 2023

AbstractTranslation of aberrant or damaged mRNAs results in ribosome stalling and collisions. The Ribosome Quality Control (RQC) mechanism detects collided ribosomes and removes aberrant mRNAs and nascent peptides, thus preventing their cytotoxic effects. Conversely, excessive or unresolved ribosome collisions can induce apoptosis. 5-Fluorouracil (5FU) forms the backbone of standard-of-care chemotherapeutic regimens for several types of cancer. Although best known for its incorporation into DNA and inhibition of thymidylate synthase, a major determinant of 5FU’s anticancer activity is its incorporation into RNAs. Nevertheless, the mechanism(s) underlying RNA-dependent 5FU cytotoxicity and the cellular response to its impact on RNA metabolism remain unclear. Here, we report a key role for RQC in mitigating the cytotoxic effects of 5FU-induced dysregulation of mRNA translation. We show that acute 5FU treatment results in the rapid induction of the mTOR signalling pathway, an enhanced rate of mRNA translation initiation, and increased ribosome collisions that trigger RQC. We also found that RQC deficiency, caused by the depletion of ZNF598, results in increased 5FU-induced cell death, a phenotype that is reversed by inhibition of mTOR or repression of mRNA translation initiation. Importantly, 5FU treatment enhances the expression of key RQC factors, including ZNF598 and GIGYF2, via an mTOR-dependent post-translational regulation mechanism. This acute adaptation likely mitigates the cytotoxic consequences of increased ribosome collisions upon 5FU treatment. Overall, our data indicate a heretofore unknown mTOR-dependent mechanism that augments the RQC process, mitigating the cytotoxicity of 5FU and undermining its anticancer efficacy.
C. elegansHedgehog-related proteins are tissue- and substructure-specific components of the cuticle and pre-cuticle
Authors: Serra Nicholas D. , Darwin Chelsea B. , Sundaram Meera V. 
Published: December 2023

AbstractInC. elegans, divergent Hedgehog-related (Hh-r) and Patched-related (PTR) proteins promote numerous processes ranging from epithelial and sense organ development to pathogen responses to cuticle shedding during the molt cycle. Here we show that Hh-r proteins are actual components of the cuticle and pre-cuticle apical extracellular matrices (aECMs) that coat, shape, and protect external epithelia. Different Hh-r proteins stably associate with the aECMs of specific tissues and with specific substructures such as furrows and alae. Hh-r mutations can disrupt matrix structure. These results provide a unifying model for the function of nematode Hh-r proteins and highlight ancient connections between Hh proteins and the extracellular matrix.
A comprehensive alignment-filtering methodology improves phylogeny particularly by filtering overly divergent segments
Authors: Zhang Qiang , Qin Xinmei , Lu Yongbin , Li Pengwei , Huang Xiyang 
Published: December 2023

Abstract​Alignment problems may be complicated and diverse and the performance of the existing alignment-filtering tools, particularly their potential effect on phylogenetic reconstruction, have remained debated or limitedly explored.​In the present study, we developed a new R package named alignmentFilter to treat the diverse alignment problems, especially masking ambiguously-aligned or overly divergent segments using a newly devised grouping-regrouping algorithms acting on sequence divergence in each of sliding windows throughout alignment. Then we tested and compared the power and accuracy of the prevalent alignment-filtering tools, particularly the effect on phylogeny based on Angiospermae genome-scale data and simulated data.​The results indicate the alignment-filtering methods alone may affect the phylogeny decisively, producing (strongly-supported) phylogenetic conflicts. In most cases, alignmentFilter most efficiently improves phylogeny, yielding more congruent phylogeny regardless of phylogeny-reconstruction methods, producing phylogeny more concordant to the priori tree regarding to both topology and branch length in simulation, and most efficiently decreasing the root-to-tip length heterogeneity that is implied to be negatively correlated with topological accuracy.​The concepts and algorithms of alignmentFilter are quite distinct from existing alignment-filtering methods. It is not susceptible to specific types of alignment errors that usually baffle other methods and can reach the optimal solution frequently with lowest computation complexity. The biological or statistical sense of the key optional stringency-controlling parameter is more straightforward and the setting and outcome may be more adjustable or predictable. A better and more comprehensive solution of alignment problems in this study will benefit tremendous downstream analyses sourced from alignment and phylogeny.
Histone deacetylase inhibitor RG2833 has therapeutic potential for Alzheimer’s disease in females
Authors: Ndukwe Kelechi , Serrano Peter A , Rockwell Patricia , Xie Lei , Figueiredo-Pereira Maria 
Published: December 2023

AbstractNearly two-thirds of patients with Alzheimer’s are women. Identifying therapeutics specific for women is critical to lowering their elevated risk for developing this major cause of adult dementia. Moreover, targeting epigenetic processes that regulate multiple cellular pathways is advantageous given Alzheimer’s multifactorial nature. Histone acetylation is an epigenetic process heavily involved in memory consolidation. Its disruption is linked to Alzheimer’s.Through our computational studies, we predicted that the investigational drug RG2833 (N-[6-(2-aminoanilino)-6-oxohexyl]-4-methylbenzamide) has repurposing potential for Alzheimer’s. RG2833 is a histone deacetylase HDAC1/3 inhibitor that is orally bioavailable and permeates the blood-brain-barrier. We investigated the RG2833 therapeutic potential in TgF344-AD rats, which are a model of Alzheimer’s that exhibits age-dependent progression, thus mimicking this aspect of Alzheimer’s patients that is difficult to establish in animal models. We investigated the RG2833 effects on cognitive performance, gene expression, and AD-like pathology in 11-month TgF344-AD female and male rats. A total of 89 rats were used: wild typen= 45 (17 females, 28 males), and TgF344-ADn= 44 (24 females, 20 males)] across multiple cohorts.No obvious toxicity was detected in the TgF344-AD rats up to 6 months of RG2833-treatment starting at 5 months of age administering the drug in rodent chow at ∼30mg/kg of body weight. We started treatment early in the course of pathology when therapeutic intervention is predicted to be more effective than in later stages of the disease. The drug-treatment significantly mitigated hippocampal-dependent spatial memory deficits in 11-month TgF344-AD females but not in males, compared to wild type littermates. This female sex-specific drug effect has not been previously reported. RG2833-treatment failed to ameliorate amyloid beta accumulation and microgliosis in female and male TgF344-AD rats. However, RNAseq analysis of hippocampal tissue from TgF344-AD rats showed that drug-treatment in females upregulated the expression of immediate early genes, such as Arc, Egr1 and c-Fos, and other genes involved in synaptic plasticity and memory consolidation. Remarkably, out of 17,168 genes analyzed for each sex, no significant changes in gene expression were detected in males atP< 0.05, false discovery rate < 0.05, and fold-change ≥ 1.5.Our data suggest that histone modifying therapeutics such as RG2833 improve cognitive behavior by modulating the expression of immediate early, neuroprotective and synaptic plasticity genes. Our preclinical study supports that RG2833 has therapeutic potential specifically for female Alzheimer’s patients. RG2833 evaluations using other AD-related models is necessary to confirm our findings.
Mitochondrial dysfunction and mitophagy blockade contribute to renal osteodystrophy in chronic kidney disease-mineral bone disorder
Authors: Hsu Shun-Neng , Stephen Louise A , Phadwal Kanchan , Dillon Scott , Carter Roderick , Morton Nicholas M , Luijten Ineke , Emelianova Katie , Amin Anish K , Macrae Vicky E , Freeman Tom C. , Staines Katherine A , Farquharson Colin 
Published: December 2023

ABSTRACTChronic kidney disease–mineral and bone disorder (CKD-MBD) presents with extra-skeletal calcification and renal osteodystrophy (ROD). The origins of ROD likely lie with elevated uremic toxins and/or an altered hormonal profile but the cellular events responsible remain unclear. Here, we report that stalled mitophagy contributes to mitochondrial dysfunction in bones of a CKD-MBD mouse model, and also human CKD-MBD patients. RNA-seq analysis exposed an altered expression of genes associated with mitophagy and mitochondrial function in tibia of CKD-MBD mice. The accumulation of damaged osteocyte mitochondria and the expression of mitophagy regulators, p62/SQSTM1, ATG7 and LC3 was inconsistent with functional mitophagy, and inmito-QC reporter mice with CKD-MBD, there was a 2.3-fold increase in osteocyte mitolysosomes. Altered expression of mitophagy regulators in human CKD-MBD bones was also observed. To determine if uremic toxins were possibly responsible for these observations, indoxyl sulfate treatment of osteoblasts revealed mitochondria with distorted morphology and whose membrane potential and oxidative phosphorylation were decreased, and oxygen-free radical production increased. The altered p62/SQSTM1 and LC3-II expression was consistent with impaired mitophagy machinery and the effects of indoxyl sulfate were reversible by rapamycin. In conclusion, mitolysosome accumulation from impaired clearance of damaged mitochondria may contribute to the skeletal complications, characteristic of ROD. Targeting mitochondria and the mitophagy process may therefore offer novel routes for intervention to preserve bone health in patients with ROD. Such approaches would be timely as our current armamentarium of anti-fracture medications has not been developed for, or adequately studied in, patients with severe CKD-MBD.Graphical AbstractTRANSLATIONAL STATEMENTRenal osteodystrophy (ROD) remains the major skeletal complication of chronic kidney disease-mineral and bone disorder (CKD-MBD). As a disease characterised by biochemical and hormone abnormalities, ROD is exacerbated by osteocyte mitochondrial dysfunction. Advances in our understanding of the mitophagy pathway are vital to improving the clinical management of ROD. The dysregulation of mitophagy in murine and human CKD-MBD bone provided evidence of delayed clearance of damaged mitochondria, which was also observed in uremic toxin-treated-osteoblasts but reversible upon rapamycin treatment. This study reveals the therapeutic potential of managing ROD by restoring defective mitophagy in osteocytes.
The neuroimmune CGRP-RAMP1 axis tunes cutaneous adaptive immunity to the microbiota
Authors: Kulalert Warakorn , Wells Alexandria C. , Link Verena M. , Lim Ai Ing , Bouladoux Nicolas , Nagai Motoyoshi , Harrison Oliver J. , Kamenyeva Olena , Kabat Juraj , Enamorado Michel , Chiu Isaac M. , Belkaid Yasmine 
Published: December 2023

AbstractThe somatosensory nervous system surveils external stimuli at barrier tissues, regulating innate immune cells under infection and inflammation. The roles of sensory neurons in controlling the adaptive immune system, and more specifically immunity to the microbiota, however, remain elusive. Here, we identified a novel mechanism for direct neuroimmune communication between commensal-specific T lymphocytes and somatosensory neurons mediated by the neuropeptide Calcitonin Gene-Related Peptide (CGRP) in the skin. Intravital imaging revealed that commensal-specific T cells are in close proximity to cutaneous nerve fibersin vivo. Correspondingly, we observed upregulation of the receptor for the neuropeptide CGRP, RAMP1, in CD8+T lymphocytes induced by skin commensal colonization. Neuroimmune CGRP-RAMP1 signaling axis functions in commensal-specific T cells to constrain Type 17 responses and moderate the activation status of microbiota-reactive lymphocytes at homeostasis. As such, modulation of neuroimmune CGRP-RAMP1 signaling in commensal-specific T cells shapes the overall activation status of the skin epithelium, thereby impacting the outcome of responses to insults such as wounding. The ability of somatosensory neurons to control adaptive immunity to the microbiota via the CGRP-RAMP1 axis underscores the various layers of regulation and multisystem coordination required for optimal microbiota-reactive T cell functions under steady state and pathology.Significance statementMultisystem coordination at barrier surfaces is critical for optimal tissue functions and integrity, in response to microbial and environmental cues. In this study, we identified a novel neuroimmune crosstalk mechanism between the sensory nervous system and the adaptive immune response to the microbiota, mediated by the neuropeptide CGRP and its receptor RAMP1 on skin microbiota-induced T lymphocytes. The neuroimmune CGPR-RAMP1 axis constrains adaptive immunity to the microbiota and overall limits the activation status of the skin epithelium, impacting tissue responses to wounding. Our study opens the door to a new avenue to modulate adaptive immunity to the microbiota utilizing neuromodulators, allowing for a more integrative and tailored approach to harnessing microbiota-induced T cells to promote barrier tissue protection and repair.