bluuebunny/crossref_metadata_2025_split huggingface dataset:
TCPGdb: A comprehensive T cell perturbation genomics database for identification of critical T cell regulators
Authors: Dong Chuanpeng , Zhang Feifei , Tang Kaiyuan , Verma Nipun , Zhu Xinxin , Feng Di , Cai James , Zhao Hongyu , Chen Sidi 
Published: January 2025

AbstractCAR-T therapies utilizing T cells engineered with chimeric antigen receptors (CARs) have revolutionized the treatment of hematologic and immune-related malignancies. However, the anti-tumor capability of engineered CAR-T cells are often not persistent, which greatly dampen its clinical efficacy. To address this limitation, massive parallel genetic screens were widely used to identified novel targets and regulators that enhance T cell anti-tumor capability and persistence in tumor microenvironment. We hypothesized that by combining the pooled screen data from multiple independent genetic screens we could provide a systematic, comprehensive, and robust analysis of the effect of gene perturbation on T-cell based immunotherapies. After collecting data from previously published T cell screens, including CRISPR-based and ORF-based screens, through Gene Expression Omnibus (GEO), we reprocessed the gene hits summary and conducting a pathway enrichment analysis. A T cell screen perturbation score (TPS) was employed to quantifies the impact of the gene on T cell function. Additionally, gene expression data (both bulk RNA level and single-cell RNA level) from autoimmune disease and T cell-derived cancers were analyzed to pick up gene perturbations that potentially augment T cell proliferation. We integrated all data and analysis on 27 T-cells screens into our state-of-the-art T cell perturbation genomics database (TCPGdb), which is made easily accessible through our webserver and allows users to interactively explore the impact of query genes on T cell function based on prior screen data and our TPS scoring module. TCPGdb is publicly accessible athttp://tcpgdb.sidichenlab.org/.
Mean gene conversion tract length in humans estimated to be 459 bp from UK Biobank sequence data
Authors: Masaki Nobuaki , Browning Sharon R. 
Published: January 2025

AbstractNon-crossover gene conversion is a type of meiotic recombination characterized by the non-reciprocal transfer of genetic material between homologous chromosomes. Gene conversions are thought to occur within relatively short tracts of DNA, estimated to be in the order of 100-1,000 bp in humans. However, the number of observable gene conversion tracts per study has so far been limited by the use of pedigree or sperm-typing data to detect gene conversion events. In this study, we propose a statistical method to estimate the mean length of gene conversion tracts in humans. Our method can handle a large number of gene conversion tracts, leading to more precise estimates of the mean tract length. We apply our method to gene conversion tracts detected in whole autosome sequence data from the UK Biobank using clusters of identity-by-descent segments. From this dataset, we estimate the mean gene conversion tract length in humans to be 459 bp (95% CI: [457, 461]). Stratifying detected gene conversion tracts by whether they overlapped with a recombination hotspot, we estimate the mean gene conversion tract length to be 418 bp (95% CI: [416, 420]) and 492 bp (95% CI: [489, 494]) respectively, for tracts that overlap and do not overlap with a recombination hotspot.
Disrupted Maternal Behavior in Morphine-Dependent Pregnant Rats and Anhedonia in their Offspring
Authors: Searles Christopher T. , Vogt Meghan E. , Adedokun Iyanuoluwa , Murphy Anne Z. 
Published: January 2025

AbstractIt is currently estimated that every 15 minutes an infant is born with opioid use disorder and undergoes intense early life trauma due to opioid withdrawal. Clinical research on the long-term consequences of gestational opioid exposure reports increased rates of social, conduct, and emotional disorders in these children. Here, we investigate the impact of perinatal opioid exposure (POE) on behaviors associated with anhedonia and stress in male and female Sprague Dawley rats. Young adult female rats were administered morphine via programmable, subcutaneous micro-infusion pumps before, during, and through one week post gestation. Maternal behavior was examined for fragmentation and entropy for the first two postnatal weeks; offspring were assessed for sucrose preference, social behavior, and stress responsivity. Overall, dams that received morphine across gestation displayed significantly less pup-directed behavior with increased fragmentation for nursing and higher entropy scores. In adolescence, male and female rat offspring exposed to morphine displayed reduced sucrose preference and, as adults, spent significantly less time socially interacting with familiar conspecifics. Changes in social behaviors were linked to increased activity in nondopaminergic mesolimbic reward brain regions. Although no treatment effects were observed in forced swim test performance, corticosterone levels were significantly increased in POE adult males. Together, these results suggest that perinatal morphine exposure results in anhedonic behavior, possibly due to fragmented and unpredictable maternal behavior in opioid-dependent dams.Significance StatementClinical and preclinical research has shown that early life stress can produce lifelong depression-like symptoms. Here, we show that maternal opioid use during pregnancy produces depression-like symptoms in the offspring. We also observed disrupted maternal behavior in morphine-exposed dams that is similar to the changes in maternal behavior reported following other forms of early life stress. We propose that the stress of opioid exposure and suboptimal rearing leads to reduced sucrose preference, increased stress reactivity, and social avoidance behavior in the offspring, all of which are characteristics of anhedonia.
From Text to Translation: Using Language Models to Prioritize Variants for Clinical Review
Authors: Li Weijiang , Li Xiaomin , Lavallee Ethan , Saparov Alice , Zitnik Marinka , Cassa Christopher 
Published: January 2025

AbstractDespite rapid advances in genomic sequencing, most rare genetic variants remain insufficiently characterized for clinical use, limiting the potential of personalized medicine. When classifying whether a variant is pathogenic, clinical labs adhere to diagnostic guidelines that comprehensively evaluate many forms of evidence including case data, computational predictions, and functional screening. While a substantial amount of clinical evidence has been developed for these variants, the majority cannot be definitively classified as ‘pathogenic’ or ‘benign’, and thus persist as ‘Variants of Uncertain Significance’ (VUS). We processed over 2.4 million plaintext variant summaries from ClinVar, employing sentence-level classification to remove content that does not contain evidence and removing uninformative summaries. We developed ClinVar-BERT to discern clinical evidence within these summaries by fine-tuning a BioBERT-based model with labeled records. When validated classifications from this model against orthogonal functional screening data, ClinVar-BERT significantly separated estimates of functional impact in clinically actionable genes, includingBRCA1(p =1.90×10−20),TP53(p =1.14×10−47), andPTEN(p =3.82×10−7). Additionally, ClinVar-BERT achieved an AUROC of 0.927 in classifying ClinVar VUS against this functional screening data. This suggests that ClinVar-BERT is capable of discerning evidence from diagnostic reports and can be used to prioritize variants for re-assessment by diagnostic labs and expert curation panels.
Using single-subject morphological networks to elucidate the patterns of disconnection and disconnectome associated with post-stroke deficits and recovery
Authors: Yuan Binke , Zhong Tao , Wang Yaling , Chen Qingwen , Guo Xiaolin , Yang Junjie , Gao Xiaowei , Hu Zhe , Li Junjing , Liu Jiaxuan , Qu Zhiheng , Li Wanchun , Li Zhongqi , Li Wanjing , Huang Yien , Chen Jiali , Wen Hao , Zhang Ye , Li Junle , Gao Han 
Published: January 2025

AbstractBACKGROUNDThe single-subject morphological network (SSMN) provides a new approach for constructing structural connectome. However, its clinical relevance in post-stroke deficits and recovery remains unexplored.METHODSThis study utilized high-resolution 3D T1-weighted images alongside behavioral and cognitive assessments across multiple domains, including language, motor, memory, and attention, collected at two weeks, three months, and one year post-stroke. The SSMN was constructed using the AAL atlas by evaluating the similarities of regional probability density derived from gray matter volume. Network disconnection and the disconnectome were evaluated by examining changes in network edges and global topological properties. The functional relevance of the SSMN was explored through its associations with post-stroke behavioral and cognitive deficits and recovery, as well as by developing machine-learning-based prediction models.RESULTSThe findings revealed that the SSMN was sensitive to post-stroke connectional and connectomal disruptions. Domain-specific disruptions in the SSMN were predictable of post-stroke deficits, with correlation pattern aligning with the neurobiological substrates of each domain. Furthermore, the predictive performance of SSMN-based models was comparable to that of other imaging modalities. Notably, normalization of the SSMN within one year post-stroke was significantly associated with functional recovery.CONCLUSIONSThese results highlight the potential of the SSMN as a novel structural imaging modality for evaluating post-stroke deficits and recovery, offering valuable insights into the neurobiological mechanisms of rehabilitation.
Psilocybin-Assisted Group Psychotherapy + Mindfulness Based Stress Reduction (MBSR) for Frontline Healthcare Provider COVID-19 Related Depression and Burnout: A Randomized Clinical Trial
Authors: Lewis Benjamin R. , Hendrick John , Byrne Kevin , Odette Madeleine , Wu Chaorong , Garland Eric L. 
Published: January 2025

AbstractObjectiveThis clinical trial sought to evaluate the safety and preliminary efficacy of psilocybin and MBSR for frontline healthcare providers with symptoms of depression and burnout related to the COVID-19 pandemic.MethodsThis was a randomized controlled trial that enrolled physicians and nurses with frontline clinical work during the COVID-19 pandemic and symptoms of depression and burnout. Participants were randomized in a 1:1 ratio to either an 8-week MBSR curriculum alone or an 8-week MBSR curriculum plus group psilocybin-assisted psychotherapy (PAP) with 25mg psilocybin. Symptoms of depression and burnout were assessed at baseline, and 2-weeks and 6-months post intervention utilizing the Quick Inventory of Depressive Symptoms (QIDS-SR-16) and Maslach Burnout Inventory Human Services Survey for Medical Professionals (MBI-HSS-MP), respectively. Secondary outcome measures included the Demoralization Scale (DS-II) and the Watt’s Connectedness Scale (WCS). Adverse events and suicidality were assessed through 6-month follow-up.Results25 participants were enrolled and randomized. There were 12 study-related AEs recorded that were Grade 1-2 and no serious AEs. There was larger decrease in QIDS score for the MBSR+PAP arm compared to MBSR-only from baseline to 2-weeks post-intervention and significant between-group differences favoring MBSR+PAP on subscales of the MBI-HSS-MP as well as the DS-II and WCS.ConclusionsGroup psilocybin-assisted therapy plus MBSR was associated with clinically significant improvement in depressive symptoms without serious adverse events and with greater reduction in symptoms than MBSR alone. Study findings suggest that integrating psilocybin with mindfulness training may represent a promising treatment for depression and burnout among physicians and nurses.
Exploring the possible interventions in children and adolescents with Developmental Coordination Disorder. How far have we come? A Scoping Review
Authors: Chiara Panciroli Maria , Simone Fiore , Andrea Baragetti , Matteo Fascia 
Published: January 2025

ABSTRACTBackgroundDevelopmental Coordination Disorder (DCD) is a common neurodevelopmental disorder. Children with DCD usually need treatment. Indications for intervention are essentially dependent on the influence of the diagnosis on activities of daily life and the proposed treatments are therefore heterogeneous.ObjectivesIdentifying and describing the current state of knowledge regarding the treatments available in the literature for the treatment of DCD, defining which of these interventions have been most investigated nowadays, identifying other possible types of intervention that have been introduced in the clinical practice and described by sporadic/anecdotal evidence.Study designScoping reviewEligibility criteriaThis review will take in account studies with any type of research design, with no geographical limit, published after 1994. This criterion was defined as corresponding to the date of publication of the DSM-IV, the first document in chronological order to be considered as a reference for the definition of diagnostic criteria in this scoping review.Inclusion is limited to articles written in either English or Italian language. The population of interest includes children and adolescents (age 0-18 years old) with a diagnose of Developmental Coordination Disorder (DCD) or a probable-DCD (based on DSM-IV or DSM-IV-TR or DSM-V or ICD-10 or ICD-11 criteria) also in possible co-presence of other neurodevelopmental disorders, with the exception of autism spectrum disorder.
Enlarged Perivascular Spaces in the Basal Ganglia Across Epilepsy Subtypes
Authors: Sinclair Benjamin , Yasuda Clarissa Lin , Nicolo John-Paul , Hlauschek Gernot , Bezerra Thais Maria Santos , Chen Zhibin , Vivash Lucy , de Campos Brunno Machado , João Rafael Batista , Brioschi Ricardo , Scardua-Silva Lucas , Alvim Marina Koutsodontis Machado , Kwan Patrick , Cendes Fernando , O’Brien Terence J. , Law Meng 
Published: January 2025

AbstractIntroductionThe glymphatic system is thought to be the brain’s primary waste clearance system, responsible for eliminating soluble metabolites and proteins from the central nervous system. It consists of the cerebrospinal fluid, the interstitial fluid, and a conduit between the two, perivascular spaces (PVS), which are channels formed by astroglial cells surrounding the blood vessels. PVS can be observed on high-resolution T1-weighted MRI images. Small studies have implicated PVS and glymphatics in the pathophysiology of epilepsy, potentially via reduced clearance of excitotoxic substances. This study investigates enlarged PVS burden in a large patient group with various types of epilepsy.MethodsPeople with various types of epilepsy were recruited from the Hospital das Clínicas, Unicamp, Brazil. They were matched approximately in age and sex with healthy volunteers as controls. All participants were scanned with T1-weighted MRI on a 3T Phillips MRI scanner, resolution 1.0x1.0x1.0 mm³. A deep-learning algorithm, PINGU, was applied to segment PVS. The volumes of PVS in the White Matter (WM) and Basal Ganglia (BG) were calculated and divided by the respective volumes of WM and BG to derive the volume fractions (PVS-VF). These were used as dependent variables in a general linear model, with the diagnostic group as the independent variable of interest and age and sex included as nuisance covariates.ResultsWe recruited 467 people with epilepsy (median age 42 years, 41.5% male), of whom 267 had temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), 71 TLE with no MRI-visible lesions (TLE-NEG), 65 with focal extratemporal epilepsy (ETLE), and 64 with Idiopathic Generalized Epilepsy (IGE)). They were matched with 473 healthy controls (median age 35 years, 38.3% male). All epilepsy subtypes had higher PVS-VF in the BG compared to controls (101-140%, effect size=0.95-1.37, p<1.33x10-15). There was no difference in PVS-VF in the WM between the epilepsy group and healthy controls, or between different epilepsy subtypes. The TLE-HS group had an asymmetry in their PVS distribution, being larger on the contra-lateral side. This was not observed in the healthy controls or any other epilepsy subtypes. There was no association between PVS-VF and duration of illness (median duration 29 years).ConclusionVolume of PVS in the BG is enlarged in people with epilepsy. Longitudinal studies are needed to determine whether seizures have a detrimental effect on the brain’s glymphatic system, or whether impaired glymphatics contribute to the development of epilepsy.
Dynamic balance of H3K9me2 heterochromatin by CoREST-2 and RE-1 in growing neurons
Authors: Drube José F. , Cardozo-Gizzi Andrés , Rozés-Salvador Victoria , Martínez Imanol , Ceschin Danilo G. , Giordano Laureano , Serniotti Lucas , Gastaldi Laura , Remedi Mónica , Moyano Ana L. , Cáceres Alfredo , Wilson Carlos 
Published: January 2025

AbstractA well-balanced chromatin dynamic is vital for the survival and physiology of all cells, including brain neurons. Heterochromatin, commonly associated with transcriptional silencing, also plays significant roles in maintaining genomic stability and facilitating DNA-repair processes. Notably, the bimethylation of histone H3 at lysine 9 (H3K9me2), a hallmark of repressive heterochromatin, supports the axonal specification of neurons. However, neuronal maintenance of H3K9me2 equilibrium remains understudied.In this work, we unveil a dynamic equilibrium of H3K9me2 regulated by the epigenetic factor CoREST-2 and RE-1 DNA motifs, sustaining axonal and dendritic outgrowth. Using primary cultures of rat hippocampal neurons and a combination of advanced imaging techniques, we observed an enriched nuclear accumulation of CoREST-2 and H3K9me2 along neuronal development. Genetic silencing of CoREST-2 induced axon-dendrite retraction, accompanied by an increase in nuclear levels of H3K9me2. To further investigate heterochromatin structure at the nanoscale, we employed STED nanoscopy and discovered that H3K9me2 is organized into small nanodomains, which were notably enlarged following the suppression of CoREST-2. In contrast, the genetic blockade of RE-1 DNA motifs led to axon-dendrite retraction alongside the disassembly of H3K9me2 nanodomains.These findings highlight that CoREST-2 and RE-1 sites actively shape neuronal H3K9me2 heterochromatin. Moreover, they uncover that maintaining a precise balance of H3K9me2 is essential for the extension of axons and dendrites, underpinning the connectivity and plasticity of brain neurons.
YX0798 Is a Highly Potent, Selective, and Orally Effective CDK9 Inhibitor for Treating Aggressive Lymphoma
Authors: Jiang Vivian , Xue Yu , Kim Hong , Cai Qingsong , Zhang Tianci , Nie Lei , McIntosh Joseph , Liu Yang , Chen Haiying , Zhou Jia , Wang Michael 
Published: January 2025

ABSTRACTNon-genetic transcription evolution has been increasingly explored and recognized to drive tumor cell progression and therapeutic resistance. As the regulation hub of transcription machinery, cyclin-dependent kinase 9 (CDK9) is the gatekeeper of RNA polymerase II (Pol II) transcription, and CDK9 dysfunction results in transcriptomic reprogramming and tumor cell progression. We recently reported that the HSP90-MYC-CDK9 network drives therapeutic resistance in mantle cell lymphoma (MCL) through transcriptomic reprogramming. We also showed that targeting CDK9 by AZD4573 and enitociclib is a safe and effective treatment in preclinical MCL models, supporting CDK9 as a valid therapeutic target for MCL. However, current CDK9 inhibitors (CDK9i) under therapeutic development have room for improvement due to limited target selectivity and oral bioavailability. To this end, YX0798 was discovered to be a novel CDK9i through structural optimization. YX0798 demonstrated remarkable target selectivity and high affinity in binding to CDK9. Furthermore, YX0798 showed good oral bioavailability. YX0798, when administrated orally (5 mg/kg, daily), led to an efficacious anti-tumor activityin vivoand showed the potency in overcoming therapeutic resistance. Mechanistically, YX0798 downregulated the short-lived oncoprotein c-MYC and pro-survival protein MCL-1 as a common mechanism of CDK9 inhibition. Moreover, YX0798 disrupted the cell cycle and resulted in transcriptomic reprogramming, eventually leading to cell death. Together, these data demonstrate that YX0798 has oral bioavailability, exquisite selectivity, and anti-tumor potency that results from driving transcription reprogramming towards tumor cell killing.KEY POINTSYX0798 showed high selectivity, target binding affinity, and anti-tumor efficacy in overcoming resistance to various therapies.YX0798 had good oral pharmacokinetics and anti-tumor effects that resulted from transcription reprogramming towards tumor cell killing.
Persistent DNA methylation and downregulation of homeostatic genes in astrocytes after pilocarpine-induced status epilepticus: Implications for epileptogenesis
Authors: Cuautle Dante Gómez , Rossi Alicia , Villarreal Alejandro , D’Alessio Luciana , Ramos Alberto Javier 
Published: January 2025

AbstractEpilepsy is a debilitating neurological disorder characterized by recurrent seizures, affecting millions of patients worldwide. Retrospective studies in Temporal lobe epilepsy (TLE) patients have shown a high incidence of an initial precipitating event (IPE) in early childhood followed by a silent period where epileptogenesis occurs to end up in chronic epilepsy. Epileptogenesis, the process through which a normal brain undergoes structural and functional changes leading to epilepsy, remains an enigmatic phenomenon. We hypothesized that epigenetics may be involved in epileptogenesis and specifically astrocytes could be affected by pathological remodeling. To study this process, we used three approaches: The lithium-pilocarpine model of TLE in rats, primary astroglial cultures exposed to epileptogenic DAMP named HMGB1, and brain tissue samples resected from TLE patients with drug-resistant epilepsy. We found that the IPE achieved by lithium- pilocarpine treatment (127/30 mg/kg IP) induced the hypermethylation of astrocytes at 7-, 21-, and 35 days post-IPE, indicating persistent epigenetic alterations in astrocytes during the epileptogenic period. In addition, we observed the downregulation of homeostatic astroglial genes AQP4; glutamine synthase (GS), and Kir4.1 with increased proinflammatory genes (C3, MAFG) and DNA methyl transferases (DNMT) expression. These alterations were mimicked in primary astrocyte cultures exposed to the epileptogenic HMGB1 (500 ng/ml; 18 hours) that also induced the hypermethylation of homeostatic astroglial genes. Astrocytes from TLE patients brains showed reactive astrogliosis, increased DNA methylation, and downregulation of homeostatic genes Kir4.1 and GS. These findings show that astrocytes are pathologically altered during the epileptogenic period, combining the proinflammatory gain of function with the loss of homeostatic profile. This may sustain the long-term alterations underlining epileptogenesis.