bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neurology Training in Italy: A Survey on Italian Residency Programmes and Compliance with European Training Standards
Authors: Farè Matteo , Angelini Luca , Nuredini Andi , Nucera Bruna , Fiume Giulia , Bombaci Alessandro , Cartella Sandy Maria 
Published: February 2025

ABSTRACTBackgroundSince 2005, the European Union of Medical Specialists – Section of Neurology and the European Board of Neurology have outlined a comprehensive curriculum, the European Training Requirements in Neurology (ETRN), which defines the essential clinical knowledge, practical skills, and research competencies that European neurology training programmes should encompass. Despite these standards, notable differences in training quality and resources persist among Italian residency programmes. This survey, conducted by the Italian Section of Young Neurologists, aimed to assess the alignment of Italian neurology residency programmes with ETRN standards and to evaluate residents’ and early-career neurologists’ self-reported knowledge, practical skills, and access to specialised training opportunities.MethodsAn anonymous, online survey was distributed to neurology residents and recently qualified neurologists across Italy in November 2023. The survey included 39 items across four sections: demographics, residency programme structure, learning objectives, and out-of-network internship opportunities. Responses were evaluated using descriptive statistics and comparative analyses across institution sizes and training years.ResultsOf 248 respondents (45.2% female, mean age 28.9 years), only 70.5% of ETRN’s basic training objectives were met, with lower compliance observed for advanced competencies. Practical skills like lumbar puncture and history-taking were widely acquired, but advanced diagnostic techniques (e.g., EMG, neuro-sonography) and subspecialty training (e.g., neuro-oncology, palliative care) showed limited availability. Out-of-network internship participation was low (21.7%), mainly due to institutional constraints and lack of financial support, limiting exposure to diverse clinical environments.ConclusionsItalian neurology training programmes align reasonably well with ETRN standards at the basic level, though significant gaps remain in advanced training, diagnostic techniques, and interdisciplinary skills. Enhanced standardisation, improved funding for extra-network internships, and focused efforts on advanced training are essential to elevate Italian neurology residency programmes to meet European standards more fully.
Cancer risks forMSH6pathogenic variant carriers
Authors: van der Werf – ‘t Lam A.S. , Dowty J.G. , Italia M. , Bakker A.C. , Koops F. , Bleeker F. , Gomez – Garcia E. , van Hest L.P. , Gille H.J.P. , Cornips M.C. , de Jong M.M. , Letteboer T.G.W. , Duijkers F.A.M. , Wagner A. , Eikenboom E.L. , van Asperen C.J. , Bajwa – ten Broeke S.W. , Win A.K. , Jenkins M.A. , Nielsen M. 
Published: February 2025

AbstractIntroductionLynch syndrome (LS) is a hereditary cancer syndrome caused by (likely) pathogenic variants (LP/P) in DNA mismatch repair genes, includingMSH6. It is associated with elevated lifetime risks for colorectal cancer (CRC), endometrial cancer (EC), and other malignancies. However, cancer risks specific toMSH6-associated LS, particularly for non-colorectal cancers, remain poorly defined. This study aims to provide refined cancer risk estimates for individuals withMSH6LP/P.MethodsWe conducted a retrospective cohort study of 360 families with 1117 knownMSH6LP/P carriers identified in the Netherlands between 1995 and 2020. Pedigree data were collected from multiple clinical centers, and cancer diagnoses were confirmed through medical records. Age- and sex-specific hazard ratios (HRs) and cumulative risks (CRs) were estimated using segregation analysis, appropriately adjusted for ascertainment.ResultsCR by age 80 forMSH6LP/P carriers were 36% in males (95% CI:25–48%) and 21% in females (95% CI 13–32%) for CRC, and 23% in females (95% CI:15–43%) for EC. Elevated risks were observed for ovarian cancer (OC) (6.4%, 95% CI:3–14.8%; HR 5.58, p=0.00037), urinary tract cancers (10.1% in males, 4.1% in females; HR 2.52, p=0.012), and biliary tract cancers (4.9% in males, 4.2% in females; HR 2.76, p=0.031). No increased risks were identified for prostate or breast cancer.ConclusionThis study refines cancer risk estimates for MSH6 LP/P carriers, suggesting the need for delayed CRC screening in males and females and proactive discussions regarding prophylactic surgery for females to address elevated risks for EC and OC.
Extending scope and power of circular RNA research with circtools 2.0
Authors: Kulkarni Shubhada R. , Dieterich Christoph , Jakobi Tobias 
Published: February 2025

AbstractCircular RNAs (circRNAs) play a pivotal role in gene regulation, acting as transcriptional modulators at various cellular levels and exhibit remarkable specificity across cell types and developmental stages. Detecting circRNAs from high-throughput RNA-seq data presents significant challenges, as it requires specialized tools to identify back-splice junctions (BSJ) in raw sequencing data. To address this need, we previously developedcirctools, a robust and user-friendly software for circRNA detection, downstream analysis, and wet-lab integration. Building on this foundation, we now introducecirctools 2.0, a significantly enhanced framework designed to advance computational and support experimental analysis for circular RNA research. Novel key features ofcirctools 2.0include: (1) an ensemble approach to circRNA detection with improved recall rates, (2) a module for automated design of circRNA padlock probes for the Xenium spatial trancriptomics platform, (3) circRNA conservation analysis across animal model species, and (4) support for the Oxford Nanopore sequencing platform for full-length circRNA detection.Availabilitycirctools 2.0 is available atgithub.com/jakobilab/circtoolsand licensed under GPLv3.0.Contacttjakobi@arizona.edu
Pamrevlumab did not meet its primary endpoint for ambulatory patients with Duchenne Muscular Dystrophy: the LELANTOS-2 trial
Authors: Wong Brenda L. , Phan Han C. , Péréon Yann , De Lucia Silvana , Dai Yi , Chen Ziyi , Campbell Craig , Sansone Valeria A. , Delstanche Stéphanie , Wang Steven , Gambetti Olga V. , Brandsema John F. , Carrier Ewa ,   LELANTOS-2 study investigators
Published: February 2025

ABSTRACTBackgroundIn Duchenne muscular dystrophy (DMD), fibrosis is linked to connective tissue growth factor (CTGF) overexpression. Pamrevlumab, a fully human monoclonal antibody that inhibits CTGF activity, showed promise as a DMD treatment in a phase 2 trial.ObjectiveLELANTOS-2 (NCT04632940) was a global phase 3 study of the safety and efficacy of pamrevlumab for ambulatory males 6 to <12 years old with DMD.MethodsPatients were randomized 1:1 to pamrevlumab 35 mg/kg every 2 weeks for 52 weeks or placebo. All received a stable corticosteroid regimen (deflazacort or prednisone/prednisolone). Primary endpoint was change in North Star Ambulatory Assessment (NSAA) total score from baseline to Week 52. Treatment-emergent adverse events (TEAEs) were noted. Patients who completed the main study period were eligible to enroll in the open-label extension (OLE).ResultsSeventy-three patients enrolled (mean [SD] age, 9.0 [1.5] years; pamrevlumab [n=37], placebo [n=36]). Between-group baseline characteristics were similar. The difference in change in NSAA score was not significant (least squares [LS] mean [SE]: pamrevlumab, –3.022 [0.5505] vs placebo, –2.494 [0.6962];p=0.5553). Across all secondary endpoints, there were no significant differences between patients treated with pamrevlumab or placebo. Nearly all patients (pamrevlumab, n=35 [97.2%]; placebo, n=35 [97.2%]) experienced TEAEs (most mild/moderate). Sixty-eight (34 from each original treatment group) patients enrolled in and received pamrevlumab during the OLE. OLE efficacy and safety were consistent with the main study period. No deaths occurred.ConclusionsPamrevlumab failed to meet its primary endpoint. Its future as a DMD treatment is uncertain.
Dynamic Prediction of Mortality Risk Following Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Spohr Philipp , Fröhlich Rebecca C. , Scharf Sebastian , Rommerskirchen Anna , Bobak Jonathan , Schweier Sarah , Jäger Paul , Kobbe Guido , Dietrich Sascha , Dilthey Alexander T. , Henrich Birgit , Pfeffer Klaus , Haas Rainer , Klau Gunnar W. 
Published: February 2025

AbstractAllogeneic hematopoietic stem cell transplantation (alloHSCT) is a potentially curative treatment for high-risk hematological malignancies, but early mortality within 100 days remains a significant challenge, affecting approximately 18% of patients. Identifying high-risk patients early is critical for timely interventions. While static risk scores like the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) and Endothelial Activation and Stress Index (EASIX) are valuable, they do not adapt to patients’ clinical trajectories. Leveraging the increasing availability of digital medical datasets, we developed a dynamic risk stratification system based on a random forest approach to continuously predict mortality risk from day 0 to day 30 post-transplantation.Analyzing data from 847 patients undergoing alloHSCT between 2004 and 2019, our model achieved high classification performance, with AUROC scores continuously exceeding 0.8 from day 17, and effectively stratified patients into high, moderate, and low-risk groups. Feature importance analysis revealed a shift over time, with early predictions utilizing diverse variables and later stages relying more on inflammation-related bloodwork parameters. This dynamic approach surpasses static methods, demonstrating improved predictive performance and adaptability across treatment phases. To promote reproducibility and broader application, we provide open access to the software and accompanying bloodwork time-series dataset.
Unbiased human genomic characterization of polyglutamine disorder genes to inform therapeutic strategies
Authors: Namuli Kevin Lucy , Drögemöller Britt I. , Wright Galen E.B. 
Published: February 2025

AbstractBackgroundPolyglutamine (polyQ) disorders, such as Huntington disease (HD) and several spinocerebellar ataxias, are severe neurological disorders caused by repeat expansions of the glutamine codon. These conditions lack effective treatments, with therapeutic research focused on pathogenic gene knockdown. We aimed to profile these genes using diverse human genomic data to guide therapeutic strategies by identifying new biology and assessing off-target effects of knocking these genes down.MethodsWe conducted an unbiased phenome-wide study to identify human traits and diseases linked to polyQ disorder genes (Open Targets L2G>0.5). Network analyses explored shared trait associations and overlapping biological processes among these genes. Lastly, we assessed the theoretical druggability of polyQ disorder genes using recently identified features predictive of clinical trial success and compared them to repeat expansion (HD) modifier genes.ResultsWe identified 215 human phenotype/polyQ disorder gene associations from 3,095 studies, indicating potential adverse effects from gene knockdown. Shared trait associations among polyQ disorder genes suggested overlapping biological processes despite distinct functions. Drug target profile analysis revealed an unfavorable risk profile for polyQ disorder genes, particularlyATN1,ATXN1,ATXN7, andHTT, due to genomic features such as constraint, molecular interactions, and tissue specificity. PolyQ disorder genes also showed significantly more safety-related risks than HD modifier genes (P=7.03×10−3).ConclusionOur analyses emphasize the pleiotropic nature of polyQ disorder genes, highlighting their potential risks as drug targets due to safety concerns. These findings reinforce the importance of exploring alternate therapeutic strategies, such as targeting genetic modifier genes, to mitigate these challenges.
Themis dominates T cell exhaustion by regulation of TCR and PD-1 signaling
Authors: Tang Jian , Jia Xian , Zeng Taoling , Bao Yuzhou , Hu Yanyan , Dong Junchen , Xu Xiaozheng , Chen Xiao Lei , Liu Yongchao , Wang Jiayu , Hou Bowen , Zhu Yuzhen , Fu Guo-Feng , Zheng Qifan , Chen Yongling , Li Wanyun , Ren Tong , Zhang Lei , Jiang Shan , Cong Yu , Quan Minxue , Yan Chaonan , Lin Shuo , Wang Ning , Liu Siyi , Huang Chenghao , Hou Lichao , Teijaro John , Brzostek Joanna , Gautam Namrata , Xiao Changchun , Wang Yan , Li Gang , Xu Bing , Hui Enfu , Wang Hong-Rui , Gascoigne Nicholas R. J. , Fu Guo 
Published: February 2025

AbstractT cell exhaustion is important to protect the host from immunopathology during chronic viral infection, but it also impairs T cell anti-tumor immunity1–5. A fundamental unresolved question is whether and how T cell exhaustion is determined at the onset of TCR signaling6–8. Here we report an unexpected role of Themis, a TCR-proximal signaling molecule9, in T cell exhaustion. Chronic viral infection in mice usually leads to T cell exhaustion and survival of the host. Surprisingly, Themis T-cell conditional knockout mice died from severe CD8+-dependent lung immunopathology in chronic viral infection, showing Themis’ importance in establishing T cell exhaustion. We found that Themis-deficient CD8+T cells were hyperactivated at the single-cell level - producing more TNF and IFNγ compared to wild-type counterparts - but defective in population-level expansion. Moreover, TCF-1 and TOX expression were inhibited in Themis-deficient CD8+T cells, thereby impairing differentiation of exhausted T cell precursors (T-pex) and maintenance of terminally exhausted T cells (T-ex), respectively. Mechanistically, Themis initially promotes TCR signaling to induce PD-1 expression and subsequently mediates PD-1 signaling. In the latter, Themis binds to PD-1 and promotes PD-1 phosphorylation and its recruitment of SHP2, thereby acting as a negative regulator to inhibit T cell effector functions. Without Themis, the orderly regulation of TCR and PD-1 signaling, and therefore exhaustion, is disrupted. Thus, our results unequivocally demonstrate that Themis-mediated early TCR signaling plays a decisive role in T cell exhaustion and provide a novel mechanism of PD-1 signaling through Themis.
Tooth development in frogs: Implications for the re-evolution of lost mandibular teeth and the origin of a morphological innovation
Authors: Paluh Daniel J. , Brinkman Madeline , Gilliam-Beale Kyliah , Salcedo-Recio Daniela , Szafranski Jacob , Hanken James , Fraser Gareth J. 
Published: February 2025

ABSTRACTTeeth have been a prominent feature of most vertebrates for 400 million years, and the core regulatory network underlying embryonic tooth formation is deeply conserved from fishes to amniotes. In frogs, however, odontogenesis is delayed, occurring instead during the postembryonic metamorphosis. Nearly all adult frogs have teeth on the upper jaw and lack lower jaw dentition, but a single species re-evolved mandibular teeth. Developmental-genetic mechanisms that underlie tooth formation in frogs are poorly understood, including whether an ancestral program is partially retained in the lower jaw that could facilitate the evolutionary reappearance of lost mandibular teeth. Using a developmental series of an unconventional model species, we assessed 1) if the gene network underlying odontogenic competence is conserved in the late-forming teeth of frogs; 2) if unique keratinized mouthparts, which function as an alternative feeding tool in anuran larvae, impede tooth induction; and 3) if transient tooth rudiments form in the anuran mandible. The tooth development network is conserved in the frog upper jaw, which displays dental expression patterns comparable to those of other vertebrates. There is, however, no evidence of tooth development in the mandible. Teeth emerge before keratinized mouthparts degenerate, but their location may be spatially constrained by keratin, and gene expression patterns of keratinized mouthparts and teeth overlap. We hypothesize that the novel mouthparts of tadpoles did not arisede novobut instead originated by partially co-opting the developmental program that typically mediates true tooth development.
The impact of self-isolation due to COVID-19 on health care workers’ mental health and wellbeing: a systematic review with narrative synthesis
Authors: Stein Madeline V. , Brooks Samantha K. , Smith Louise E. , Rubin G. James , Amlôt Richard , Greeberg Neil , Martin Alex F. 
Published: February 2025

AbstractBackgroundSelf-isolation is a key public health strategy for infectious disease control. Globally implemented during the COVID-19 pandemic, it remains an essential strategy in ongoing mitigation efforts. Healthcare workers (HCWs) often face isolation due to occupational exposure to infectious diseases and may face unique psychological challenges.AimsThis systematic review synthesized evidence on (1) the impact of isolation on HCWs’ psychological wellbeing, (2) factors associated with wellbeing, and (3) the effectiveness of interventions to improve wellbeing during or after isolation for COVID-19.MethodsA pre-registered systematic review (PROSPERO: CRD42024559971) was conducted in accordance with PRISMA and Cochrane guidelines. Searches in PsycInfo, Embase, MEDLINE, PubMed, and grey literature included studies on HCWs’ psychological wellbeing during or after self-isolation. Risk of bias was assessed using ROBINS-E or CASP tools.ResultsFrom 20,798 records screened, 19 studies (10 quantitative, 7 qualitative, 2 mixed methods) were included. Quantitative findings on anxiety, depressive, and stress symptoms were inconsistent. Qualitative studies consistently reported distress, loneliness, and stigma. Factors associated with wellbeing included socio-cultural influences and protective factors. No studies assessed interventions targeting wellbeing during self-isolation.ConclusionSelf-isolation appears to have variable effects on HCWs’ wellbeing, including significant challenges and opportunities for resilience. Public health strategies should prioritize timely, clear communication, accessible evidence-based psychological support, and practical resources. Future research must prioritize evaluation of interventions to mitigate psychological harm and support HCWs during infectious disease outbreaks.Teaser textSelf-isolation is vital for infectious disease control but poses psychological challenges for healthcare workers (HCWs). We synthesized findings on the impact of self-isolation on HCWs’ wellbeing, associated factors, and interventions to enhance wellbeing. Quantitative studies reported inconsistent wellbeing findings, while qualitative data highlighted distress, stigma, and resilience. Public health strategies must ensure psychological and practical support, clear communication, and intervention development to mitigate harm and enhance HCWs’ wellbeing during future infectious disease outbreaks.
Epigenetic changes, neuronal dysregulation and metabolomic abnormalities inZmym2mutant mice, a genetic model of schizophrenia and neurodevelopmental disorders
Authors: Huang Wei-Chao , Mandell Kira Perzel , Aryal Sameer , Song Bryan J. , Valle-Tojeiro Antia , Goble Nathaniel , Geng Chuhan , Asan Ahmet S. , Liu Xiao-Man , Dennis Courtney , Dailey Lucas , Deik Amy , Inunciaga Lucia , Mashin Eivgeni , Farsi Zohreh , Wang Yining , Pan Jen Q. , Clish Clary B. , Keshishian Hasmik , Carr Steven A. , Sheng Morgan 
Published: February 2025

ABSTRACTLoss-of-function mutations inZMYM2are associated with an increased risk of schizophrenia (SCZ) and neurodevelopmental disorders (NDD). ZMYM2 interacts with proteins involved in histone modification and gene regulation, including LSD1 and ADNP; however, its specific roles in the brain remain poorly understood. In this multi-omics study, we demonstrate that heterozygous knockout ofZmym2in mice results in widespread disturbances in gene expression affecting diverse molecular pathways, including those related to histone modifications and neuronal activity. Proteomic analysis of synapses reveals dysregulation of lipid metabolism and neurofilament-associated pathways, while metabolomic profiling identifies alterations in sphingomyelin and ceramide levels. Furthermore,Zmym2mutant mice exhibit abnormal brain oscillation patterns on EEG and locomotor hyperactivity in the open field test. Collectively, these findings underscore the critical role ofZMYM2in brain development and function and highlightZmym2mutant mice as a genetic animal model for SCZ and NDD.
Dynamic early recruitment of GAK-Hsc70 regulates coated pit maturation
Authors: He Zhangping , Zuo Peiyao , Xu Peiliu , Yuan Haozhi , Bhave Madhura , Wei Xiangying , Yang Ziyan , Han Lu , Schmid Sandra L. , Chen Zhiming 
Published: February 2025

AbstractClathrin-mediated endocytosis (CME) is the process by which clathrin assembles on the plasma membrane to form clathrin-coated pits (CCPs), which then invaginate, accumulate cargo and are released by fission from the membrane to form clathrin-coated vesicles (CCVs). A transition of nascent CCPs from flat-to-curved has been observed by various methods. However, what drives this transition remains unknown and controversial. GAK and its chaperone protein, Hsc70, are well-known to mediate clathrin release from CCVs and several studies have observed a late burst of GAK recruitment as CCVs form. Other studies have proposed that early recruitment of GAK-Hsc70 could function to provide the necessary energy source to remodel nascent flat clathrin lattices, replacing hexagons with pentagons and enabling a gain of curvature and invagination of the growing CCP; however, direct functional evidence is lacking. Here we show that GAK knockdown inhibits CCP formation and invagination. Furthermore, mutations in the J domain of GAK that abolish Hsc70 recruitment to and activation at CCPs, lead to the accumulation of GAK at CCPs, hinder CCP stabilization and invagination and result in a striking increase in the proportion of short-lived, abortive CCPs. These findings support the hypothesis that GAK-Hsc70 promotes the turnover and remodeling of nascent clathrin assemblies required for curvature development during CME.Significance StatementGAK and its chaperone protein, Hsc70, are known to be recruited to clathrin-coated vesicles (CCVs) to mediate clathrin uncoating. Previous studies have proposed that early recruitment of GAK-Hsc70 to CCPs could function to remodel nascent flat clathrin lattices, replacing hexagons with pentagons and enabling a gain of curvature of the assembling polymeric coat. However, there are conflicting views, and direct functional evidence is lacking. Here we show that GAK knockdown inhibits CCP formation and invagination. A detailed domain-specific mutational analysis of GAK pinpointed the importance of J domain-Hsc70 interactions in regulating crucial early steps of CME including CCP stabilization and invagination. These findings support a hypothesis that GAK-Hsc70 promotes turnover of clathrin at nascent CCPs required for curvature development.