bluuebunny/crossref_metadata_2025_split huggingface dataset:
LRRC8A-containing anion channels promote glioblastoma proliferation via a WNK1/mTORC2-dependent mechanism
Authors: Fidaleo Antonio M. , Bach Martin D. , Orbeta Shaina , Abdullaev Iskandar F. , Martino Nina , Adam Alejandro P. , Boulos Mateo A. , Dulin Nickolai O. , Paul Alexandra R. , Kuo Yu-Hung , Mongin Alexander A. 
Published: February 2025

SUMMARYLeucine-rich repeat-containing protein 8A (LRRC8A) is the essential subunit of ubiquitous volume-regulated anion channels (VRACs). LRCC8A is overexpressed in several cancers and promotes negative survival outcomes via a poorly defined mechanism. Here, we explored the role of LRRC8A and VRACs in the progression of glioblastoma (GBM), the most common and deadly primary brain tumor. We found that, as compared to healthy controls,LRRC8AmRNA was strongly upregulated in surgical GBM specimens, patient-derived GBM cell lines, and GBM datasets from The Cancer Genome Atlas (TCGA). Our in-silico analysis indicated that patients belonging to the lowestLRRC8Aexpression quartile demonstrated a trend for extended life expectancy. In patient-derived GBM cultures, siRNA-driven LRRC8A knockdown reduced cell proliferation and additionally decreased intracellular chloride levels and inhibited activity of mTOR complex 2. The antiproliferative effect of LRRC8A downregulation was recapitulated with a pharmacological inhibitor of VRAC. Our ensuing biochemical and molecular biology analyses established that the LRRC8A-containing VRACs facilitate GBM proliferation via a new mechanism involving non-enzymatic actions of the chloride-sensitive protein kinase WNK1. Accordingly, the chloride-bound WNK1 stimulates mTORC2 and the mTORC2-dependent protein kinases AKT and SGK, which promote proliferation. These findings establish the new mTORC2-centric axis for VRAC dependent regulation of cellular functions and uncover potential targets for GBM intervention.SUBJECT AREASCell biologyMolecular biologyCancer
Life Events Extraction From Healthcare Notes for Veteran Acute Suicide Prediction
Authors: Morrow Destinee , Zamora-Resendiz Rafael , Beckham Jean C. , Kimbrel Nathan A. , McMahon Benjamin H. , Crivelli Silvia 
Published: February 2025

ABSTRACTBackground/AimsPredictive models of suicide risk have focused on predictors extracted from structured data found in electronic health records (EHR), with limited consideration of predisposing life events (LE) expressed in unstructured clinical text such as housing instability and marital troubles. Additionally, there has been limited work in large-scale analysis of natural language processing (NLP) derived predictors for suicide risk and integration of extracted LE into longitudinal models of suicide risk. This study aims to expand upon previous research, demonstrating how high-performance computing (HPC) and machine learning technologies such as language models (LM) can be used to annotate and integrate 8 LE across all Veterans Health Administration (VHA) unstructured clinical text data with enriched performance metrics.Materials/MethodsVHA-wide clinical text from January 2000 to January 2022 were pre-processed and analyzed using HPC. Data-driven lexicon curation was performed for each LE by scaling a nearest-neighbor search over a precomputed index with LM embeddings. Data parallelism was applied to a rule-based annotator to extract LE, followed by random forest for improved positive predictive value (PPV). NLP results were analyzed and then integrated and compared to a baseline statistical model predicting risk for a combined outcome (suicide death, suicide attempt and overdose).ResultsFirst-time LE mentions, with a PPV of 0.8 or higher, showed a temporal correlation to suicide-related events (SRE) (suicide ideation, attempt and/or death). A significant increase of LE occurrences was observed starting 2.5 months prior to an SRE. Predictive models integrating NLP-derived LE show an improved AUC of 0.81 vs. a 0.79 obtained with the baseline and novel patient identification of up to 57%.DiscussionOur analysis shows that: 1) performance metrics, specifically PPV, improved significantly from previous work and outperform related works; 2) the mentions of LE in the unstructured data increase as time to a SRE approaches; 3) LE identified from the notes in the weeks prior to a SRE were not associated with administrative bias caused by outreach; and 4) LE improved the AUC of predictive models and identified novel patients at risk for suicide.ConclusionThe resulting person-period longitudinal data demonstrated that NLP-derived LE served as acute predictors for suicide-related events. NLP integration into predictive models may help improve clinician decision support. Future work is necessary to better define these LE.
Successive failure triggered by motor exploration in a reinforcement-based reaching task
Authors: Saito Risa , Takemi Mitsuaki , Kodama Midori , Ogasawara Toyo , Nozaki Daichi 
Published: February 2025

SummaryMotor exploration, a key process in reinforcement-based motor learning, is triggered by suboptimal performance and leads to increased movement variability. Consequently, failure in one trial may increase the likelihood of failure in subsequent trials. If this pattern emerges, successive failures (SFs) are not merely events to be avoided but part of the trial-and-error process of identifying optimal movements, which can facilitate motor learning. This study investigated whether and how SFs occur above chance levels during a motor learning task with binary success/failure feedback and explored the relationship between SFs and motor learning outcomes. Thirty-three healthy young adults participated in the study, performing a reaching task to pass through a target without visual feedback of their hand position. Binary feedback was provided after each trial, indicating whether the hand trajectory overlapped with the target. The results showed that the probability of two SFs was significantly higher than the square of the overall failure probability, indicating that failure streaks occurred above chance levels. A computational model, in which motor variability comprised constant motor noise and exploratory variability regulated by recent reward history (where variability increased following failure), successfully explained SF emergence. However, the learning index, defined as the difference in failure probability between the first and latter halves of the experiment, was unrelated to SF emergence. Additionally, failure streaks disappeared when participants were asked to reach one of seven randomly selected targets in each trial, suggesting that introducing environmental variability can help alleviate SFs.
USP30 inhibition improves mitochondrial health through both PINK1-dependent and independent mechanisms
Authors: Williamson Matthew G. , Heon-Roberts Rachel , Franks Sarah N. J. , Mock Elliot , Jones Hannah B. L. , Britti Elena , Malpartida Ana , Bassal Mahmoud , Lavelle Martha , Connor Jack , Barcons Aina Mogas , Hammond Katherine , Savory Katrina , Rai Pavandeep , Lavayssiere Anna , McGuinness William , Sepke Natalie , Vowles Jane , Vendrell Iolanda , Guenther Franziska , Kessler Benedikt M. , Cowley Sally A. , England Katherine S. , Murphy Emma J. , Davis John B , Wade-Martins Richard , Ryan Brent J 
Published: February 2025

AbstractMitochondrial dysfunction is a key feature of many pathologies, including Parkinson’s disease. The selective vulnerability of dopaminergic neurons is thought to be influenced by mitochondrial dysfunction and mutations in the mitophagy regulating proteins PINK1 and Parkin that are known to cause early-onset Parkinsonism in an autosomal recessive manner.Augmentation of mitophagy through inhibition of USP30 may be a viable therapeutic strategy for a number of diseases including Parkinson’s. USP30 inhibition has been demonstrated to augment PINK1/PRKN mitophagy but also potentiate basal mitophagy to support the removal of dysfunctional mitochondria. Therefore, long-term de-regulation of mitophagy has been proposed to lead to mitochondrial depletion.We have used an integrated approach across cell lines, primary neurons and iPSC-derived dopaminergic neuronal cultures to assess the short and long-term effects of USP30 inhibition on mitochondrial health and neuronal activity. We investigated the dependence of USP30 inhibition phenotypes on the PINK1/Parkin pathway using genetic ablation and in iPSC-derived neurons from Parkinson’s patients with PINK1 or PRKN mutations.Loss of USP30 through CRISPRn-mediated knockout resulted in increased basal and depolarisation-induced mitophagy in SH-SY5Y cells. Loss of USP30 or pharmacological inhibition altered mitochondrial morphology and led to increases in membrane potential and ATP levels with decreased oxygen consumption, suggesting that USP30 loss results in a more efficient mitochondrial network. These changes in morphology were found to be independent of PINK1 or Parkin. Chronic pharmacological inhibition of USP30 or CRISPRi-mediated knockdown of USP30 did not impact dopaminergic neuronal activity, as assessed by electrophysiological profiling. These results support a dual role for USP30 in modulating the trigger threshold for mitophagy and regulating mitochondrial morphology without deleterious effects on dopaminergic neuronal activity.
Neuronal Silencing and Protection in a Mouse Model of Demyelination
Authors: Das Aniruddha , Borovicka Julie , Tobin Hale , Bhatia Shruti , Icardi Jacob , Tahmasebi Ghazaal , Agochiya Priyanka , Singh Shriya , Trapp Bruce , Dana Hod 
Published: February 2025

AbstractDamage to the myelin sheath that protects axons in the central nervous system is a hallmark pathology of demyelinating diseases like multiple sclerosis. Cuprizone-induced demyelination in mice is a common model for studying demyelination and remyelination. However, the relationship between myelin damage and recovery and the functional properties of ensheathed neurons remains poorly understood. Using concurrent monitoring of hippocampal myelination and neuronal firing rates in the same mouse, we assessed longitudinal changes during cuprizone consumption and remyelination treatment. The data revealed a rapid decline in neuronal activity that preceded myelin loss. Females showed a more severe decrease after 4 days of cuprizone, which correlated with enhanced neuronal activity and myelin loss 51 days later, whereas male mice showed a more severe decline in neuronal activity after 55 days of cuprizone. Following cuprizone cessation, mice were treated with Clemastine or vehicle for 45 days. A short-term recovery was found in both groups, before the Clemastine group showed increased remyelination and higher neuronal firing rates. The mean increase and decrease in firing rates were proportional to the same-neuron baseline firing rate in the Clemastine and vehicle groups, respectively, highlighting a potential linkage between the status of myelin recovery and cellular activity.
Germline pathogenic variation impacts somatic alterations and patient outcomes in pediatric CNS tumors
Authors: Corbett Ryan J. , Kaufman Rebecca S. , McQuaid Shelly W. , Vaksman Zalman , Phul Saksham , Brown Miguel A. , Mason Jennifer L. , Waszak Sebastian M. , Zhang Bo , Zhong Chuwei , Desai Heena , Hausler Ryan , Naqvi Ammar S. , Chroni Antonia , Geng Zhuangzhuang , Gonzalez Elizabeth M. , Zhu Yuankun , Heath Allison P. , Li Marilyn ,   Penn Medicine BioBank,   Regeneron Genetics Center, Storm Phillip B. , Resnick Adam C. , Maxwell Kara N. , Cole Kristina A. , Waanders Angela J. , Bornhorst Miriam , MacFarland Suzanne P. , Rokita Jo Lynne , Diskin Sharon J. 
Published: February 2025

AbstractThe contribution of rare pathogenic/likely pathogenic (P/LP) germline variants to pediatric central nervous system (CNS) tumor development remains understudied. Here, we characterized the prevalence and clinical significance of germline P/LP variants in cancer predisposition genes across 830 CNS tumor patients from the Pediatric Brain Tumor Atlas (PBTA). We identified germline P/LP variants in 24.2% (201/830) of patients and the majority (154/201) lacked clinical reporting of genetic tumor syndromes. Among P/LP carriers, 30.7% had putative somatic second hits or loss of function tumor alterations. Finally, we linked pathogenic germline variation with novel somatic events and patient survival to highlight the impact of germline variation on tumorigenesis and patient outcomes.
An experimental model of clinical immunity for human malaria
Authors: Hou Mimi M. , Harding Adam C. , Barber Natalie M. , Kundu Prasun , Bach Florian A. , Salkeld Jo , Themistocleous Yrene , Greenwood Nicola M. , Cho Jee-Sun , Barrett Jordan R. , Nugent Fay L. , Rawlinson Thomas A. , Hodgson Susanne H. , Khozoee Baktash , Mac Lochlainn Dylan J. , Cowan Rachel E. , Poulton Ian D. , Baker Megan , Kingham Lucy , Mitton Celia H. , Platt Abigail , Lopez Ramon Raquel , Ramos Lopez Fernando , Thomas Merin , Skinner Katherine , Quinkert Doris , Pipini Dimitra , Lias Amelia M. , Bardelli Martino , Edwards Nick J. , Donnellan Francesca R. , Biswas Sumi , Rayner Julian C. , Nielsen Carolyn M. , Silk Sarah E. , Draper Simon J. , Nahrendorf Wiebke , Spence Philip J. , Minassian Angela M. 
Published: February 2025

AbstractClinical immunity to malaria can reduce fever and lead to asymptomatic infection but the underlying mechanisms remain unclear. To examine the development of clinical immunity, we conducted a multi-cohort, repeat controlled human malaria infection (CHMI) study withPlasmodium vivax, and a heterologous rechallenge withP. falciparum. Malaria-naïve adults underwentP. vivaxCHMI up to three times, at an interval of 5 to 20 months, by administration of red blood cells infected with theP. vivaxPvW1 clone. In the final cohort of the study, a subset of participants underwent heterologous repeat CHMI with theP. falciparum3D7 clone. Clinical parameters and the host response to infection were measured up to 3 months after each CHMI. Nineteen participants underwent primary CHMI withP. vivax, 12 returned for secondary homologous CHMI and 2 for tertiary homologous CHMI with the same parasite clone. During rechallenge, parasite growth was not attenuated and there was minimal induction of invasion-blocking antibodies. Nonetheless, clinical symptoms including fever and laboratory abnormalities were less frequent and of lower severity during rechallenge and multi-analyte plasma profiling revealed an attenuated inflammatory response. Six participants who had completedP. vivaxCHMI, then underwent heterologous rechallenge withP. falciparum. Previous infection withP. vivaxdid not protect participants against symptoms, fever or inflammation upon exposure toP. falciparum. Clinical immunity toP. vivaxdeveloped rapidly after a single CHMI, protecting participants against fever and laboratory abnormalities associated with malaria and was underpinned by the attenuation of inflammation. In contrast, there was no evidence of anti-parasite immunity, suggesting that mechanisms of clinical immunity can operate independently of pathogen load to reduce the damage caused by malaria. Clinical immunity toP. vivaxwas parasite species-specific and provided no protection against CHMI withP. falciparum.
Evaluating the Reliability of a Custom GPT in Full-Text Screening of a Systematic Review
Authors: Davis Rachel C. , List Saskia S. , Chappell Kendal G. , Heen Espen 
Published: February 2025

ABSTRACTObjectiveThe purpose of this study is to evaluate the reliability and time-saving potential of a custom GPT (cGPT) in full text screening of a systematic review focusing on average 24-hour urine production and 24-hour creatinine excretion in populations.MethodsA cGPT model, developed using ChatGPT4o (OpenAI Plus), was trained on a subset of articles previously assessed in duplicate by human reviewers. The human operator of the cGPT manually uploaded individual articles into the cGPT conversation with a standardized prompt. The outputs were coded to simulate cGPT in 3 different roles: (1) autonomous reviewer, (2) assistant to the 1streviewer, and (3) assistant to the 2ndreviewer. Cohen’s kappa was used to measure interrater agreement between cGPT and each human reviewer, as well as against human consensus decisions (the “gold standard”). The threshold for practical use was determined to be a cGPT-consensus kappa score which existed within the confidence intervals of at least one human-human pairing at inclusion/exclusion and exclusion reason.ResultsOf the three reviewer roles, cGPT as assistant to the 2ndreviewer was the only role which met the threshold for practical use, producing a cGPT-consensus kappa score of 0.733 (95% CI: 0.607, 0.859) compared to a human-human kappa range between 0.713 (95% CI: 0.606, 0.821) and 0.784 (95% CI: 0.656, 0.912) for inclusion/exclusion. In the classification of exclusion reason, cGPT-consensus kappa score was 0.632 (95% CI: 0.568, 0.696) compared to the human-human kappa range from 0.713 (95% CI: 0.606, 0.821) to 0.784 (95% CI: 0.656, 0.912). The study found that there is a clear time saving advantage to using cGPT in this way for full text screening, estimating 10.1 to 84.4 hours saved in the data set investigated here. cGPT as an autonomous reviewer or as assistant to the 1streviewer did not meet reliability thresholds.ConclusionWhile cGPT did not have sufficiently reliable and accurate performance to replace human reviewers in full text screening, its use as an assistant holds promise in expediting the screening process, particularly with a large full-text corpus. There is a considerable deficit in published data exploring ChatGPT models for full text screening and more advanced models will require continued validation to determine which role is best suited to the capabilities of custom GPTs. More research is needed to establish a standardized threshold for practical use.
Smartphone-based measures as real-world indicators of functional status in advanced cancer patients
Authors: Straczkiewicz Marcin , Keating Nancy L. , Schonholz Stephanie M. , Matulonis Ursula A. , Horowitz Neil , Campos Susana , Onnela Jukka-Pekka , Wright Alexi A 
Published: February 2025

ABSTRACTObjectiveThis study evaluated the feasibility of using smartphone-based metrics to monitor physical functioning and quality of life in patients with advanced gynecological cancers. We analyzed associations between gait (step count, cadence, stride acceleration) and measures of mobility (home time, distance traveled, number of significant locations visited) with patient-reported outcomes (PROMs).MethodsWe studied raw accelerometer and GPS data from smartphones over 180-days for 85 patients with advanced gynecologic cancers. We computed measures of gait and mobility from smartphone sensor data, and PROMs (performance status, health-related quality of life, physical functioning) from smartphone surveys at baseline, 30, 90, and 180 days. We assessed longitudinal associations of digital gait and mobility measures with PROMs using linear mixed-effects models, with attention to smartphone adherence and temporal trends.ResultsSmartphone adherence was high: 83% of participants reported daily smartphone usage >1 hour; 74.1% had >16 hours of daily use. Gait measures, particularly step count and stride acceleration, were statistically associated with PROMs. Worsening patient-reported ECOG performance status corresponded to reduced step count (ECOG 3 vs. 0: -1837 steps/day,p<0.001), while higher PROMIS Physical Function was associated with step count increase (+72.64 steps/day per one-point increase,p<0.001). Mobility measures were less strongly associated with PROMs but provided complementary insights into patients’ behavioral patterns.ConclusionSmartphone-based gait and mobility metrics offer robust, real-world insights into individuals’ health statuses, providing a scalable, low-burden alternative to wearable devices. The high levels of smartphone use among participants underscore the feasibility of integrating this technology into routine oncology care.
Uterine conservative surgery vs hysterectomy for placenta accreta spectrum disorders–a systematic review and meta-analysis
Authors: Lino Gabriel Moreira , Machado Galvão Pauliana Valéria , Maranhão Conrado George Alessandro 
Published: February 2025

ABSTRACTBackgroundResection and reconstruction of the uterus may be an alternative to hysterectomy in placenta accreta spectrum disorders. We aimed to review whether surgical and maternal outcomes were comparable between these techniques.MethodsThe Cochrane Library, PubMed, and Embase databases were searched until 1 January 2025 for randomized controlled trials (RCT) and observational studies comparing uterine conservative surgery to hysterectomy. The risk of bias was assessed with ROB-2 or ROBINS-I, and the quality of evidence with GRADE. The main outcomes were blood loss and transfusion, reoperation, intraoperative visceral organ injury, and long-term complications.Main resultsWe included one RCT and eleven nonrandomized studies. Compared to hysterectomy, conservative surgery may result in similar intraoperative blood loss (MD -320.89 mL, 95% CI -574.95 to -66.82; 1 RCT and 3 prospective studies, 637 women; I2= 14%; low-certainty evidence) and transfused red blood cell packs (MD -0.70 packs, 95% CI -1.28 to -0.12; 1 RCT and 4 prospective studies, 649 women; I2= 0%; low-certainty evidence). There may be no difference in intraoperative visceral organ injury, reoperation, and duration of surgery (low-certainty evidence). Other outcomes were uncertain because of very low evidence.ConclusionsOn the basis of low evidence, conservative surgery did not increase the risk of clinically important harm compared to hysterectomy, with the benefit of uterus preservation. Further RCTs are needed to reach definitive conclusions about potential benefits. To improve the quality of evidence from low to moderate, a trial with an additional 181 participants in the conservative surgery arm would be necessary to avoid downgrading for imprecision.RegistrationPROSPERO CRD42024601117.
NEUTROPHIL ELASTASE AS A PREDICTIVE BIOMARKER FOR POST-STROKE INFECTION
Authors: Díaz-Benito B , Calleja P , Alzamora L , Ruiz A , Martínez-Salio A , Ostos F , Gutiérrez-Sánchez M , García-Culebras A , Moro MA , Moraga A , Lizasoain I 
Published: February 2025

ABSTRACTBACKGROUND.Ischemic stroke, a major cause of death and disability, triggers immune suppression and inflammation, increasing the risk of infections, particularly early post-stroke. These infections worsen outcomes, prolong hospitalization, and lack reliable predictive protocols. Current management with broad-spectrum antibiotics is not proven effective and may disrupt microbiota balance. Neutrophil elastase (NE), vital for immune defense, can exacerbate inflammation and infection susceptibility. The main objective of this study is to explore the role of NE in the development of infections after ischemic stroke.METHODS.This study enrolled 544 ischemic stroke patients to evaluate NE as a biomarker for post-stroke infections. Data regarding age, sex, cardiovascular risk factors, stroke etiology and severity were collected. Blood samples from eligible patients, meeting strict inclusion and exclusion criteria, were analyzed using ELISA and multiplex assays to measure NE, myeloperoxidase, and immune mediators.RESULTS.This study analyzed post-stroke infections in ischemic stroke patients, with 27.57% developing infections, respiratory (48.9%) and urinary (24.8%), mostly within three days. Infected patients were older, more often women, and diabetic, with higher NIHSS scores and larger infarct volumes. Elevated NE levels, higher leukocyte counts, and reduced lymphocytes at admission correlated with infection. Logistic regression showed NE, NIHSS, and diabetes as independent predictors. A matched case-control analysis confirmed higher NE levels in infected cases. Cytokine analysis revealed distinct immune profiles, with NE and IL-6 linked to respiratory infections.CONCLUSIONS.NE levels at admission may help identify stroke patients at high infection risk, guiding targeted treatment and supporting potential anti-NE therapies and prophylactic antibiotic strategies.