bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnosis and clinical description of leptospirosis cases identified through hospital-based active surveillance in Puerto Rico, 2019-2021
Authors: Munoz-Zanzi Claudia , Mueller Melissa , Coriano-Díaz Natalia , Rivera-Gutierrez Ralph , Rivera-Cátala Christian , Millán-Rodríguez Rachel , Cantres Rosa , Piñeiro-Falcón Natalie M. , Ríos-Núñez Daiana M. , Maldonado-Alfonzo Josean G. , Galloway Renee , Santiago-Ramos Luis J. , Kircher Amy , Hallman Deana , Martinez Lemuel , Russel-Orama Robin , Schafer Ilana J.
Published: February 2025

Introduction

Leptospirosis is endemic to Puerto Rico, affecting people through seasonal increases and outbreaks. This report describes the diagnostic approach and clinical characteristics of leptospirosis cases identified through active undifferentiated acute febrile illness (UAFI) surveillance in Puerto Rico.

Materials and Methods

From 2019-2021, active surveillance was conducted in four emergency departments (ED), with standardized recruitment of patients aged ≥5 years, presenting with fever or a history of fever of unknown origin within the past two weeks. Additional cases were recruited from referrals of patients with positive leptospirosis diagnostic tests routinely ordered by clinicians. All enrolled patients were subject to a standardized diagnostic algorithm using PCR and serology to identify probable and confirmed leptospirosis cases. Patient data was collected from electronic medical records and interviews.

Results

Leptospirosis was diagnosed in 4% of 406 ED-enrolled UAFI patients, eight confirmed and eight probable cases. Referrals resulted in identification of 12 routinely detected cases (five confirmed and seven probable). Of the 28 cases, 71% were ≤7 days-post-onset, 71% were male, average age was 43 years old, and the most common presentations included lower back pain (82%), headache (75%), fatigue (71%), vomiting (71%), myalgia (71%), and calf pain (64%). Common clinical laboratory findings were elevated AST (78%), hyperglycemia (74%), thrombocytopenia (48%), proteinuria (62%), and hematuria (62%). Classification of four isolates identifiedL. interrogansserovar Icterohaemorrhagiae/Copenhageni (n=2),L. borgpeterseniiserovar Ballum/Guangdong, andL. kirschneri(no serovar match). All but one of the leptospirosis cases met the current Council of State and Territorial Epidemiologists’ definition for clinical compatibility with leptospirosis. Hemorrhagic symptoms and acute kidney injury with jaundice were associated with being a leptospirosis case.

Conclusions

These findings underscore the role of leptospirosis among febrile illness in Puerto Rico, the need for increased awareness to optimize diagnosis and treatment, and further research to improve prevention and intervention strategies.
Centella asiaticaimproves sleep quality and quantity in aged mice
Authors: Dovek Laura , Tinsley Carolyn E. , Gutowsky Katelyn , McDaniel Kayla , Potter Zoe , Ruffins Matthias , Milman Noah E.P. , Wong Claire , Soumyanath Amala , Gray Nora E. , Lim Miranda M.
Published: February 2025

Age-related sleep disruption is common in older adults. Not only does the total amount of time spent in sleep decline, but the number of arousals during sleep increases with age. As sleep is important for both memory consolidation and to prevent neurodegenerative pathology, this decline in sleep and/or sleep consolidation may underlie age-related cognitive decline and dementias. Furthermore, treatment of sleep disruption can improve quality of life. However, few interventions have successfully reversed age-related sleep decline. Extracts from the plantCentella asiaticahave demonstrated neuroprotective effects in human, rodent, and fly models of aging and neurodegenerative diseases, and is a promising intervention for dementias, yet little is known about how these extracts affect sleep patterns. Here, we administeredCentella asiatica water extract(CAW)dosed or control chow to male and female C57BL6/J mice aged 18 months. Effects on sleep composition were determined using electrodes that recorded EEG and EMG signals. We found that CAW dosed chow (1000 mg/kg/day) increased REM sleep time in aged male mice and decreased the number of arousals during sleep observed in aged females, compared to age- and sex-matched controls. We conclude that CAW administered in food has a moderate, sex-dependent effect on sleep quantity and quality.

Statement of Significance

Sleep declines with age and may underline age-related cognitive changes. However, few interventions have successfully reversed age-related sleep and cognitive decline. This study found that botanical extract from the plantCentella asiaticaincreased total REM sleep time in aged male mice, and decreased sleep fragmentation in aged female mice, compared to age- and sex-matched controls. Whether these moderate, sex-dependent effect sizes on sleep in aged mice are impactful enough to affect cognition, quality of life, and/or neurodegenerative pathology could be explored in future studies.
Anti-Parkinsonian Drugs Rescue Locomotor Deficits in JIP3 Knockout Zebrafish: Implications for Treating Patients withMAPK8IP3-related Neurodevelopmental Disorders
Authors: Foksinska Aleksandra , Souder Paige , Smith Gabrielle , Travis Kinnsley , Rucka Sienna , Allred Addie , Bender Rebeca , Brunson Jackie , Lanier Avary , Glaze Amber , Crouse Andrew , Might Matt , Crowder Camerron M.
Published: February 2025

MAPK8IP3-related neurodevelopmental disorders are a spectrum of rare conditions caused byde novomutations in theMAPK8IP3gene that encodes the JIP3 protein. These disorders are associated with a spectrum of neurodevelopmental symptoms that manifest in children and cause brain abnormalities, profound intellectual disabilities, movement disorders, and developmental delays. JIP3 is required for axonal transport of proteins and organelles between the soma and the synaptic terminal of neurons, a process critical for normal brain development and function. Homozygous loss-of-function mutations in JIP3 lead to impaired axonal transport and aggregation of cargo, which result in axonal swelling and stunted elongation. Despite these severe outcomes, disease mechanisms are poorly understood, and no current treatments are available.

Here we conduct thorough morphological, behavioral, and motility phenotyping in the JIP3 knockout zebrafish and identify locomotor deficits and morphological abnormalities. To identify treatment options, we used insights from expert clinicians and the artificial intelligence tool, mediKanren, to identify drug candidates hypothesized to improve patient symptoms or compensate for the loss of JIP3 at the molecular level. We then prioritized drugs that are FDA-approved, safe for children, and readily available. These collective efforts identified amantadine and levodopa as candidate therapies and rescued motor phenotypes associated with JIP3 loss-of-function in zebrafish.
Single-cell Transcriptomics Unravel Stereocilia Degeneration as a Key Contributor to Age-related Vestibular Dysfunction in Mice and Humans
Authors: Kulasooriya Samadhi , Liu Huizhan , Vijayakumar Sarath , Bloom Celia , Tu Su , Borgmeier Benjamin J. , Zhou Mi , Tao Litao , Kachar Bechara , He David Z.
Published: February 2025

Age-related vestibular dysfunction (ARVD) is a prevalent, debilitating condition in the elderly. The etiology and molecular mechanisms are poorly understood. We focused on mechanosensitive hair cells (HCs) as they are particularly vulnerable to aging. Using single-cell RNA-seq transcriptomes of young and old mouse vestibular HCs, we show that aging HCs display both universal molecular blueprints, such as genomic instability, mitochondrial dysfunction, and impaired proteostasis, and cell type-specific aging signatures associated with deterioration of hair bundles and mechanotransduction. These signatures are also observed in aged human vestibular HCs, suggesting shared mechanisms. Importantly, morphological and functional analysis revealed that bundle degeneration and vestibular functional decline precede HC loss, highlighting the deterioration of mechanotransduction as a key contributor to ARVD. Furthermore, molecular and cellular changes associated with aging signatures are less pronounced in vestibular HCs than in cochlear HCs, underscoring the different pace of aging between the two mammalian inner ear sensory epithelia.
Novel neurofilament light (Nefl) E397K mouse models of Charcot-Marie-Tooth type 2E (CMT2E) present early and chronic axonal neuropathy
Authors: Pérez-López Dennis O. , Shively Audrey A. , Torres F. Javier Llorente , Abu-Salah Mohammed T. , Garcia Michael L. , Arnold W. David , Lorson Monique A. , Lorson Christian L.
Published: February 2025

Charcot-Marie-Tooth (CMT) is the most common hereditary peripheral neuropathy with an incidence of 1:2,500. CMT2 clinical symptoms include distal muscle weakness and atrophy, sensory loss, toe and foot deformities, with some patients presenting with reduced nerve conduction velocity. Mutations in the neurofilament light chain (NEFL) gene result in a specific form of CMT2 disease, CMT2E.NEFLencodes the protein, NF-L, one of the core intermediate filament proteins that contribute to the maintenance and stability of the axonal cytoskeleton. To better understand the underlying biology of CMT2E disease and advance the development of therapeutics, we generated aNefl+/E397Kmouse model. While theNefl+/E397Kmutation is inherited in a dominant manner, we also characterizedNeflE397K/E397Kmice to determine whether disease onset, progression or severity would be impacted. Consistent with CMT2E, lifespan was not altered in these novel mouse models. A longitudinal electrophysiology study demonstrated significant in vivo functional abnormalities as early as P21 in distal latency, compound muscle action potential (CMAP) amplitude and negative area. A significant reduction in the sciatic nerve axon area, diameter, and G-ratio was also present as early as P21. Evidence of axon sprouting was observed with disease progression. Through the twelve months measured, disease became more evident in all assessments. Collectively, these results demonstrate an early and robust in vivo electrophysiological phenotype and axonal pathology, makingNefl+/E397KandNeflE397K/E397Kmice ideal for the evaluation of therapeutic approaches.
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

Leucine-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 AREAS

Cell biology

Molecular biology

Cancer
Unified high-resolution immune cell fraction estimation in blood tissue from birth to old age
Authors: Guo Xiaolong , Sulaiman Mahnoor , Neumann Alexander , Zheng Shijie C , Cecil Charlotte A.M. , Teschendorff Andrew , Heijmans Bas
Published: February 2025

Background: Blood is composed of many different immune cell-types, whose proportions vary throughout life. If not accounted for, these variations can seriously cause confounding or hamper interpretation of DNAm-based biomarkers. Although cell-type deconvolution methods can address this challenge for cord and adult blood, there is currently no method that can be applied to blood tissue from other age groups, including infants and children. Results: Here we construct and extensively validate a DNAm reference panel, called UniLIFE, for 19 immune cell-types, applicable to blood tissue of any age. We use UniLIFE to delineate the dynamics of immune-cell fractions from birth to old age, and to infer disease associated immune cell fraction variations in newborns, infants, children and adults. In a prospective longitudinal study of type-1 diabetes in infants and children, UniLIFE identifies differentially methylated positions that precede type-1 diabetes diagnosis and that map to diabetes related signaling pathways. In contrast to previous studies, we are able to validate these biomarker associations in an independent DNAm dataset comprising purified monocytes from monozygotic twins discordant for type-1 diabetes, but not in lymphocytes, highlighting the importance of epigenetic changes in the innate immune system in the development of type-1 diabetes. Conclusions: In summary, we present a life course immune-cell estimator for blood tissue of any age to help improve the identification and interpretation of blood-based DNAm biomarkers for any age groups and specially for longitudinal studies that include infants and children. The UniLIFE DNAm reference panel and algorithms to estimate cell-type fractions and perform cell-type deconvolution are available from our EpiDISH Bioconductor R-package: https://bioconductor.org/packages/release/bioc/html/EpiDISH.html
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

Background/Aims

Predictive 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/Methods

VHA-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).

Results

First-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%.

Discussion

Our 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.

Conclusion

The 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

Motor 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.
Haplotype Matching with GBWT for Pangenome Graphs
Authors: Sanaullah Ahsan , Villalobos Seba , Zhi Degui , Zhang Shaojie
Published: February 2025

Traditionally, variations from a linear reference genome were used to represent large sets of haplotypes compactly. In the linear reference genome based paradigm, the positional Burrows-Wheeler transform (PBWT) has traditionally been used to perform efficient haplotype matching. Pangenome graphs have recently been proposed as an alternative to linear reference genomes for representing the full spectrum of variations in the human genome. However, haplotype matches in pangenome graph based haplotype sets are not trivially generalizable from haplotype matches in the linear reference genome based haplotype sets. Work has been done to represent large sets of haplotypes as paths through a pangenome graph. The graph Burrows-Wheeler transform (GBWT) is one such work. The GBWT essentially stores the haplotype paths in a run length compressed BWT with compressed local alphabets. Although efficient in practice count and locate queries on the GBWT were provided by the original authors, the efficient haplotype matching capabilities of the PBWT have never been shown on the GBWT. In this paper, we formally define the notion of haplotype matches in pangenome graph-based haplotype sets by generalizing from haplotype matches in linear reference genome-based haplotype sets. We also describe the relationship between set maximal matches, long matches, locally maximal matches, and text maximal matches on the GBWT, PBWT, and the BWT. We provide algorithms for outputting some of these matches by applying the data structures of the r-index (introduced by Gagie et al.) to the GBWT. We show that these structures enable set maximal match and long match queries on the GBWT in almost linear time and in space close to linear in the number of runs in the GBWT. We also provide multiple versions of the query algorithms for different combinations of the available data structures. The long match query algorithms presented here even run on the BWT in the same time complexity as the GBWT due to their similarity.
Internet images reveal bumblebee-mimicking hoverflies have evolved to follow flower colour preferences of their models
Authors: Gilbert James DJ , Craig-Jackson Joseph , Morrell Lesley , Gilbert Francis S
Published: February 2025

Batesian mimics, such as hoverflies, can gain protection by resembling noxious species that predators avoid, such as bees. Such resemblance can be behavioural as well as morphological. Bees commonly have a preference for blue flowers, whilst flies generally prefer yellow and white. We predicted that, driven by selection for enhanced mimicry, bee-mimicking hoverflies would have switched flower preference from yellow to blue, to follow the flower choices of their models. We gathered internet photographs of flower-visiting bees and wasps, their hoverfly mimics, and non-mimicking hoverflies, and compared the colours of the visited flowers. Flowers visited by bumblebees were "bluer" than those visited by other hymenopterans (honeybees, wasps and solitary bees). Correspondingly, flowers visited by bumblebee-mimicking hoverflies were bluer than those visited by non-mimics, and were indistinguishable in blueness from those visited by bumblebees. There was no such pattern in flower "yellowness", where all flies and most hymenopterans preferred similar yellowness, and only bumblebees chose less yellow flowers than the others. Our study demonstrates widespread changes in microhabitat choice (specifically flower preference) among a diverse group of Batesian mimics, consistent with the idea of behavioural mimicry. Mildly noxious models such as bumblebees are thought to exert particularly strong selection for mimetic accuracy, suggesting that habitat-choice mimicry may be selected as a way of enhancing morphological mimicry.
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

Mitochondrial 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

Damage 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

The 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

Clinical 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

Objective

The 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.

Methods

A 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.

Results

Of 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.

Conclusion

While 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

Objective

This 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).

Methods

We 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.

Results

Smartphone 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.

Conclusion

Smartphone-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

Background

Resection 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.

Methods

The 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 results

We 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.

Conclusions

On 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.

Registration

PROSPERO 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

BACKGROUND.

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.
A DC-sensitive video/electrophysiology monitoring unit for long-term continuous study of seizures and seizure-associated spreading depolarization in a rat model
Authors: Liu Jiayang , Gluckman Bruce J.
Published: February 2025

There has been a long-term need for a low-cost, highly efficient, and high-fidelity epilepsy monitoring unit (EMU) suitable for home-cage monitoring of small-animal models of epilepsy. We show an accessible, scalable, highly space and energy-efficient EMU capable of fulfilling chronic, continuous synchronized multiple animal monitoring jobs. Each rig within the EMU can provide 16-channel high-fidelity, DC-sensitive biopotential recordings, head acceleration monitoring, synchronized voltammetry applications, and video recording on one freely moving rat. We present the overall EMU architecture design and subsystem details in each recording rig. We demonstrate long-term continuous in vivo recordings of spontaneous seizure and seizure-associated spreading depolarization (SD) from freely moving rats prepared under the tetanus toxin model of temporal lobe epilepsy.
Homeostasis After Injury: How Intertwined Inference and Control Underpin Post-Injury Pain and Behaviour
Authors: Mahajan Pranav , Dayan Peter , Seymour Ben
Published: February 2025

Injuries are an unfortunate but inevitable fact of life, leading to an evolutionary mandate for powerful homeostatic processes of recovery and recuperation. The physiological responses of the body and the immune system must be coordinated with behaviour to allow protected time for this to happen, and to prevent further damage to the affected bodily parts. Reacting appropriately requires an internal control system that represents the nature and state of the injury and specifies and withholds actions accordingly. We bring the formal uncertainties embodied in this system into the framework of a partially observable Markov decision process (POMDP). We discuss nociceptive phenomena in light of this analysis, noting particularly the paradoxical behaviours associated with injury investigation, and the propensity for transitions from normative, tonic, to pathological, chronic, pain states. Importantly, these simulation results provide a quantitative account and enable us to sketch a much needed roadmap for future theoretical and experimental studies on injury, tonic pain, and transition to chronic pain. Ultimately, we seek novel ways to target chronic pain.
Computational detection, characterization, and clustering of microglial cells in a mouse model of fat-induced postprandial hypothalamic inflammation
Authors: Sanchez Clara , Nadal Morgane , Cansell Céline , Laroui Sarah , Descombes Xavier , Rovère Carole , Debreuve Éric
Published: February 2025

Obesity is associated with brain inflammation, glial reactivity, and immune cells infiltration. Studies in rodents have shown that glial reactivity occurs within 24 hour of high-fat diet (HFD) consumption, long before obesity development, and takes place mainly in the hypothalamus (HT), a crucial brain structure for controlling body weight. Understanding more precisely the kinetics of glial activation of two major brain cells (astrocytes and microglia) and their impact on eating behavior could prevent obesity and offer new prospects for therapeutic treatments. To understand the mechanisms pertaining to obesity-related neuroinflammation, we developed a fully automated algorithm, NutriMorph. Although some algorithms were developed in the past decade to detect and segment cells, they are highly specific, not fully automatic, and do not provide the desired morphological analysis. Our algorithm cope with these issues and performs the analysis of cells images (here, microglia of the hypothalamic arcuate nucleus), and the morphological clustering of these cells through statistical analysis and machine learning. Using the k-Means algorithm, it clusters the microglia of the control condition (healthy mice) and the different states of neuroinflammation induced by high-fat diets (obese mice) into subpopulations. This paper is an extension and re-analysis of a first published paper showing that microglial reactivity can already be seen after few hours of high-fat diet (Cansell et al., 2021). Thanks to NutriMorph algorithm, we unravel the presence of different hypothalamic microglial subpopulations (based on morphology) subject to proportion changes in response to already few hours of high-fat diet in mice.
Universal bacterial clade dynamics dominate under predation despite altered phenotypes and mutation targets
Authors: Kičiatovas Dovydas , Cairns Johannes , Partanen Veera , Hoffmann Julius , Becks Lutz , Hiltunen Teppo , Mustonen Ville
Published: February 2025

Recent studies have revealed bacterial genome-wide evolution to be complex and dynamic even in a constant environment. The evolution is characterized by the emergence of new clades competing or temporarily coexisting as each clade continues to undergo evolutionary change. Previous studies on predator-prey dynamics tracking simple ecological and phenotypic metrics have shown predation to fundamentally alter prey evolution, often giving rise to defense evolution followed by frequency dependent selection between defended and undefended prey genotypes as well as coevolution. Moreover, these dynamics can differ between prey species depending, for example, on mutation rate and the physiological and fitness effects of the mutations available. Here we sought to consolidate these fields by examining genome-wide evolution in five bacterial prey species separately subjected to long-term evolution under ciliate predation. For all species, we found mutational signals of prey defense evolution, with phenotypic data demonstrating change in phenotypic composition for defense trait over time. Mutational targets and dynamics also differed between prey species. Intriguingly, however, overall temporal molecular dynamics across the prey species were strikingly similar to those of bacteria evolving alone, with constant emergence, competition and quasi-stable coexistence of clades. This makes molecular evolution more interesting and less predictable than we might expect based on existing coevolutionary theories.
IGLV3-21R110-directed bispecific antibodies activate T cells and promote killing in a high-risk subset of chronic lymphocytic leukemia
Authors: Fischer Claudia , Stücheli Simon , Chen Shih-Shih , Nimmerfroh Johanna , Schultheiß Christoph , Widmer Corinne , Heim Dominik , Kasenda Benjamin , Passweg Jakob , Kobold Sebastian , Egli Lukas , Coianiz Nicolò , Chijioke Obinna , Chiorazzi Nicholas , Follo Marie , Läubli Heinz , Peipp Matthias , Binder Mascha
Published: February 2025

We previously used a disease-specific B cell receptor (BCR) point mutation (IGLV3-21R110) for selective targeting of a poor-risk subset of chronic lymphocytic leukemia (CLL) with chimeric antigen receptor (CAR) T cells. Since CLL is a disease of the elderly and a significant fraction of patients is not able to physically tolerate CAR T cell treatment, we explored bispecific antibodies as an alternative for precision targeting of this tumor mutation. Heterodimeric IgG1-based antibodies consisting of a fragment crystallizable region (Fc) attached to either an anti-IGLV3-21R110Fab or an anti-CD3 (UCHT1) single chain variable fragment (R110-bsAb) selectively killed cell lines engineered to express high levels of the neoepitope as well as primary CLL cells using healthy donor and CLL patient-derived T cells as effectors. R110-bsAb spared polyclonal human B cells (as opposed to CD19-targeting Blinatumomab) as well as CD34+human stem cells. Yet, R110-bsAb induced lower T cell activation than Blinatumomab with primary CLL cells likely due to lower expression of target antigen. In vivo, R110-bsAb specifically killed IGLV3-21R110-expressing cell lines and CLL cells while sparing peripheral blood mononuclear cells. These findings highlight bispecific antibodies as a promising, off-the-shelf immunotherapy for high-risk CLL patients, offering selective targeting while preserving healthy B cells.