bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selecting a Window Size for the Analysis of Whole Genome Alignments using AIC
Authors: Ivan Jeremias , Frandsen Paul , Lanfear Rob 
Published: February 2025

AbstractThe variation of evolutionary histories along the genome presents a challenge for phylogenomic methods to identify the non-recombining regions and reconstruct the phylogenetic tree for each region. To address this problem, many studies used the non-overlapping window approach, often with an arbitrary selection of fixed window sizes that potentially include intra-window recombination events. In this study, we proposed an information theoretic approach to select a window size that best reflects the underlying histories of the alignment. First, we simulated chromosome alignments that reflected the key characteristics of an empirical dataset and found that the AIC is a good predictor of window size accuracy in correctly recovering the tree topologies of the alignment. Due to the issue of missing data in empirical datasets, we then designed a stepwise non-overlapping window approach and applied this method to the genomes oferato-sara Heliconiusbutterflies and great apes. We found that the best window sizes for the butterflies’ chromosomes ranged from<125bp to 250bp, which are much shorter than those used in a previous study even though this difference in window size did not significantly change the most common topologies across the genome. On the other hand, the best window sizes for great apes’ chromosomes ranged from 500bp to 1kb with the proportion of the major topology (grouping human and chimpanzee) falling between 60% and 87%, consistent with previous findings. Additionally, we observed a notable impact of stochastic error and concatenation when using small and large windows, respectively. For instance, the proportion of the major topology for great apes was 50% when using 250bp windows, but reached almost 100% for 64kb windows. In conclusion, our study highlights the challenges associated with selecting a window size in non-overlapping window analyses and proposes the AIC as a more objective way to select the optimal window size for whole genome alignments.
Averted mortality by COVID-19 vaccination in Belgium between 2021 and 2023
Authors: Stouten Veerle , Van Evercooren Izaak , Vernemmen Catharina , Braeye Toon , Catteau Lucy , Roelants Mathieu , Billuart Matthieu , Lamot Thomas , Sierra Natalia Bustos , Hammami Naïma , Vermeiren Elias , Rosas Angel , Blot Koen , Schmelz Anna I. , Nasiadka Léonore , Nganda Serge , van Loenhout Joris A.F. 
Published: February 2025

ABSTRACTBackgroundVaccination campaigns were rolled out primarily to limit the impact of COVID-19 on severe health outcomes, including mortality.AimWe aimed to estimate the number of averted deaths by COVID-19 vaccination in the Belgian population aged 65 years and older, between January 2021 and January 2023.MethodsNationwide data on COVID-19 infections, vaccine administrations and all-cause mortality were individually linked. We estimated Vaccine Effectiveness against COVID-19 mortality (VE) among persons having received a vaccine dose in the last 6 months, using a Cox proportional hazards model adjusted for age, sex, time since vaccination, previous infection, underlying health conditions, province and income. COVID-19 death was defined as a person with a laboratory-confirmed SARS-CoV-2 infection who died within a specified interval. Based on obtained VE estimates, vaccine coverage and national COVID-19 mortality data, we estimated the number of averted deaths.ResultsWe estimated VE (0-59 days after vaccination) for 65-79 year and ≥80 year-olds respectively, at 81.9% (78.1%-85.1%) and 74.7% (71.2%-77.7%) during Alpha, at 90.5% (88.8%-91.9%) and 91.4% (90.4%- 92.4%) during Delta and at 84.0% (81.8%-85.9%) and 74.5% (72.4%-76.5%) during Omicron period. Among the Belgian population aged 65 years and older, we estimated 12,806 deaths averted (11,633- 13,982), representing a 54% reduction (51%-56%) in the expected deaths (without vaccination). During the Delta period COVID-19 deaths were reduced by 68%, during Omicron by 54% and during Alpha by 31%.DiscussionVaccinating against COVID-19 reduced deaths by 54% among the Belgian population aged 65 years and older, underscoring the importance of COVID-19 vaccines in reducing mortality.
Toward Localizing Psychosis in Pathologically Confirmed Neurodegenerative Disease
Authors: Breithaupt Andrew G. , Naasan Georges , Shdo Suzanne M , Lopez Lucia , Spina Salvatore , Grinberg Lea , Seeley William W , Gorno-Tempini Maria Luisa , Rabinovici Gil , Kramer Joel H. , Rosen Howard J. , Miller Bruce L , Rankin Katherine P 
Published: February 2025

AbstractPsychosis is a common symptom in neurodegenerative diseases that contributes to significant patient and caregiver burden. While neuroimaging studies have implicated various brain regions in psychosis, findings have been inconsistent across different disease entities and psychosis subtypes. This study aimed to identify structural neuroanatomic changes associated with specific patterns of psychotic content across pathologically confirmed neurodegenerative diseases. We examined 283 autopsy-confirmed neurodegenerative disease cases (70 with psychosis) at a tertiary medical center, representing diverse clinical syndromes and pathologies. Psychotic content was systematically classified using standardized criteria. Voxel-based morphometry analyses of MRI were conducted to identify structural correlates of psychotic features across all syndromes, within specific clinical syndromes, and within pathological subtypes. Overall, delusions were associated with atrophy in the right temporal lobe and bilateral frontal lobes, particularly when the delusions were persecutory or paranoid. Together, these regions support processing of external stimuli, reward, emotion, self-awareness, and executive function. By contrast, misidentification delusions correlated with right ventral temporal-occipital atrophy, implicating selective disruption of ventral visual stream processing. No consistent patterns of atrophy were found with hallucinations. Our findings suggest that damage to temporal and frontal subregions predisposes individuals with neurodegeneration to develop delusions across clinical syndromes and pathologies. This study provides support for the theory that dysfunction in brain circuits supporting reward, emotion, self-awareness, processing of external sensory signals, and executive functioning can lead to new-onset delusional beliefs in neurodegenerative disease. These insights suggest shared mechanisms between “neurologic” and “psychiatric” disorders that could inform future prognostic and therapeutic approaches.
Longitudinal epigenetic rewiring in lung immune cells in patients with post-COVID-19 condition
Authors: Nikesjö Frida , Smiljanic Jelena , Sayyab Shumaila , Martínez-Enguita David , Gustafsson Mika , Rosvall Martin , Hedman Kristofer , Lerm Maria 
Published: February 2025

AbstractBackgroundPost-COVID-19 condition (PCC) affects millions globally, presenting as persistent multisystem symptoms. Despite various hypotheses, the biological mechanisms underlying PCC remain unclear. Previous studies have linked PCC to alterations in the DNA methylome of blood immune cells, but the effects on lung cells over time remain unknown.MethodsPatients (n=13) with persistent symptoms following COVID-19 in 2020-2021 donated blood and sputum samples at inclusion and after one year. Symptom and physiological testing data were collected concurrently. DNA methylation (DNAm) profiles were analysed longitudinally and compared to pre-pandemic DNAm data from healthy controls.ResultsWhile peripheral blood mononuclear cells (PBMCs) showed no significant changes, longitudinal DNAm changes were observed in neutrophil- and macrophage-enriched fractions. The changes were significantly associated with symptoms and physiological measures. Pathway analysis showed enrichment for cellular processes involved in cardiac function.ConclusionsWe identified longitudinal DNAm changes in lung immune cells associated with pathways linked to cardiac function. These changes correlate with symptom burden and heart and lung metrics. The results suggest potential disease mechanisms and aid the development of diagnostic tools.
Machine Learning Models for Dynamic Assessment of Extubation Readiness in Pediatric Critical Care
Authors: Liu Yuxuan , Cuevas-Asturias Sofia , Alexander Emma C , Ormond Jake , Aw Tuan Chen , Aramburo Angela , Ray Samiran , Faisal A. Aldo , Ramnarayan Padmanabhan 
Published: February 2025

AbstractImportanceDetermining the optimal timing for extubation in critically ill children remains challenging, with premature extubation leading to increased morbidity and mortality, while prolonged ventilation exposes patients to ventilator-associated complications.ObjectiveTo develop and validate machine learning models for dynamic assessment of extubation failure risk (nowcasting) and extubation readiness (forecasting) in mechanically ventilated children.Design, Setting, and ParticipantsRetrospective cohort study using electronic health records from two pediatric intensive care units in London, UK (2013-2022), including 3,815 ventilation episodes in children aged 0-17 years.Exposure(s)Mechanical ventilation via endotracheal tube using pressure control-BIPAP (PC) or spontaneous pressure support CPAP (PS) modes.Main outcomes and measuresPrimary outcomes were extubation failure (requiring reintubation within 48 hours) and extubation readiness (successful extubation within 12 hours). Both models incorporated demographic, physiological, ventilation, and medication data, with varying historical context lengths to optimize prediction accuracy.ResultsThe median age of children in the study cohort (n=3815 ventilation episodes) was 8.0 months (56.2% male); extubation failure occurred in 315/3815 (8.3%). The nowcasting model achieved an area-under-the-receiver-operating-characteristic curve (AUROC) of 0.77. The forecasting model reached an AUROC of 0.85. Ventilation parameters dominated the nowcasting model, while medication response and patient characteristics drove the forecasting model.Conclusions and RelevanceOur dual-model approach offers a structured framework for extubation decision-making in critically ill children, combining continuous monitoring of readiness with snapshot assessment of extubation failure risk. Prospective validation is needed; however, this strategy may help clinicians optimize the timing of ventilation liberation within pediatric intensive care.
Feasibility and acceptability of collecting passive phone usage and sensor data via Apple SensorKit
Authors: Funk Courtney , Zhao Zhuo , Horwitz Adam G. , Fang Yu , Pereira-Lima Karina , Kheterpal Vik , Sen Srijan , Frank Elena 
Published: February 2025

AbstractPrivacy is a growing concern in mobile health research, particularly regarding passive data. Apple SensorKit provides a novel platform for collecting phone and wearable usage and sensor data, however the acceptability and feasibility of collecting these sensitive data to research subjects remains unknown. We piloted the SensorKit platform with a large sample of first-year U.S. medical residents as part of the longitudinalIntern Health Study. Findings demonstrate that successful enrollment and retention rates can be achieved in a longitudinal e-Cohort study that collects SensorKit data, however lower opt-in rates among racial minorities suggest the need for further evaluation of the equity implications around specific data types in mobile health research.
Striatal and cerebellar interactions during reward-based motor performance
Authors: Lee Joonhee Leo , Casamento-Moran Agostina , Bastian Amy J , Cullen Kathleen E , Chib Vikram S 
Published: February 2025

AbstractGoal-directed motor performance relies on the brain’s ability to distinguish between actions that lead to successful and unsuccessful outcomes. The basal ganglia (BG) and cerebellum (CBL) are integral to processing performance outcomes, yet their functional interactions remain underexplored. This study scanned participants’ brains with functional magnetic imaging (fMRI) while they performed a skilled motor task for monetary rewards, where outcomes depended on their motor performance and also probabilistic events that were not contingent on their performance. We found successful motor outcomes increased activity in the ventral striatum (VS), a functional sub-region of the BG, whereas unsuccessful motor outcomes engaged the CBL. In contrast, for probabilistic outcomes unrelated to motor performance, the BG and CBL exhibited no differences in activity between successful and unsuccessful outcomes. Dynamic causal modeling revealed that VS-to-CBL connectivity was inhibitory following successful motor outcomes, suggesting that the VS may suppress CBL error processing for correct actions. Conversely, CBL-to-VS connectivity was inhibitory after unsuccessful motor outcomes, potentially preventing reinforcement of erroneous actions. Additionally, interindividual differences in task preference, assessed by having participants choose between performing the motor task or flipping a coin for monetary rewards, were related to inhibitory VS-CBL connectivity. These findings highlight a performance-mediated functional network between the VS and CBL, modulated by motivation and subjective preferences, supporting goal-directed behavior.
Immunomodulation of Pancreatic Cancer via Inhibition of SUMOylation and CD155/TIGIT Pathway
Authors: de la Torre Medina Jorge , Joshi Utsav , Sonowal Himangshu , Kuang Yixuan , Ren Tianchen , Chen Dai-Hua , Tharuka Mohottige Don Neranjan , Nguyen-Ta Kim , Gros Hélène , Mikulski Zbigniew , Chen Yuan , White Rebekah R. 
Published: February 2025

AbstractPancreatic ductal adenocarcinoma (PDAC) is the deadliest major cancer and has a profoundly immunosuppressive tumor microenvironment (TME). Previous studies have shown that inhibition of the E1 enzyme, which catalyzes the small ubiquitin-like modifiers (SUMO), with the small molecule TAK-981, can reprogram the TME to enhance immune activation and suppress tumor growth. We found that the CD-155/TIGIT pathway, a key regulator of immune evasion in PDAC, is influenced by SUMOylation. We hypothesized that the combination of SUMO E1 and TIGIT inhibition would synergistically induce anti-tumor immune effects. We used a clinically relevant orthotopic mouse model that consistently develops liver metastases to study this combination therapy alone and in the perioperative setting with surgical resection. The combination of SUMO E1 and TIGIT inhibition significantly prolonged survival. Complete responders exhibited protective immunity and enhanced T cell reactivity to model-specific alloantigens. Complementary immune analyses of resected tumors demonstrated that combination therapy more significantly reduces the abundance of regulatory FOXP3+CD4+ T cells than each monotherapy alone. The findings suggest that SUMO E1 inhibition enhances antibody-mediated elimination of Tregs through innate immune cells, potentially by activation of type I interferon responses. Our results highlight a mechanism to enhance the efficacy of anti-TIGIT therapy.Brief SummarySUMOylation is a post-translational modification process critical for cancer. Inhibition of SUMOylation can improve the sensitivity of pancreatic cancer to immune checkpoint inhibition.
Identifying JNK-regulated phosphoproteome markers of anxiety-like behaviour in mouse hippocampus
Authors: Hong Ye , Siino Valentina , Flinkman Dani , Deshpande Prasannakumar , Martinez Sylvia Ortega , Fagerholm Veronica , Varidaki Artemis , Heemeryck Pierre , Sourander Christel , James Peter , Coffey Eleanor 
Published: February 2025

AbstractJNKs mediate neuronal damage in neurodegenerative disease and inhibitors of JNK1 have shown anxiolytic and anti-depressive effects in mice. Here, we analyze the phosphoproteomes of hippocampus and nucleus accumbens from DJNKI-1 (JNK inhibitor)-infused mice. We correlate phospho-site changes with anxiety-like behaviours in the elevated plus maze and light-dark test and identify unique changes in responder mice. Among the DJNKI-1 regulated phosphosites, several lie within GSK3 motifs and are exclusively down-regulated. Consistent with this, GSK3β is inhibited and AKT activated. Importantly, we detect multilevel regulation of glucose metabolism enzymes including increased PDPK1-S241 phosphorylation, and a 5-fold increase in pyruvate dehydrogenase (PDHA1)-S-293 phosphorylation, signifying its inhibition. This suggests that JNK inhibitor drives a metabolic transformation to the neuronal Warburg response. This and a range of identified synaptic and cytoskeletal protein phosphosite changes are discussed in the context of JNK-regulated anxiety responses. The annotated hippocampal and nucleus accumbens phosphoproteomes described here will support a mechanistic understanding of the JNK pathway for future studies of brain disorders.
Whole-body Bacteriophage Distribution Characterized by a Physiologically based Pharmacokinetic Model
Authors: Echterhof Arne , Dharmaraj Tejas , Blankenberg Patrick , Targ Bobby , Bollyky Paul L. , Smith Nicholas M. , Blankenberg Francis 
Published: February 2025

AbstractIn 2019 there were over 2.8 million cases of antibiotic-resistant bacterial infection in the US with gram negative organisms having up to a 6% rate of mortality. Bacteriophage (phage) therapy holds great promise to treat such infections. However, the biologic features which influence the pharmacokinetics (PK) of phage have been difficult to characterize due to a lack of standardized protocols of phage purification, tissue assay, and labeling. Here we present robust methods for ultrapure phage preparation as well as non-destructive highly stable attachment of radio-iodide to phage using the well described Sulfo-SHPP linker. We purified and radiolabeled the phage strains, PAML-31-1, OMKO1, and Luz24 lytic to drug-resistant Pseudomonas aeruginosa for biodistribution assay in normal young adult CD-1 mice injected via penile vein. Groups of 5 mice were euthanized and tissues/organs removed for weighing and scintillation well counting of I-125 activity at 30 min, 1h, 2h, 4h, 8h, and 24h. A physiologically based PK (PBPK) model was then constructed focusing on compartments describing blood, lung, muscle, bone, liver, stomach, spleen, small intestines, large intestines, and kidney. Model permeability coefficient (PS) was estimated across all organs as being 0.0227. Tissue partition coefficients (KP) were estimated for high perfusion organs (lung and kidney) as 0.000138, GI organs (liver, spleen, and stomach) as 0.627, and all other organs as 0.220. Elimination was governed by MPS-mediated elimination (TMPS,deg) and active secretion at epithelial barriers (CLActive), which were estimated as 0.00301 h and 0.0145 L/h/kg, respectively. Monte Caro simulations showed that the rapid elimination phage in humans is expected, resulting in phage blood concentrations being lower than 102PFU/mL (limit of quantification by plaque assay) by 12 hours. As such, multi-dose regimens and continuous infusion regimens were the only strategies that allowed continuously detectible phage concentrations. Evaluation of different dose levels showed that at a maximum dose of 1012PFU, phage concentrations are expected to be approximately 107PFU/g. Our physiologically based PK model of phage represents the first rigorous pre-clinical assessment of phage PK utilizing contemporary pharmacometric approaches amenable to both pre-clinical and clinical study design.
HP-Bodies – Ancestral Condensates that Regulate RNA Turnover and Protein Translation in Bacteria
Authors: Guan Jian , Hurto Rebecca Lee , Rai Akash , Azaldegui Christopher A. , Ortiz-Rodríguez Luis A. , Biteen Julie S. , Freddolino Lydia , Jakob Ursula 
Published: February 2025

SUMMARYUncovering what drives select biomolecules to form phase-separated condensatesin vivoand identifying their physiological significance are topics of fundamental importance. Here we show that nitrogen-starvedEscherichia coliproduce long-chain polyphosphates, which scaffold the RNA chaperone Hfq into phase-separating high molecular weight complexes together with components of the RNA translation and processing machinery. The presence of polyphosphate within these condensates, which we termed HP-bodies, controls Hfq function by selectively stabilizing polyadenylated RNAs involved in transcription and protein translation, and promoting interactions with translation- and RNA-metabolism-associated proteins involved inde novoprotein synthesis. Lack of polyphosphate prevents HP-body formation, which increases cell death and significantly hinders recovery from N-starvation. In functional analogy, we demonstrate that polyP contributes specifically to the formation of Processing (P)-bodies in human cell lines, revealing that a single, highly conserved and ancestral polyanion serves as the universal scaffold for functional phase-separated condensate formation across the tree of life.
mRNA stability factor HuR promotes immune evasion in pancreatic ductal adenocarcinoma
Authors: Guo Yifei , Finan Jennifer M. , Bartlett Alexandra Q. , Sivagnanam Shamilene , Blise Katie E. , Kirchberger Nell , Betre Konjit , Hawthorne Kevin , Chen Canping , Grossberg Aaron , Xia Zheng , Coussens Lisa M. , Sears Rosalie C. , Brody Jonathan R. , Eil Robert 
Published: February 2025

ABSTRACTThe tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is characterized by a limited infiltration of tumor-specific T cells and anti-tumor T cell activity. Extracellular factors in the PDAC TME have been widely reported to mediate immune suppression, but the contribution from tumor-intrinsic factors is not well understood. The RNA-binding protein, HuR (ELAVL1), is enriched in PDAC and negatively correlates with T cell infiltration. In an immunocompetent Kras-p53-Cre (KPC) orthotopic model of PDAC, we found that genetic disruption of HuR impaired tumor growth. Importantly, we found that HuR depletion in tumors enhanced both T cell number and activation states. Mechanistically, HuR mediated the stabilization of mTOR pathway transcripts, and inhibition of mTOR activity rescued the impaired function of local T cells. Phenotypically, we found that HuR induced T-cell suppression in PDAC, as HuR depletion sensitize PDAC tumors to immune checkpoint blockade, while isogenic, wildtype tumors are resistant. Our findings describe a novel role of HuR in facilitating tumor immune suppression in the PDAC TME by inhibiting T cell infiltration and function, and implicate HuR inhibition as a potential therapeutic combination with immunotherapy.SIGNIFICANCEThis study identified a novel mechanism that HuR supports pancreatic tumor growth by restricting T cell infiltration, promoting immune evasion. Our work supports targeting strategies against HuR in PDAC with the goal of enhancing PDAC sensitivity to immune-based cancer therapies, such as checkpoint blockade and T cell transfer.