bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ex Vivo Drug Responses and Molecular Profiles of 597 Pediatric Acute Lymphoblastic Leukemia Patients
Authors: Enblad Anna Pia , Krali Olga , Gezelius Henrik , Lundmark Anders , Blom Kristin , Andersson Claes , Palle Josefine , Frost Britt-Marie , Ryhänen Samppa , Flægstad Trond , Jónsson Ólafur G , Schmiegelow Kjeld , Heyman Mats , Harila Arja , Nygren Peter , Larsson Rolf , Lönnerholm Gudmar , Nordlund Jessica 
Published: December 2024

AbstractEx vivodrug response profiling is emerging as a valuable tool for identifying drug resistance mechanisms and advancing precision medicine in hematological cancers. However, the functional impact of dysregulation of the epigenome and transcriptome in this context remains poorly understood. In this study, we combinedex vivodrug sensitivity profiling with transcriptomic and epigenomic analyses in diagnostic samples from 597 pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients.Ex vivoresistance to antimetabolites (e.g., cytarabine, thioguanine), glucocorticoids (e.g., dexamethasone, prednisolone), and doxorubicin was independently associated with reduced relapse-free survival (RFS, p < 0.05). Molecular profiling identified pre-treatment DNA methylation and gene expression patterns distinguishing resistant from sensitive cases, revealing key drug resistance signatures. These included aberrant expression of genes related to heme metabolism (e.g.ATPV06A) andKRASsignaling (e.g.ABCB1). Notably, we also observed atypical expression of genes usually restricted to T-cells and other immune cells (e.g.,ITK) in resistant BCP-ALL cells. Our findings demonstrate thatex vivodrug response patterns are predictive of clinical outcomes and reflect intrinsic molecular states associated with drug tolerance. This integrative multi-omics approach highlights potential therapeutic targets and underscores the value of functional precision medicine in identifying treatment vulnerabilities in pediatric ALL.Key pointsEx vivodrug response profiling provides predictors of outcome that complement standard clinical risk stratification, identifying high-risk phenotypes not captured by traditional methods.Pre-treatment transcriptional and epigenetic profiles reveal resistance-primed molecular states detectable at diagnosis, mechanisms driving treatment resistance and offer potential therapeutic targets to counteract drug tolerance.
Unique nigral and cortical pathways implicated by epigenomic and transcriptional analyses in a rotenone rat model of Parkinson’s disease
Authors: Tsalenchuk Maria , Farmer Kyle , Castro Sandra , Scheirer Abigail , Ye Yuqian , Greenamyre J. Timothy , Rocha Emily M. , Marzi Sarah J. 
Published: December 2024

AbstractPesticide exposure is increasingly recognised as a potential environmental factor contributing to the onset of idiopathic Parkinson’s disease, yet the molecular mechanisms underlying this connection remain unclear. This study aims to explore how pesticide exposure disrupts key brain regions involved in Parkinson’s disease pathology by reshaping gene regulatory landscapes. Using the well-established rotenone rat model of the disease, we performed H3K27ac ChIP-sequencing to profile active regulatory elements in the substantia nigra and cortex. In this model, rotenone distributes uniformly throughout the brain, and the degree of complex I inhibition is equivalent in cortical and substantia nigra neurons. Despite the uniformity of complex I inhibition, we identified widespread epigenomic differences, with brain region specific acetylation patterns associated with rotenone exposure. We showed consistent changes in transcriptomic activity by RNA-sequencing. Our results indicate there is a strong immune response to rotenone localised to the substantia nigra and highlight an enrichment of immune-related motifs in this brain region, suggesting that the immune response is at least partially driven by gene regulatory mechanisms. We also noted an increase in C1q complement pathway activity in the substantia nigra. In contrast, we identified widespread dysregulation of synaptic function at the gene regulatory level in the cortex of these same rats. Our results highlight a role for gene regulatory mechanisms potentially mediating the effects of pesticide exposure, driving region-specific functional responses in the brain that may contribute to the pathology and selective vulnerability that characterise Parkinson’s disease.
cfos principal cells and interneurons are strongly reactivated by sharp wave ripples
Authors: Javed M. H. , Robles-Hernandez E. M. , Patel R. , Haberl M.G. , da Silva S. Viana 
Published: December 2024

AbstractThe hippocampal formation is central for the learning and consolidation of spatial memories. While it is known that the high-frequency oscillations, called sharp wave ripples, play a critical role for memory processes, it is unclear if they interact with the memory engram and spatial engram cells. Here we identify the effect of these oscillations on engram cells as mice explored two environments over several days. We found that both principal cells and interneurons are part of the cfos-tagged engram. cfos-tagged principal cells, place cells and interneurons are highly reactivated by SWRs, whereas none of the negatively SWR-modulated cells are part of the engram. Together, our findings reveal a critical link between cellular and network mechanisms for memory formation and imply that interneurons play a key role in it.
Single-particle analysis of small extracellular vesicles from the follicular fluid of women undergoing fertility treatments reveals distinct PD-L1+populations
Authors: Bortot Barbara , Di Florio Roberta , Zito Gabriella , Valle Francesco , Brucale Marco , Ricci Giuseppe , Viganò Paola , Biffi Stefania 
Published: December 2024

AbstractIn some cell systems, small extracellular vesicles bearing PD-L1 (PD-L1+sEVs) have been shown to be able to suppress T-cell immunity. We have herein investigated whether a distinct profile of PD-L1+ sEVs exists in human follicular fluid (FF). Single-particle interferometric reflectance imaging sensing combined with a single-particle antibody capture and immunofluorescence labelling were used to determine the expression and colocalization of CD63, CD81, CD9, and PD-L1 in sEVs derived from FF of women undergoing fertility treatments (n=10). In addition, the size distribution of sEVs was investigated via atomic force microscopy. Our data indicate that the bulk of tetraspanin-expressing EVs in human FF are less than 50 nm in size. Tetraspanins and PD-L1 exhibit distinct expression and colocalization profiles at sEV level across all cohort samples. A total of 42%, 46%, and 50% of all the particles captured by anti-CD63, anti-CD81, and anti-CD9 antibodies, respectively, were positive for CD81. PD-L1 was expressed at the highest level on CD9+ sEVs, with an average value of 5% within the cohort. The presence of distinct PD-L1+ sEV subpopulations suggests that they may play a role in regulating the immune response in the follicular microenvironment. Further research is needed to fully understand the functional significance of PD-L1+ sEVs in this context and their potential as biomarkers for predicting fertility outcomes.Abstract Figure
Venomics AI: a computational exploration of global venoms for antibiotic discovery
Authors: Guan Changge , Torres Marcelo D. T. , Li Sufen , de la Fuente-Nunez Cesar 
Published: December 2024

AbstractThe relentless emergence of antibiotic-resistant pathogens, particularly Gram-negative bacteria, highlights the urgent need for novel therapeutic interventions. Drug-resistant infections account for approximately 5 million deaths annually, yet the antibiotic development pipeline has largely stagnated. Venoms, representing a remarkably diverse reservoir of bioactive molecules, remain an underexploited source of potential antimicrobials. Venom-derived peptides, in particular, hold promise for antibiotic discovery due to their evolutionary diversity and unique pharmacological profiles. In this study, we mined comprehensive global venomics datasets to identify new antimicrobial candidates. Using machine learning, we explored 16,123 venom proteins, generating 40,626,260 venom-encrypted peptides (VEPs). Using APEX, a deep learning model combining a peptide-sequence encoder with neural networks for antimicrobial activity prediction, we identified 386 VEPs structurally and functionally distinct from known antimicrobial peptides. Our analyses showed that these VEPs possess high net charge and elevated hydrophobicity, characteristics conducive to bacterial membrane disruption. Structural studies revealed considerable conformational flexibility, with many VEPs transitioning to α-helical conformations in membrane-mimicking environments, indicative of their antimicrobial potential. Of the 58 VEPs selected for experimental validation, 53 displayed potent antimicrobial activity. Mechanistic assays indicated that VEPs primarily exert their effects through bacterial membrane depolarization, mirroring AMP-like mechanisms.In vivostudies using a mouse model ofAcinetobacter baumanniiinfection demonstrated that lead VEPs significantly reduced bacterial burdens without notable toxicity. This study highlights the value of venoms as a resource for new antibiotics. By integrating computational approaches and experimental validation, venom-derived peptides emerge as promising candidates to combat the global challenge of antibiotic resistance.
Delineating sex-dependent and anatomic decline of motor functions in the SOD1G93A mouse model of amyotrophic lateral sclerosis
Authors: Shelest Oksana , Tindel Ian , Lauzon Marie , Dawson Ashley , Ho Ritchie 
Published: December 2024

AbstractThe transgenic SOD1G93A mouse model is the most widely used animal model of amyotrophic lateral sclerosis (ALS), a fatal disease of motor neuron degeneration. While genetic background influences onset and progression variability of motor dysfunction, the C57BL/6 background most reliably exhibits robust ALS phenotypes; thus, it is the most widely used strain in mechanistic studies. In this model, paresis begins in the hindlimbs and spreads rostrally to the forelimbs. Males experience earlier onset, greater disease severity, and shorter survival than females. However, the influence of sex on patterns of declining motor function between forelimbs and hindlimbs as well as among distinct, spinal-innervated muscle groups within each limb are not fully understood. To provide a higher resolution framework of degenerating motor function across the body, we conducted more comprehensive, limb-dependent and independent measures of motor decline over the course of disease. Subsequently, we compared the timing and intensity of these features across sex, and we consider to what extent these patterns are conserved in clinical observations from human ALS patients. We found male mice experienced earlier and less localized onset than females. We also report distinct motor features decline at different rates between sexes. Finally, mice showed differences in correlation between the decline of left- and right-side measures of the hindlimb. Consequently, our findings reinforce and refine the utility of the SOD1 mouse in modeling more highly resolved, sex-specific differences in ALS patient motor behavior. This may better guide preclinical studies in stratifying patients by sex and anatomical site of onset.
Decoding pre-movement neural activity from thalamic LFPs for adaptive neurostimulation in tremor patients
Authors: Plazas Fernando Rodriguez , Simpson Thomas G. , Wehmeyer Laura , Shah Rahul S. , Brannigan Jamie , Hart Michael G. , Andrade Pablo , Morgante Francesca , Visser-Vandewalle Veerle , Pereira Erlick A. , Tan Huiling , He Shenghong 
Published: December 2024

ABSTRACTObjectiveUnderstanding the neural mechanisms underlying movement initiation is crucial for advancing movement-driven adaptive deep brain stimulation therapies for tremor disorders. We investigated the feasibility of decoding pre-movement periods of upper limb movements by machine learning using thalamic local field potentials (LFPs) and scalp electroencephalography (EEG) signals.ApproachData were analysed from 11 patients undergoing deep brain stimulation surgery, employing machine learning models—including logistic regression, gradient-boosted decision trees, and convolutional neural networks—to distinguish rest periods from pre-movement periods.Main resultsOur results demonstrate that early neural correlates can predict movement onset, achieving above-chance decoding performance starting approximately 680 ms before movement execution using thalamic LFPs and 1.09 s using EEGs. Individualized, patient-specific decoders outperformed cross-patient models, reflecting substantial inter-patient variability in neural modulatory patterns. Additionally, multiple frequency bands contributed independently to decoding performance, emphasizing the importance of incorporating a broad spectrum of frequencies rather than relying solely on single canonical bands.SignificanceThese findings underscore the value of personalized, multi-band machine learning approaches in capturing the neural correlates preceding movement. They support the development of adaptive neurostimulation therapies that enhance the effectiveness of clinical interventions through tailored models that account for patient-specific neural activity.
Theory of Mind Variability in Schizophrenia: A Neurodevelopmental Perspective through Neurological Soft Signs and Premorbid Adjustment
Authors: Giralt-López M. , Miret S. , Campanera S. , Moreira M. , Sotero-Moreno A. , Hostalet N. , Lázaro L. , Krebs MO. , Fañanás L. , Fatjó-Vilas M. 
Published: December 2024

ABSTRACTBackgroundTheory of Mind (ToM) is impaired in individuals with schizophrenia (SZ). Given the neurodevelopmental nature of both social cognition and SZ, variations in ToM abilities likely originate early in life. Thus, indirect markers of altered neurodevelopment, such as neurological soft signs (NSS) and premorbid adjustment (PA), may help explain these differences.MethodsThe study included 38 patients with schizophrenia-spectrum disorder (SSD), 26 healthy siblings and 47 controls. ToM was assessed using the Hinting Task (HT). NSS were evaluated with the Neurological Evaluation Scale (NES) and PA with the Premorbid Adjustment Scale (PAS), yielding Social and Academic scores. Intelligence Quotient (IQ) was estimated two subtests of the WAIS-III and Family History (FH) through the Family Interview for Genetic Studies (FIGS).ResultsFirst, patients presented more deficits in two subscales of the NES (motor coordination and sequencing of complex motor acts) than siblings and controls, with siblings performing intermediate in the sequencing subscale (linear mixed models, adjusted for age, sex and IQ). Patients showed worse social PA than siblings during childhood and late adolescence. Second, patients showed poorer HT performance than siblings and controls, but the neurodevelopmental markers did not modulate such differences. Third, within each group, neurodevelopmental vulnerability markers were not associated with ToM performance (linear regression analyses adjusted for age, sex, IQ and FH).ConclusionIn our sample, while patients showed more evidence of neurodevelopmental deviances than siblings and controls, such differences did not contribute to ToM variability, suggesting that they may stem from different neurodevelopment-related pathways.
Intracerebral Hemorrhage Outcomes after Reversal of Subtherapeutic Warfarin: Analysis of Data from GWTG-Stroke
Authors: LacKamp Aaron N. , Weber Jeremy M. , Mac Grory Brian C. , Caye Adrien J. , Stenuf Chaeli , Smith Eric E. , Daniels Justin D. , Barkley Tiffany T , Messe Steven R. , Alhanti Brooke , Sheth Kevin N. , Blanco Rosalia G , Fonarow Gregg C. , Xian Ying , Mangat Halinder S. 
Published: December 2024

AbstractBackgroundCurrent guidelines recommend reversal of warfarin anticoagulation with intracranial hemorrhages. The benefit of reversing subtherapeutic warfarin anticoagulation in acute spontaneous intracerebral hemorrhage (ICH) is uncertain.MethodsAn observational cohort used Get With The Guidelines® Stroke registry between January 2015 and January 2022 to determine association of reversal with outcomes for subtherapeutic anticoagulation (INR 1.5 to 1.9). Exclusions were thrombolytics, direct oral anticoagulants, transferring out, or leaving against medical advice.ResultsThe primary outcome (mRS 0-3 at discharge) was assessed among 1868 patients (mean age 73 years, 42% female), which occurred in 188/894 (21.0%) with reversal and 225/974 (23.1%) without reversal (adjusted odds ratio (aOR) 0.80 [95% CI 0.63-1.005]). Ordinal analysis showed higher odds of mRS 0-4 vs. 5-6 with reversal {52.7% vs 42.5% (aOR 1.21 [1.001, 1.48])}. Outcomes not requiring mRS were analyzed among 2569 patients. Mortality or discharge to hospice was lower with reversal {30.6% vs 41.5% (aOR 0.75 [95% CI, 0.63, 0.89])}. Fewer were ambulatory at discharge {25.8% vs 35.7% (aOR 0.68 [0.54, 0.85])}, fewer discharged to home {18.4% vs 21.7% (aOR 0.79 [0.65, 0.97])}, more discharged to skilled nursing {21.0% vs 15.7% (aOR 1.33 [1.08, 1.65])}, and more discharged to rehabilitation {24.9% vs 18.9% (aOR 1.20 [0.98, 1.47])}. Hospital length of stay was longer {median 6 vs 4 days (adjusted risk ratio (aRR) 1.25 [95% CI, 1.13, 1.37]). There was no difference in venous thromboembolism {2.9% vs 2.3% (aOR 1.47 [0.88, 2.46])}.DiscussionReversal of subtherapeutic warfarin with acute spontaneous intracerebral hemorrhage and INR 1.5 - 1.9 was not associated with improvement in functional outcome based upon discharge mRS 0-3 vs 4-6. Patients that received a reversal agent had 25% lower odds of dying in the hospital or being discharged to hospice, but had a longer hospital stay and were less likely to be fully ambulatory at discharge.
Wireless bioelectronic device for wound healing
Authors: Baniya Prabhat , Tebyani Maryam , Hee Wan Shen , Li Houpu , Asefifeyzabadi Narges , Yang Hsin-ya , Zhu Kan , Keller Gordon , Franco Celeste , Schorger Kaelan , Devarajan Koushik , Barbee Alexie , Hernandez Cristian , Nguyen Tiffany , Lu Fan , Gallegos Anthony , Recendez Cynthia , Isseroff Roslyn Rivkah , Zhao Min , Gomez Marcella , Rolandi Marco , Teodorescu Mircea 
Published: December 2024

AbstractWound healing is a prolonged biological process that goes through multiple phases spanning several weeks. In order to improve wound healing, we introduce a wireless, bioelectronic device that can deliver various treatments for multiple days while continuously monitoring the delivery. Devices are developed for delivery of fluoxetine cations (Flx+) and electric field (EF) in freely moving pigs. The treatments can be controlled and monitored real-time via WiFi, with options for both user specified delivery rate and duration as well as automated closed-loop control. The devices are designed to handle various failure scenarios that can come in dynamic, real-world experiments such as communication and power interruptions so that valuable experimental data can continue to be gathered. The ion pump on the wireless device consists of eight channels, arranged in a circular pattern near the edge of a 20 mm diameter wound, to deliver charged biomolecules such as Flx+. For EF delivery, an additional center reference channel is provided. When the applied voltages at the outer eight channels are higher than the center channel, it results in the applied EF to be in the same direction as the endogenous EF and aids the healing process. The device locally records the applied voltages and currents as a function of time on a microSD card at a high sampling rate while simultaneously sending real-time measurements, via a local WiFi network to a wound healing algorithm, running on a remote laptop. The closed-loop control of current/delivery rate is done by onboard microcontroller unit (MCU) and current sources based on the instructions received from the wound healing algorithm. A graphical user interface (GUI) is developed to provide seamless user control and data viewing capabilities with support for multiple devices. Using immunohistochemistry (IHC) staining, we found that the M1/M2 ratio of a Flx+—treated wound at the edge had improved by 70.2% compared with a control wound, both harvested after three days of wound creation. Similarly, using hematoxylin and eosin (H&E) staining, we found that the re-epithelialization of a Flx+-treated wound had improved by 39.5% compared with a standard-of-care wound, both harvested after seven days of wound creation. Both of these results indicate the potential of the wireless bioelectronic device to improve wound healing.
Stimulation parameters shape effective connectivity pathways: insights from microstate analysis on TMS-evoked potentials
Authors: Lucarelli Delia , Guidali Giacomo , Sulcova Dominika , Zazio Agnese , Bonfiglio Natale Salvatore , Stango Antonietta , Barchiesi Guido , Bortoletto Marta 
Published: December 2024

ABSTRACTTranscranial magnetic stimulation (TMS)-evoked potentials (TEPs) represent an innovative measure for examining brain connectivity and developing biomarkers of psychiatric conditions. Minimising TEP variability across studies and participants, which may stem from methodological choices, is therefore vital. By combining classic peak analysis and microstate investigation, we tested how TMS pulse waveform and current direction may affect effective connectivity when targeting the primary motor cortex (M1). We aim to disentangle whether changing these parameters affects the degree of activation of the same neural circuitry or may lead to changes in the pathways through which the induced activation spreads.Thirty-two healthy participants underwent a TMS-EEG experiment in which the pulse waveform (monophasic, biphasic) and current direction (posterior-anterior, anterior-posterior, latero-medial) were manipulated. We assessed the latency and amplitude of M1-TEP components and employed microstate analyses to test differences in topographies.Results revealed that TMS parameters strongly influenced M1-TEP components’ amplitude but had a weaker role over their latencies. Importantly, microstate analysis showed that the current direction in monophasic stimulations changed the pattern of evoked microstates at the early TEP latencies, as well as their duration and the overall amount of activated brain resources associated.This study shows that the current direction of monophasic pulses may modulate cortical sources contributing to TEP signals, activating neural populations and cortico-cortical paths more selectively. Biphasic stimulation reduces the variability associated with current direction and may be better suited when TMS targeting is blind to anatomical information.