bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of Sarm1 Mitigates Axonal Degeneration and Promotes Neuronal Repair After Ischemic Stroke
Authors: Wang Jack T. , Toh Brian , An Jennifer , Komuro Yutaro , Godoy Marlesa I. , Putman Jennifer , Carmichael S. Thomas , Damoiseaux Robert , Hinman Jason D. 
Published: February 2025

ABSTRACTAxonal degeneration is a core feature of ischemic brain injury that limits functional recovery (1). The pro-degenerative molecule Sarm1 is required for Wallerian axon degeneration after traumatic and chemotoxic nerve injuries (2), however it is unclear if a similar mechanism mediates axonal degradation after ischemic injury. Here we show that loss of Sarm1 results in profound attenuation of axonal degeneration after focal ischemia to the subcortical white matter. Moreover, absence of Sarm1 significantly promotes the survival of neurons remote from but connected to the infarct after ischemic injuries to the subcortical white matter as well as to the cortex. To further understand the mechanism ofSarm1-/-mediated neuronal protection, we performed differential gene expression analyses of wildtype andSarm1-/-stroke-injured neurons and found that the loss of Sarm1 activates a pro-growth molecular program that promotes new axon and synapse formation after white matter ischemia. Using a functional genomics approach to recapitulate such a molecular program inSarm1-/-neurons, we identify molecular compounds sufficient to enhance cortical neurite outgrowthin vitro, and all of which elicit a conserved epigenetic signature promoting axonogenesis. These results indicate that Sarm1 promotes axonal degeneration and concurrently inhibits an axonal reparative program encoded at the level of the epigenome that can be modulated pharmacologically. Our findings thus reveal a novel role for Sarm1 as a crucial regulator of both axonal degeneration and axonal remodeling after ischemic stroke.SIGNIFICANCE STATEMENTAxon degeneration is a pivotal event following ischemic stroke, however the mechanism of white matter loss in stroke is unknown. We demonstrate that the pro-degenerative molecule Sarm1 is required for axonal and neuronal degeneration after ischemic injuries, and that loss of Sarm1 surprisingly induces the activation of a reparative program driving new axon and synapse formation. Using functional genomics, we uncover molecular candidates that phenocopy this pro-growth molecular signature inSarm1-/-neurons, and show that these compounds are sufficient to promote de novo axonal growth via an epigenetic mechanism. Our results thus reveal a novel role for Sarm1 as a regulator of both axonal degeneration and axonal remodeling after ischemia, and identify pharmacologic candidates to promote axonal repair in stroke.
PARP inhibitors affect the replisome and replication fork progression during a single S phase
Authors: Briu Lina-Marie , Maric Chrystelle , Valentin Nicolas , Panara Nicolas , Chevreux Guillaume , Baldacci Giuseppe , Cadoret Jean-Charles 
Published: February 2025

ABSTRACTPoly(ADP-ribosyl)ation (PARylation) is a protein modification mostly synthesised and degraded by PARP1/2 and PARG enzymes, respectively. PARylation is involved in many covalent and non-covalent protein-protein interactions in the nucleus, making it a powerful form of molecular signaling in DNA metabolism. PARP inhibitors (PARPi) have shown efficacy in the treatment of Homologous Recombination (HR)-deficient cancers, yet the full range of molecular mechanisms underlying the activity of these drugs is not fully understood. Here, we decipher the direct consequences of PARPi-induced loss of PARylation on DNA replication. First, PARPi treatment during a single S phase induces replicative stress, delays S phase progression and causes genome-wide replication timing changes of disease-associated regions. These DNA replication alterations appear to be caused by an accumulation of SSBs in the DNA replicative template when PARylation is inhibited, which then seems to lead to one-ended DSBs and fork collapse during S phase. Second, PARPi deplete FANCD2-I, BRCA, monoubiquitinated PCNA and RAD18 proteins from the replisomes. The two PARPi tested then appear to modulate the choice of fork restart mechanisms and influence replisome dynamics in different ways. Taken together, our study highlights the common and unique primary effects of two PARPi on unperturbed DNA replication in human cells.GRAPHICAL ABSTRACT
Morphine self-administration induces region-specific brain volume changes and microglial phenotypic alterations without affecting neuronal density in male Wistar rats
Authors: Elizarrarás-Herrera Ana Débora , Medina-Sánchez David , Serrano-Ramírez Mariana Stefania , Angeles-Valdez Diego , Trujillo-Villarreal Luis A. , Carbajo-Mata María Antonieta , Carranza-Aguilar César J. , Garza-Villarreal Eduardo A. 
Published: February 2025

AbstractAddiction to opioids, including morphine, is a major public health crisis in the U.S. It has been associated with brain volume changes in reward-related regions, neuronal death, and neuroinflammation. However, the link between structural changes and neuroinflammation is not well understood. In this study, we used operant conditioning to induce morphine self-administration in rats and examined brain volume and cellular changes, focusing on microglial phenotypes. Male Wistar rats were conditioned to morphine self-administration (0.01 mg/kg) for 20 days under a fixed-ratio 1 schedule. In vivo structural Magnetic Resonance Imaging (MRI) scans were conducted at the beginning and end of self-administration. Brains were stained for Iba1 and NeuN proteins, and confocal images were analyzed for cell counts and microglial morphology. We used Deformation-Based Morphometry for MRI volume analysis and Principal Component Analysis with K-means clustering for microglial phenotyping. Our results showed that morphine self-administration led to volume changes in addiction-related brain regions, including increased globus pallidus and decreased insular cortex volume. Additionally, morphine caused widespread neuroinflammation, evidenced by elevated microglial density in the caudate-putamen, dentate gyrus, globus pallidus, and insular cortex, without affecting neuron counts. Finally, we observed region-specific variations in microglial phenotypes, suggesting region-specific neuroinflammatory roles. In conclusion, our study shows that morphine self-administration induces structural and microglial changes in addiction-related brain regions without neuronal loss, highlighting the role of neuroinflammation in opioid-induced adaptations. The variability in microglial phenotypes underscores their complexity, emphasizing the need to study their progression in addiction and their potential as therapeutic targets.
Dopaminergic Modulation of Short-Term Associative Memory inCaenorhabditis elegans
Authors: McMillen Anna , Minervini Caitlin , Green Renee , Johnson Michaela E. , Ansaar Radwan , Chew Yee Lian 
Published: February 2025

AbstractForgetting, the inability to retrieve previously encoded memories, is an active process involving neurotransmission, second messenger signalling, and cytoskeletal modifications. Forgetting is thought to be essential to remove irrelevant memories and to increase the capacity to encode new memories. Therefore, identifying key regulators of active forgetting is crucial to advance our understanding of neuroplasticity. In this study, we utilised the compact and tractableCaenorhabditis elegansmodel to investigate the role of the neurotransmitter dopamine in forgetting. We conducted butanone associative learning assays based on an established protocol and used mutant strains deficient in dopamine synthesis (tyrosine hydroxylase CAT-2 and dopamine transporter DAT-1) and signalling (G protein-coupled receptors DOP-1, DOP-2, and DOP-3) to assess the impact on learning and memory retention. Learning was measured immediately post-training, and memory retention was evaluated every 0.5 hours up to 2 hours. Our results show that animals lacking dopamine display a modest enhancement in learning relative to wild-type, with the learned association persisting for at least 2 hours after training. We also found that the D2-like receptors DOP-2 and DOP-3 function together to modulate the forgetting process, with D1-like receptor DOP-1 having an antagonistic effect. Furthermore, re- expression of CAT-2 tyrosine hydroxylase in ADE or CEP neurons showed that dopamine synthesis in both neuron types is essential for short-term memory retention, albeit at different time points after learning. These findings highlight the critical role of dopamine in forgetting, consistent with findings inDrosophila, and suggest potential relevance for understanding memory retention during healthy ageing and in conditions with dopamine imbalances such as Parkinson’s disease.
Comparison of Nanopore with Illumina Whole Genome Assemblies of the Epstein-Barr Virus in Burkitt Lymphoma
Authors: Kim Isaac E. , Fola Abebe A. , Puig Enrique , Maina Titus K. , Hui Sin Ting , Ma Hongyu , Zuckerman Kaleb , Agwati Eddy , Leonetti Alec , Crudale Rebecca , Luftig Micah A. , Moormann Ann M. , Oduor Cliff , Bailey Jeffrey A. 
Published: February 2025

ABSTRACTEndemic Burkitt lymphoma (eBL) is one of the most prevalent cancer in children in sub-Saharan Africa, and while prior studies have found that Epstein-Barr virus (EBV) type and variation may alter the tumor driver genes necessary for tumor survival, the precise relationship between EBV variation and EBV-associated tumorigenesis remains unclear due to lack of scalable, cost-effective, viral whole-genome sequencing from tumor samples. This study introduces a rapid and cost-effective method of enriching, sequencing, and assembling accurate EBV genomes in BL tumor cell lines through a combination of selective whole genome amplification (sWGA) and subsequent 2-tube multiplex polymerase chain reaction along with long-read sequencing with a portable sequencer. The method was optimized across a range of parameters to yield a high percentage of EBV reads and sufficient coverage across the EBV genome except for large repeat regions. After optimization, we applied our method to sequence 18 cell lines and 3 patient tumors from fine needle biopsies and assembled them with median coverages of 99.62 and 99.68%, respectively. The assemblies showed high concordance (99.61% similarity) to available Illumina-based assemblies. The improved method and assembly pipeline will allow for better understanding of EBV variation in relation to BL and is applicable more broadly for translational research studies, especially useful for laboratories in Africa where eBL is most widespread.
At-Home Movement State Classification Using Totally Implantable Bidirectional Cortical-Basal Ganglia Neural Interface
Authors: Ramesh Rithvik , Fekri Azgomi Hamid , Louie Kenneth H. , Balakid Jannine P. , Marks Jacob H. , Wang Doris D. 
Published: February 2025

ABSTRACTMovement decoding from invasive human recordings typically relies on a distributed system employing advanced machine learning algorithms programmed into an external computer for state classification. These brain-computer interfaces are limited to short-term studies in laboratory settings that may not reflect behavior and neural states in the real world. The development of implantable devices with sensing capabilities is revolutionizing the study and treatment of brain circuits. However, it is unknown whether these devices can decode natural movement state from recorded neural activity or accurately classify states in real-time using onboard algorithms. Here, using a totally implanted bidirectional neurostimulator to perform long-term, at-home recordings from the motor cortex and pallidum of four subjects with Parkinson’s disease, we successfully identified highly sensitive and specific personalized signatures of gait state, as determined by wearable sensors. Additionally, we demonstrated the feasibility of using these neural biomarkers to drive adaptive stimulation with the classifier embedded onboard the neurostimulator. These findings offer a pipeline for ecologically valid movement biomarker identification that can advance therapy across a variety of diseases.
Delay-related harm: direct and indirect impacts of boarding medical patients in the Emergency Department on the urgent and emergency care pathway. A retrospective observational cohort study
Authors: Howlett Nicholas C , Cameron James A , Wood Richard M 
Published: February 2025

AbstractBackgroundPrevious studies have indicated that crowding within the Emergency Department (ED) is associated with longer lengths of stay in the ED and higher mortality. Boarding, the time patients spend waiting for an inpatient bed after ED assessment, represents a clinically unproductive delay, and occupies scarce ED resources. We aimed to explore the impact of medical patients boarding not only on their outcomes but also indirectly on other patients in the ED and in and awaiting ambulances.MethodsA retrospective cohort study using routine data for 3 EDs in England from June 2021 to May 2024 was performed. Direct outcomes of medical patient boarding time were investigated: inpatient length of stay, 30-day readmission rate and mortality. Indirect outcomes of medical patient boarding levels consisted of time in ED for non-admitted patients, ambulance handover times, and ambulance response times. Regression analysis was used to model each relationship while controlling for other potentially confounding variables.ResultsIn all, data on 223,856 ambulance responses, 117,800 ambulance handovers, 367,985 non-admitted ED patients, and 46,976 medical admissions were studied. Medical patients, covering two-thirds of ED admissions, constituted 82% of total ED boarding time. Regression analysis showed that for a typical 25-bed ED, each additional five medical boarders was associated with an extra 12 and 39 minutes for Category 2 and 3 ambulance response times (p<0.001) and an extra 20 minutes for ambulance handover times (p<0.001). For admitted medical patients, each additional 4 hours of boarding time was associated with an extra 13 hours inpatient length of stay (p<0.001) and a 6% increase in odds of 30-day mortality (p<0.01).ConclusionBoarding of medical patients in the ED is associated with direct harm for those patients, and indirect harms for other patients in the ED and awaiting ambulances.What is already known on this topicA prolonged length of stay in the Emergency Department is known to increase mortality for those patients.What this study addsMedical admissions make up 85% of boarding time in the ED waiting for an inpatient bed. This delay affects them directly with increased mortality, readmission and length of stay. It affects other patients with delayed ambulance offload and ambulance response times for other patients.How this study might affect research, practice or policyThe boarding delay for medical patients in the ED results in a longer inpatient length of stay and therefore fewer beds available for future patients. Stopping this practice would free up much needed hospital capacity, improve ambulance response times, and reduce mortality.
Comparison of methods for characterizing skin pigment diversity in research cohorts
Authors: Lipnick Michael S. , Chen Danni , Law Tyler , Moore Kelvin , Lester Jenna C. , Monk Ellis P. , Hendrickson Carolyn M. , Chou Yu , Hughes Caroline , Behnke Ella , Elmankabadi Seif , Ortiz Lily , Negussie Fekir , Leeb Gregory , Ehie Odinakachukwu , Auchus Isabella , Igaga Elizabeth N. , Bisegerwa Ronald , Okunlola Olubunmi , Bickler Philip , Feiner John , Shmuylovich Leonid 
Published: February 2025

AbstractBackgroundSome pulse oximeters perform worse in people with darker skin, and this may be due to inadequate diversity of skin pigment in device development study cohorts. Guidance is needed to accurately and equitably characterize skin pigment to ensure diversity in research cohorts. We tested multiple methods for characterizing skin pigment to assess comparability and impact on cohort diversity.ObjectivesAssess reliability and comparability of common skin pigment measurement methodsCompare findings from different anatomical sitesDemonstrate that pigment cannot be assumed from US National Institutes for Health (NIH) race categoriesMethodsWe used three subjective methods (perceived Fitzpatrick pFP, Monk Skin Tone MST and Von Luschan VL) and two objective methods (Konica Minolta CM-700d spectrophotometer and Delfin Skin Color Catch DSCC colorimeter) for individual typology angle (ITA), across multiple measurement sites in adults. We calculated ΔE to estimate operator perceptibility thresholds for subjective methods and to determine reproducibility for objective methods. We used each method to categorize participants as ‘light, medium, or dark’ and compared the impact of method selection on cohort diversity.ResultsWe studied 789 participants, with 33,856 assessments. The MST had the widest luminosity range, and VL had the least discernible adjacent categories. With ‘dark’ defined as ITA <-30°, 14% of participants were categorized ‘dark’ as compared to 26% by pFP or 16% by MST. Approximately half of the ‘dark’ cohort had an ITA <-50°. With an ITA threshold <-50°, only 7% of the cohort was categorized as ‘dark.’ When ‘Black or African American’ self-identification was used to define ‘dark’, 23% of the cohort was categorized as such. Each self-assigned NIH race category included a wide range of ITA and subjective scale categories. Both ITA and L* from the KM-700d and DSCC demonstrated strong correlation (⍴ > 0.7).ConclusionCommon methods for skin pigment characterization, especially the use of race or subjective scales, have significant limitations. When applied to the same cohort, different methods yield significantly different results, and some may overestimate diversity. Previously published ITA thresholds for defining ‘dark’ skin are too light and lead to underrepresentation of people with darker skin.
Saccadic Suppression Enhances Saliency of Prey-Like Stimuli in the Optic Tectum
Authors: Soto Giulia , Thomas Carina , Hladnik Tim C. , Dehmelt Florian A. , Hafed Ziad M. , Arrenberg Aristides B. 
Published: February 2025

AbstractSaccadic suppression, a reduction in visual sensitivity around the time of a rapid eye movement, is a robust perceptual phenomenon, extensively studied in primate psychophysics. However, the mechanisms and purpose of saccadic suppression are still debated in the field. Here, we demonstrate saccadic suppression in zebrafish, and trace its origins not only in retinal circuits, but also in downstream visual and motor-related neurons of the optic tectum. Using electrophysiology, we first established that retinal ganglion cells jumpstart saccadic suppression, in a spatial frequency dependent manner. Calcium imaging of the optic tectum, combined with 360° visual stimulation and behavioral tracking, revealed that motor signals enhance peri-saccadic suppression strength up to 0.5 s after the saccade. Notably, vision-mediated saccadic suppression lasts more than 3 s. Suppression strength depends on saccade size. Interestingly, we found much weaker saccadic suppression in the optic tectum for stimuli related to hunting behavior than for behaviorally less relevant global flashes, suggesting a selectivity of saccadic suppression aimed at increasing the salience of particular types of visual stimuli after saccades. These findings demonstrate that saccadic suppression in zebrafish integrates visual and motor signals to optimize sensory processing within neural constraints, providing insights into evolutionarily conserved visual strategies.
A humanized mouse model system mimics prenatal Zika infection and reveals premature differentiation of neural stem cells
Authors: Horvath Allison R. , Abdelmalek Clara M. , Park Eunbin , Alexander Aubrey P. , Maheswaran Sadhana A. , Patel Arnav H. , Patel Nandi G. , Ruan Janet E. , Adeyemo Ademide T. , Li Erin C. , Helmicki Katherine E. , Lin Stephen , Wang Paul C. , Li Zhen , Wang Li , Gordish-Dressman Heather A. , Haydar Tarik F. , Mansour Tamer A. , Kousa Youssef A. 
Published: February 2025

ABSTRACTZika, a mosquito-borne flavivirus, has been found in 87 countries and territories. Global outbreaks peaked in 2016. Prenatal infection of Zika virus was found to be associated with microcephaly, arthrogryposis, intracranial calcifications, fetal growth restriction, and fetal demise. The most severely affected children were diagnosed with congenital Zika syndrome, which impacts thousands worldwide. With no approved treatment or preventative measures for Zika, future viral outbreaks have the potential to cause epidemic levels of prenatal brain injury, as seen over the past 70 years. Therefore, there is a great need for a reliable and clinically translational experimental system that mimics the human condition of prenatal Zika infection. To this end, we developed a humanized, immunocompetent mouse model system of virally induced brain injury from prenatal Zika infection, which ranges from mild to severe. Here, we describe the extent to which this system mirrors the human phenotypic spectrum. Using our thorough preclinical system, we find that prenatal Zika infection of mice impacts survival rate, anthropometric measurements, tissue formation, and neurological outcomes, all of which are typical of prenatal infection. Single-cell RNA sequencing of the Zika-infected cerebral cortex reveals severely disrupted transcriptome profiles and suggests that these injuries are a result of a depletion of neural stem cells. Current and future applications include the identification of genetic or environmental modifiers of brain injury, molecular or mechanistic studies of pathogenesis, and preclinical evaluation of future therapies.
Hyper-ovulation in an ovarian-specific transgenic mouse model
Authors: Muñiz Luis C. , Reilly James , Spigelman Melissa , Molina Carlos A. 
Published: February 2025

ABSTRACTOvulation is a fundamental prerequisite for achieving successful reproduction. In vertebrates, ovulation is controlled by the cyclical action of hormones, particularly the gonadotropins such as follicle stimulating hormone (FSH) and luteinizing hormone (LH). A critical component of the intracellular activity of these two hormones is relayed by the second messenger cAMP. Although it is well established that a family of transcription factors facilitate cAMP mediated gene expression, it remains unknown how these factors directly affect ovulation. In particular, the Inducible cAMP Early Repressor (ICER) has been implicated in the transcriptional repression of FSH inducible genes during folliculogenesis. Here we show, using an ovarian-specific transgenic mouse model that ICER potentiates ovulation. We observed a twofold rate increase in ovulation for transgenic mice when compared to the wild type in response to exogenous gonadotropin treatment. Furthermore, mature cycling transgenic mice display a significantly enhanced ovulation rate compared to the wild-type. The observed changes in ovulation in the transgenic females are accompanied by altered gonadotropins production and gene expression. Most significantly, the expression of inhibin alpha subunit (INHA) was found to be about 5-fold higher in the transgenic mice. These observations may aid in unraveling some of the molecular mechanisms underlying ovulation and be relevant to the development of novel reproductive technologies.Summary SentenceGeneration of an FSH inducible ovarian specific FLAG-ICER-II© Tg Mice results in hyper-ovulation upon gonadotropin stimulation.