bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diverse and Location-Specific Roles of PlexinA2, PlexinA4, and NCAM in Developing Hippocampal Mossy Fibers
Authors: Zhao Xiao-Feng , Kohen Rafi , Van Battum Eljo Y. , Zeng Ying , Zhang Xiaolu , Johnson Craig N. , Wang Karen , Lim Brian C. , Oses-Prieto Juan A. , Rasband Joshua M. , Burlingame Alma L. , Pasterkamp R. Jeroen , Rasband Matthew N. , Giger Roman J. 
Published: January 2025

AbstractMossy fibers (MFs) originate from dentate granule cells and innervate area CA3 of the hippocampus. Upon entry of CA3, MFs partition into two prominent axon bundles, the suprapyramidal tract (SPT) and infrapyramidal tract (IPT) and form lamina specific synaptic contacts in the stratum lucidum (SL) and stratum oriens (SO), respectively. Here we employed new mouse lines to dissect the function of Sema6A and its receptors, PlexinA2 (PlxnA2) and PlxnA4, in developing MFs. InSema6a−/−mice, MF partitioning into SPT and IPT bundles is incomplete and IPT axons in the SO are overextended, while the SPT correctly innervates the SL. Loss of neuronalSema6aresults in defective MF patterning and we show that this involves Sema6A reverse signaling.Plxna4controls MF partitioning, SPT axon bundling and laminar targeting to the SL, as well as IPT length. Many of these defects are replicated in mice deficient for PlxnA4 GAP catalytic activity, underscoring the importance of this GAP domain. MFs are tightly fasciculated inPlxna2−/−mice and fail to separate into SPT and IPT bundles, and defects are significantly reduced in PlxnA2 GAP mutants, highlighting the involvement of GAP-independent signaling events. To further explore the molecular basis of aberrant axon fasciculation, we employed anti-PlxnA2 dependent proximity biotinylation and identified several PlxnA2-associated Ig-CAM family members. We observed a genetic interaction betweenPlxna2andNcam1,but notPlxna4andNcam1, for SPT and IPT formation and positioning in CA3. Together, our studies provide insights into the multifaceted and overlapping, yet distinct, functions of PlxnA family members in orchestrating specific guidance decisions in developing MFs.
Adolescent alcohol consumption produces long term alterations in response inhibition and orbitofrontal-striatal activity in a sex-specific manner
Authors: McCane Aqilah M , Kronheim Lo , Moghaddam Bita 
Published: January 2025

AbstractAlcohol use disorder (AUD) is strongly associated with initiation of drinking during adolescence. Little is known about neural mechanisms that produce the long-term detrimental effects of adolescent drinking. A critical feature of AUD is deficits in response inhibition, or the ability to withhold a reward-seeking response. Here we sought to determine if adolescent drinking affects response inhibition and encoding of neural events by the orbitofrontal cortex (OFC) and dorsomedial striatum (DMS), two regions critical for expression of response inhibition. Adolescent male and female rats were given access to alcohol for four hours a day for five consecutive days. Then, rats were tested in a cued response inhibition task as adolescents or adults while we recorded concomitantly from the OFC and DMS. Adolescent voluntary alcohol drinking impaired response inhibition and increased alcohol drinking in adult male but not female rats. Adolescent alcohol drinking also resulted in sex-specific effects on both unit firing and local field potential measures in the OFC and DMS during premature and correct actions. Collectively, these data suggest sex-specific effects of adolescent alcohol drinking on response inhibition and corresponding alterations in cortical-striatal circuitry.HighlightsModerate adolescent alcohol drinking disrupts adult response inhibitionAction encoding in the OFC and DMS changes after adolescent alcohol drinkingOFC-DMS connectivity is altered in males after adolescent alcohol drinkingAdolescent alcohol drinking promotes increased alcohol intake in adult males
Large Language Model Symptom Identification from Clinical Text: A Multi-Center Study
Authors: McMurry Andrew J. , Phelan Dylan , Dixon Brian E. , Geva Alon , Gottlieb Daniel , Jones James R. , Terry Michael , Taylor David , Callaway Hannah Grace , Mahoharan Sneha , Miller Timothy , Mandl Kenneth D. 
Published: January 2025

AbstractRecognition of patient symptoms is core to medicine, research, and public health. We tested four large language models (LLMs) identifying 11 symptoms of infectious respiratory diseases from emergency department notes (N=204). Each LLM outperformed ICD-10-based identification. GPT-4 had highest tested accuracy, F1 score 91.4% vs. 45.1% for ICD-10. GPT-4 performance in an independent validation cohort (N=308) was even higher with an F1 score of 94.0%.
Psilocybin causes sex, time, and dose dependent alterations in brain signaling pathways
Authors: Barnett J. Hudson , Todd Kennedi T. , Benetatos Joseph , Rabichow Benjamin E. , Gibson Katelin A. , Olney Kimberly C. , Fryer John D. 
Published: January 2025

AbstractPsilocybin is a psychedelic tryptamine that has emerged as a potential candidate for the treatment of a variety of conditions, including treatment resistant depression and post-traumatic stress disorder. Clinical trials which have assessed the efficacy of psilocybin for these conditions report a rapid and sustained improvement in patient- and clinician-rated depression scores. The established mechanism of action for psychedelics such as psilocybin is agonism of the serotonin 2A receptor (5HT2AR), however, the downstream events that mediate their therapeutic effects remain uncertain. As high doses of psychedelics are known to induce strong perceptual alterations, an additional outstanding question is whether subperceptual doses induce similar molecular effects as psychoactive dosages. Here, we report the first analysis of dose- and sex-dependent transcriptional changes in forebrains of female and male mice at 3 timepoints (8 hours, 24 hours, and 7 days) following a single administration of psilocybin at low (0.25 mg/kg) or high (1 mg/kg) doses. Grouped analysis of both sexes reveals dose- and time-dependent transcriptomic alterations. We report more rapid transcriptional changes and attenuation of such changes in females following a single low-dose relative to males treated identically. Females also responded more robustly to high-dose administration relative to males at 8 and 24 hours, with signal attenuation in both sexes by 7 days. A notable observation was the persistent transcriptional effect of low-dose psilocybin at 7 days, which outlasted high-dose changes, and which suggests that low doses may have prolonged biological effects. A myriad of pathways were altered depending on sex and timepoint, but common features included functions related to neuronal differentiation, neurogenesis, and changes in receptor signaling. These data reveal dose- and sex-dependent molecular effects of psilocybin and support previous studies demonstrating its effect on dendritogenesis. Given ongoing clinical interest in psilocybin for treating mental health disorders, our results suggest that these sexually divergent changes should be considered when weighing treatment strategies. Additional consideration should be given to temporal effects of low vs high dosages on gene transcription, especially when timing psilocybin with adjuvant cognitive behavioral therapy.
Synergistic Neural Circuits for Novelty and Goal-Directed Behavior
Authors: Elliott Blake L. , O’Brien Katey , Fain Matthew , Ellman Lauren M. , Murty Vishnu P. 
Published: January 2025

AbstractThe ability to adapt in a dynamic world relies on detecting, learning, and responding to environmental changes. The detection of novelty serves as a critical indicator of such changes, prompting mechanisms to detect and respond to goal-relevant information. However, neural regions that support novelty detection and learning (hippocampus), salience detection (dopaminergic midbrain [VTA]), and executive function (prefrontal cortex [PFC]) have yet to be described as a sequential process that unfolds over time. Using functional magnetic resonance imaging (fMRI) we explored interactions between the hippocampus, VTA, and PFC in humans performing a novelty-imbued target-detection task. Hippocampal novelty activation predicted subsequent goal-directed VTA activity, enhancing readiness to detect goal-relevant information. Concurrently, goal-directed PFC activation modulated VTA target activation, refining focus on behaviorally significant cues. These circuits function both synergistically and independently, promoting subsequent hippocampal activity. This work provides new insights into how distributed circuits coordinate to optimize adaptive behavior.
Integrating Support Vector Machines and Deep Learning Features for Oral Cancer Histopathology Analysis
Authors: Pham Tuan D. 
Published: January 2025

AbstractThis study introduces an approach to classifying histopathological images for detecting dys- plasia in oral cancer through the fusion of support vector machine (SVM) classifiers trained on deep learning features extracted from InceptionResNet-v2 and vision transformer (ViT) models. The classification of dysplasia, a critical indicator of oral cancer progression, is of- ten complicated by class imbalance, with a higher prevalence of dysplastic lesions compared to non-dysplastic cases. This research addresses this challenge by leveraging the comple- mentary strengths of the two models. The InceptionResNet-v2 model, paired with an SVM classifier, excels in identifying the presence of dysplasia, capturing fine-grained morphological features indicative of the condition. In contrast, the ViT-based SVM demonstrates superior performance in detecting the absence of dysplasia, effectively capturing global contextual information from the images. A fusion strategy was employed to combine these classifiers through class selection: the majority class (presence of dysplasia) was predicted using the InceptionResNet-v2-SVM, while the minority class (absence of dysplasia) was predicted us- ing the ViT-SVM. The fusion approach significantly outperformed individual models and other state-of-the-art methods, achieving superior balanced accuracy, sensitivity, precision, and area under the curve. This demonstrates its ability to handle class imbalance effectively while maintaining high diagnostic accuracy. The results highlight the potential of integrating deep learning feature extraction with SVM classifiers to improve classification performance in complex medical imaging tasks. This study underscores the value of combining comple- mentary classification strategies to address the challenges of class imbalance and improve diagnostic workflows.
Attention-based whole-slide image compression achieves pathologist-level pre-screening of multi-organ routine histopathology biopsies
Authors: Aswolinskiy Witali , van der Post Rachel S , Simons Michiel , Munari Enrico , Campora Michela , Baronchelli Carla , Ardighieri Laura , Vatrano Simona , Nagtegaal Iris , van der Laak Jeroen , Ciompi Francesco 
Published: January 2025

AbstractScreening programs for early detection of cancer such as colorectal and cervical cancer have led to an increased demand for histopathological analysis of biopsies. Advanced image analysis with Deep Learning has shown the potential to automate cancer detection in digital pathology whole-slide images. Particularly, techniques of weakly supervised learning can achieve whole-slide image classification without the need for tedious, manual annotations, using only slide-level labels. Here, we used data from n=12,580 whole-slide images from n=9,141 tissue blocks to train and validate a deep learning approach based on Neural Image Compression with Attention (NIC-A) and show how it can be leveraged to pre-screen (pre)malignant lesions in colorectal and cervical biopsies and to analyze duodenal biopsies for celiac disease. Our NIC-A classifies normal tissue, low-grade dysplasia, high-grade dysplasia and cancer in colon and uterine cervix, and identifies celiac disease in duodenal biopsies. We validated NIC-A for colon and cervix against a panel of four and three pathologists, respectively, on cohorts from two European centers. We show that the proposed approach reaches pathologist-level performance at detecting and classifying abnormalities, suggesting its potential to assist pathologists in pre-screening workflows by reducing workload in digital pathology routine diagnostics.
Minimal Role of Hamstring Hypertrophy in Strength Transfer Between Nordic Hamstring and Stiff-Leg Deadlift: A Blinded Randomized Controlled Trial
Authors: Morin Titouan , Doguet Valentin , Nordez Antoine , Caillet Arnault , Lacourpaille Lilian 
Published: January 2025

ABSTRACTStrength transfer refers to the gain in strength in an untrained exercise resulting from training another exercise. This study aims to determine whether whole and selective hamstring hypertrophy influence the magnitude of strength transfer between the Nordic hamstring exercise (NHE) and the stiff-leg Deadlift (SDL). Using a blinded randomized controlled design, thirty-six resistance-untrained individuals were assigned either to a control group (CON), a NHE group, and a SDL group, the two resistance training programs being performed three times per week for nine weeks. Semimembranosus (SM), semitendinosus (ST), and biceps femoris (BF) hypertrophy was estimated from changes in the muscle volume. Strength transfer was measured by changes in the one-repetition maximum (1RM) of the non-trained exercise. After the resistance training programs, similar and significant whole hypertrophy was observed in both training groups (NHE: 11.4±6.5%, and SDL: 7.0±8.1%). The NHE group and SDL group, however, presented a selective hypertrophy of ST (24.3±10.8%) and SM (11.2±12.7%), respectively. Conversely, no difference in strength transfer was observed between the NHE group (10.7±8.5%) and the SDL group (20.7±15.0%) (p=0.06). Finally, non-significant correlations were found between strength transfer and both whole and selective hamstring hypertrophy (r≤0.3), except for the BF in SDL (r=0.6). We conclude that hamstring hypertrophy has a minimal role in strength transfer in resistance-untrained individuals. These findings suggest that, even in presence of hypertrophy, prevention and rehabilitation programs should include both Nordic hamstring and stiff-leg Deadlift exercises in the same training block to increase hamstring strength across both knee flexion-oriented and hip extension-oriented tasks.
Outer membrane tube formation byFrancisella novicidainvolves extensive envelope modifications and is linked with type VI secretion and alterations to the host phagosomal membrane
Authors: Rashid Maheen , Tachiyama Shoichi , Zhu Shiwei , Zhao Hang , McCaig William D. , Sun Jingchuan , Li Hulin , Liu Jun , Thanassi David G. 
Published: January 2025

ABSTRACTFrancisella tularensisis a Gram-negative, intracellular pathogen that causes the zoonotic disease tularemia. Due to its ease of dissemination and high lethality,F. tularensisis classified as a Tier 1 Select Agent with potential for misuse as a bioweapon. The mechanisms by whichFrancisellareplicates intracellularly and interacts with the host during infection are not well understood.Francisellaproduces spherical outer membrane vesicles (OMV) and novel tubular extensions of its cell surface that are also released extracellularly. These OMV and outer membrane tubes (OMT) containFrancisellavirulence factors and are produced in response to amino acid starvation and during infection of macrophages. To investigate how the OMT are formed, we used cryogenic electron tomography to examine the modelFrancisellaspecies,F. novicida, duringin vitroculture and within the macrophage phagosome. OMT formation involved progressive alterations of the bacterial envelope, resulting in extensions of both the inner and outer membranes. A dynamic cytoplasmic structure was present at the base of the OMT that extended into the tubes during elongation, together with cytoplasmic material. OMT produced within the macrophage phagosome were associated with changes to the phagosomal membrane, suggesting a role in phagosomal escape. Consistent with this, using confocal microscopy, we observed colocalization of theFrancisellatype VI secretion system with the OMT, both within bacteria and in released tubular vesicles. These findings reveal the cellular transformations that occur during membrane tubulation byFrancisellaand provide insights into the function of membrane-derived structures during host-pathogen interactions.
Structural basis for collagen recognition by theStreptococcus pyogenesM3 protein and its involvement in biofilm
Authors: Wojnowska Marta , Wajima Takeaki , Yelland Tamas , Ludewig Hannes , Hagan Robert M. , Watt Grant , Hamaia Samir W. , Bihan Dominique , Malcor Jean-Daniel , Bonna Arkadiusz , Bergsten Helena , Svensson Mattias , Oppegaard Oddvar , Skrede Steinar , Arnell Per , Hyldegaard Ole , Farndale Richard W. , Norrby-Teglund Anna , Schwarz-Linek Ulrich 
Published: January 2025

AbstractThe M protein is an essential virulence factor ofStreptococcus pyogenes, or group A streptococci (GAS), one of the most common and dangerous human pathogens. Molecular and functional characterization of M protein variants and their interactions with host components is crucial for understanding streptococcal pathogenesis and vaccine development. The M3 protein is produced by the prevalentemm3 GAS serotype, which is frequently associated with severe invasive diseases. Here we characterize the interaction of M3 with human collagens through detailed structural and biochemical binding analysis. High-resolution structures of the N-terminal M3 domain in the free state as well as bound to a collagen peptide derived from the Collagen Ligands Collection reveal a novel T-shaped protein fold that presents binding sites complementing the characteristic topology of collagen triple helices. The structure of the M3/collagen peptide complex explains howemm3 GAS and related streptococci, such as the emerging human pathogenStreptococcus dysgalactiaesubsp.equisimilis, can target collagens to enable colonization of various tissues. In line with this, we demonstrate that the M3/collagen interaction promotes enhanced biofilm formation ofemm3 GAS in anemmtype specific manner, which can be inhibited with the recombinant M3 N-terminal domain fragment. Further,emm3 GAS, but not anemm1 strain, are shown to colocalize with collagen in tissue biopsies from patients with necrotizing soft tissue infections, where GAS biofilms are common. This observation is reproduced in organotypic skin models. Together, these data provide detailed molecular insights into an important streptococcal virulence mechanism with implications for the understanding of invasive infections, strategies for treating biofilm and M-protein based vaccine design.
Differential roles of NaV1.2 and NaV1.6 in neocortical pyramidal cell excitability
Authors: Garcia Joshua D. , Wang Chenyu , Banks Emmie , Fenton Timothy , DeKeyser Jean-Marc , Abramova Tatiana V. , George Alfred L. , Ben-Shalom Roy , Hackos David H. , Bender Kevin J. 
Published: January 2025

ABSTRACTMature neocortical pyramidal cells functionally express two sodium channel (NaV) isoforms: NaV1.2 and NaV1.6. These isoforms are differentially localized to pyramidal cell compartments, and as such are thought to contribute to different aspects of neuronal excitability. But determining their precise roles in pyramidal cell excitability has been hampered by a lack of tools that allow for selective, acute block of each isoform individually. Here, we leveraged aryl sulfonamide-based molecule (ASC) inhibitors of NaVchannels that exhibit state-dependent block of both NaV1.2 and NaV1.6, along with knock-in mice with changes in NaV1.2 or NaV1.6 structure that prevents ASC binding. This allowed for acute, potent, and reversible block of individual isoforms that permitted dissection of the unique contributions of NaV1.2 and NaV1.6 in pyramidal cell excitability. Remarkably, block of each isoform had contrasting—and in some situations, opposing—effects on neuronal action potential output, with NaV1.6 block decreasing and NaV1.2 block increasing output. Thus, NaVisoforms have unique roles in regulating different aspects of pyramidal cell excitability, and our work may help guide development of therapeutics designed to temper hyperexcitability through selective NaVisoform blockade.
Targeting de novo cholesterol synthesis in rhabdomyosarcoma induces cell cycle arrest and triggers apoptosis through ER stress-mediated pathways
Authors: Gizaw Nebeyu Yosef , Kolari Kalle , Alitalo Kari , Kivelä Riikka 
Published: January 2025

AbstractRhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, but the outcomes of high-grade RMS patients remain poor, underscoring the critical need for novel therapeutic strategies. Although metabolic pathways in RMS are incompletely characterized, emerging evidence suggests that metabolic adaptations in RMS resemble those in other malignancies. Here, we identify elevated cholesterol biosynthesis driven by the PROX1 transcription factor as a defining feature of RMS. Our findings demonstrate that the cholesterol biosynthesis pathway is essential for RMS cell growth, proliferation, and survival. Blocking this pathway through genetic or pharmacological inhibition of the key cholesterol biosynthesis enzymes significantly impairs RMS cell proliferation, halts cell cycle progression, and triggers apoptosis through activation of endoplasmic reticulum stress pathways. We furthermore validate the critical role of cholesterol biosynthesis in RMS progression in tumor xenograft models, demonstrating that silencing of the DHCR7 gene significantly suppresses tumor growth. Transcriptomic analysis revealed widespread downregulation of cell cycle-related genes following DHCR7 silencing, further supporting the role of cholesterol metabolism in cell cycle regulation. These results highlight the vulnerability of RMS cells to cholesterol biosynthesis inhibition and suggest that targeting this metabolic pathway as a promising therapeutic approach for improving RMS outcomes. Our findings provide a rationale for the development of novel therapies targeted to cholesterol biosynthesis in this aggressive cancer.SignificanceThis study reveals that targeting cholesterol biosynthesis in rhabdomyosarcoma induces ER-stress, apoptosis and cell cycle arrest, highlighting a potential therapeutic strategy for treating this aggressive pediatric cancer.
Heat stress drives transcription of LTR retrotransposons in the regenerative flatwormMacrostomum lignano
Authors: Ustyantsev Kirill , Mouton Stijn , Biryukov Mikhail , Wudarski Jakub , Glazenburg Lisa , Berezikov Eugene 
Published: January 2025

AbstractThe evolutionary arms race between transposable elements (TEs) and their hosts contributes to genomic complexity. As TEs mobilization is deleterious for individual cells and organisms, their activity is restricted. During stress, TEs can be reactivated; however, the exact mechanisms vary. We discovered that in the flatwormMacrostomum lignano, LTR retrotransposons hijack the heat shock response pathway to boost their transcription at elevated temperatures. While it has been well-described in cruciferous plants, this is the first report of this mechanism in animal LTR retrotransposons. Our results suggest a convergent evolution of the heat stress response in LTR retrotransposons from animals and plants.