bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differentiating unirradiated mice from those exposed to conventional or FLASH radiotherapy using MRI
Authors: Jansen Jeannette , Kimbler Adam , Drayson Olivia , Lanz Bernard , Mosso Jessie , Grilj Veljko , Petit Benoit , Franco-Perez Javier , Simon Aaron , Limoli Charles L. , Vozenin Marie-Catherine , Stark Craig , Ballesteros-Zebadua Paola 
Published: February 2025

AbstractBackground and purposeThe FLASH effect expands the therapeutic ratio of tumor control to normal tissue toxicity observed after delivery of ultra-high (>100 Gy/s FLASH-RT) vs. conventional dose rate radiation (CONV-RT). In this first exploratory study, we assessed whether ex-vivo Magnetic Resonance Imaging (MRI) could reveal long-term differences after FLASH-RT and CONV-RT whole-brain irradiation.Materials and methodsFemale C57BL/6 mice were divided into three groups: control (non-irradiated), conventional (CONV-RT 0.1 Gy/s), and ultra-high dose rates (FLASH-RT 1 pulse, 5.5 x 10˄6 Gy/s), and received 10 Gy of whole-brain irradiation in a single fraction at 10 weeks of age. Mice were evaluated by Novel Object Recognition cognitive testing at 10 months post-irradiation and were sampled at 13 months post-irradiation. Ex-vivo brains were imaged with a 14.1 Tesla/26 cm magnet with a multimodal MRI protocol, including T2-weighted TurboRare (T2W) and diffusion-weighted imaging (DWI) sequences.ResultsIn accordance with previous results, cognitive tests indicated that animals receiving CONV-RT exhibited a decline in cognitive function, while FLASH-RT performed similarly to the controls. MRI showed decreased hippocampal mean intensity in the CONV-RT mice compared to controls but not in the FLASH-RT group. Comparing CONV-RT to control, we found significant changes in multiple whole-brain diffusion metrics, including the mean Apparent Diffusion Coefficient (ADC) and Mean Apparent Propagator (MAP) metrics. By contrast, no significant diffusion changes were found between the FLASH-RT and control groups. In an exploratory analysis compared to controls, regional diffusion metrics were primarily altered in the basal forebrain and the insular cortex after CONV-RT, and after FLASH-RT, a trend reduction was also observed.ConclusionThis study presents initial evidence that MRI can uncover clear changes in the brain after CONV-RT but not after FLASH-RT. The MRI results aligned with the observed cognitive protection after FLASH-RT, indicating the potential use of MRI to analyze the FLASH response.
Neuro-behavioral impact of Tourette-related striatal disinhibition in rats
Authors: Loayza Joanna , Taylor Charlotte , Renstrom Jacco , Allen Rachel Grasmeder , Jackson Stephen , Bast Tobias 
Published: February 2025

AbstractTourette syndrome has been linked to reduced GABAergic inhibition, so called neural disinhibition, in the dorsal striatum. Dorsal-striatal neural disinhibition in animal models, caused by local microinfusion of GABA-A-receptor antagonists, produces striatal local field potential (LFP) spike-wave discharges and tic-like movements resembling motor tics. Here, we characterized further the neuro-behavioral impact of striatal disinhibition, by unilateral picrotoxin infusion into the anterior dorsal striatum, in adult male Lister hooded rats. In vivo electrophysiology under anesthesia revealed enhanced neuronal burst firing in the striatum, alongside spike-wave LFP discharges. In freely moving rats, striatal picrotoxin reliably induced tic-like movements, which mainly involved lifting of the contralateral forelimb and concomitant rotational movements of head and torso, as well as occasional rotations of the whole body around its long axis. Prepulse inhibition (PPI) of the acoustic startle response was not affected, but startle reactivity tended to be reduced. Both locomotor and non-ambulatory movements, measured in photo-beam cages, were increased. Our findings suggest that, apart from generating tic-like movements, dorsal striatal disinhibition may contribute to hyperactivity, which is often comorbid with Tourette syndrome. Enhanced striatal burst firing may be important for these behavioral effects. Our findings do not support that striatal disinhibition contributes to PPI disruption, which has been associated with Tourette syndrome and suggested to contribute to tic generation.Significance StatementStriatal disinhibition has been implicated in tic generation. Using a rat model, we show that a key neural effect of striatal disinhibition is enhanced firing of striatal neurons in bursts. We also characterized further the tic-like movements caused by unilateral disinhibition of the anterior dorsal striatum. These mainly involved lifting of the contralateral forelimb and concomitant rotational movements of head and torso, as well as occasional rotations of the whole body around its long axis. Striatal disinhibition did not affect prepulse inhibition (PPI) but caused locomotor hyperactivity. This suggests that striatal disinhibition may contribute to the general hyperactivity often comorbid with Tourette syndrome, but that other brain mechanisms underlie the PPI deficits that have been reported in the condition.
The impact of systematized generation, evaluation, and incorporation of machine learning algorithms for clinical variant classification
Authors: Fresard Laure , Facio Flavia M , Chen Elaine , Colavin Alexandre , Johnson Britt , Araya Carlos , Manders Toby , Wahl Alexander , Metz Hillery , Nicoludis Jack , Ouyang Karen , Padigepati Samskruthi , Kobayashi Yuya , Reuter Jason , Nykamp Keith 
Published: February 2025

SummaryVariants of uncertain significance (VUS) pose a significant challenge for those undergoing genetic testing, leading to prolonged uncertainty and inappropriate medical care. VUS rate reduction is critical to fully realize the utility of genetic testing for all populations. With the growth of large-scale biological data sources and modern Machine Learning (ML) techniques, predictive modeling has enormous potential for VUS reduction.For this purpose, we developed the Invitae Evidence Modeling™ Platform (EMP), with key features designed to maximize the utility and confidence of predictive algorithms for variant classification. First, input data for a new model is curated to correspond to a single major evidence category within a variant classification framework. Second, gene-specific training and/or validation is performed for each model type. Third, accuracy thresholds are set to filter out gene-specific models that do not meet stringent accuracy metrics. Finally, prediction scores for variant pathogenicity are calibrated to ensure internally consistent evidence weighting within the classification framework.The EMP has accelerated the development of ML algorithms and greatly expanded the amount of evidence available for variant classification. EMP evidence has been applied to more than 800,000 variants across 1 million individuals, 42% of which would have been VUS without this evidence. Importantly, definitive classifications (P, LP, LB, B) made with EMP evidence have high prospective concordance (>99%) with ClinVar submissions. Finally, we demonstrate that further use and development of EMP evidence for variant classification has the potential to reduce the VUS disparity across race/ethnicity/ancestry (REA) groups.
Radiation exposure induced blood-brain barrier injury via mitochondria-mediated sterile inflammation
Authors: Wang Peng , Liu Jiayue , Zhang Min , Yang Juan , Lian Peihan , Cheng Xiu , Qin Jianhua 
Published: February 2025

AbstractRadiation-induced brain injury (RIBI) is caused by exposure to high doses of ionizing radiation and characterized by severe cognitive dysfunction and brain necrosis. The widespread application of radiotherapy and rapid development of deep space exploration have substantially increased the risk of RIBI. However, the pathogenesis of RIBI is not fully understood, and no effective intervention is available. This work described a blood-brain barrier (BBB) microphysiological system (MPS), that allowed to explore the responses of BBB and distinct brain cells to radiation exposure. This BBB MPS can recapitulate the interface structure and function of BBB in brain microenvironment, including brain endothelial cells, astrocytes, pericytes and microglia co-cultured under flow condition. Following acute exposure to radiation of X-ray or γ-ray, characteristic RIBI-associated pathological responses were observed, including BBB compromise, DNA breaks, inhibited cell proliferation, cell hypertrophy and pro-inflammatory cytokine release. Among the distinctive types of cells, brain endothelial cells showed the highest radiosensitivity as compared to other cells in the MPS. Intriguingly, X-ray and γ-ray radiation consistently induced prominent sterile inflammation responses, especially type I interferon response, in the BBB MPS. These responses were mediated by radiation-induced mitochondrial DNA release and subsequent activation of cGAS-STING signaling pathway. Furthermore, we found abrocitinib (JAK1 inhibitor) and idebenone (mitochondrial protectant) can attenuate radiation-induced inflammation and ameliorate BBB injury. These findings revealed the involvement of mitochondria-mediated inflammation in RIBI pathogenesis, identifying mitochondria as a potential target for new radioprotective measures.
Psilocybin as a Treatment for Repetitive Mild Head Injury: Evidence from Neuroradiology and Molecular Biology
Authors: Brengel Eric K. , Axe Bryce , Maheswari Ashwath , Abeer Muhammad I. , Ortiz Richard J. , Woodward Taylor J. , Walhof Reagan , Utama Rachel , Sawada Courtney , Balaji Shreyas , Kulkarni Praveen P. , Bradshaw Heather B. , Gitcho Michael A. , Ferris Craig F. 
Published: February 2025

AbstractRepetitive mild head injuries incurred while playing organized sports, during car accidents and falls, or in active military service are a major health problem. These head injuries induce cognitive, motor, and behavioral deficits that can last for months and even years with an increased risk of dementia, Parkinson’s disease, and chronic traumatic encephalopathy. There is no approved medical treatment for these types of head injuries. To this end, we tested the healing effects of the psychedelic psilocybin, as it is known to reduce neuroinflammation and enhance neuroplasticity. Using a model of mild repetitive head injury in adult female rats, we provide unprecedented data that psilocybin can reduce vasogenic edema, restore normal vascular reactivity and functional connectivity, reduce phosphorylated tau buildup, enhance levels of brain-derived neurotrophic factor and its receptor TrkB, and modulate lipid signaling molecules.
Sphingosine-1-phosphate signaling through Müller glia regulates neuroprotection and the accumulation of immune cells in the rodent retina
Authors: Taylor Olivia , Kelly Lisa , El-Hodiri Heithem , Fischer Andy J. 
Published: February 2025

AbstractThe purpose of this study was to investigate how Sphingosine-1-phosphate (S1P) signaling regulates glial phenotype, neuroprotection, and reprogramming of Müller glia (MG) into neurogenic MG-derived progenitor cells (MGPCs) in the adult mouse retina. We found that S1P-related genes were dynamically regulated following retinal damage.S1pr1(encoding S1P receptor 1) andSphk1(encoding sphingosine kinase 1) are expressed at low levels by resting MG and are rapidly upregulated following acute damage. Overexpression of the neurogenic bHLH transcription factor Ascl1 in MG downregulatesS1pr1, and inhibition of Sphk1 and S1pr1/3 enhances Ascl1-driven differentiation of bipolar-like cells and suppresses glial differentiation. Treatments that activate S1pr1 or increase retinal levels of S1P initiate pro-inflammatory NFκB-signaling in MG, whereas treatments that inhibit S1pr1 or decreased levels of S1P suppress NFκB-signaling in MG in damaged retinas. Conditional knock-out of NFκB-signaling in MG increases glial expression ofS1pr1but decreases levels ofS1pr3andSphk1. Conditional knock-out (cKO) ofS1pr1in MG, but notSphk1, enhances the accumulation of immune cells in acutely damaged retinas. cKO ofS1pr1 is neuroprotective to ganglion cells, whereas cKO ofSphk1is neuroprotective to amacrine cells in NMDA-damaged retinas. Consistent with these findings, pharmacological treatments that inhibit S1P receptors or inhibit Sphk1 had protective effects upon inner retinal neurons. We conclude that the S1P-signaling pathway is activated in MG after damage and this pathway acts secondarily to restrict the accumulation of immune cells, impairs neuron survival and suppresses the reprogramming of MG into neurogenic progenitors in the adult mouse retina.
Adolescents’ Use of Music for Pain Management
Authors: Lepping Rebecca J. , Black Lora L. , Kline Kymberly A. , Hanson-Abromeit Deanna , Chadwick Andrea L. , Wallace Dustin P. , Black William R. 
Published: February 2025

AbstractTo investigate the experiences of adolescents with chronic pain who participated in an intensive interdisciplinary pain treatment program, this secondary study analyzes the themes that emerged regarding the spontaneous utilization of music in coping strategies for chronic pain. During research interviews focused on coping skills and treatment engagement, participants spontaneously reported using music as an effective coping strategy for managing pain. A deductive thematic analysis revealed key themes related to their usage, including using music as a distractor, motivator and in other ways as coping strategies. Since participants indicated that music is essential to their experiences of coping with pain, incorporating these strategies could improve the effectiveness of treatment protocols. To this end, further investigation is necessary to assess the impact of music on adolescents with chronic pain, focusing on its role in enhancing interdisciplinary treatment.
Mild cognitive impairment cases affect the predictive power of Alzheimer’s disease diagnostic models using routine clinical variables
Authors: Finney Caitlin A. ,   Alzheimer’s Disease Neuroimaging Initiative, Shvetcov Artur 
Published: February 2025

AbstractDiagnostic models using primary care routine clinical variables have been limited in their ability to identify Alzheimer’s disease (AD) patients. In this study we sought to better understand the effect of mild cognitive impairment (MCI) on the predictive performance of AD diagnostic models. We sourced data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. CatBoost was used to assess the utility of routine clinical variables that are accessible to primary care physicians, such as hematological and blood tests and medical history, in multiclass classification between healthy controls, MCI, and AD. Our results indicated that MCI indeed affected the predictive performance of AD diagnostic models. Of three subgroups of MCI that we found, this finding was driven by a subgroup of MCI patients that likely have prodromal AD. Future research should focus on distinguishing MCI from prodromal AD as the utmost priority for improving translational AD diagnostic models for primary care physicians.
Early life phthalate exposure impacts gray matter and white matter volume in infants and young children
Authors: Werder Emily J. , Lu Kun , Liu Chih-Wei , Thistle Jake E. , Rager Julia E. , Li Gang , Wu Zhengwang , Li Tengfei , Wang Li , Sandler Dale P. , Gilmore John H. , Piven Joseph , Zhu Hongtu , Lin Weili , Engel Stephanie M. 
Published: February 2025

AbstractObjectivePrenatal phthalate exposure is associated with adverse neurodevelopmental outcomes, yet data on impacts of early life exposure remains limited. We investigated phthalate and replacement plasticizer exposures from 2 weeks to 7 years of age in relation to brain anatomical attributes, using serial structural magnetic resonance imaging (sMRI).Material and MethodsChildren were enrolled after birth into the UNC Baby Connectome Project, a longitudinal neuroimaging study. Urine samples (n=406) were collected at each visit and analyzed for 17 phthalate and replacement plasticizer metabolites. Among 157 children contributing 369 sMRIs, we calculated metabolite-specific average exposures across each individual’s urine samples and used linear mixed models to estimate longitudinal associations of log transformed, specific gravity-adjusted average metabolite concentrations with gray (GMV) and white matter (WMV), and cortical volume (CV), thickness (CT), and surface area (CSA). We examined sex-specific differences in these associations.ResultsHigher average metabolite concentration was associated with lower GMV (MCPP: (−1.73 cm3, 95% CI: −3.36, −0.10) and higher WMV (∑DEHP: 2.28 cm3, 95% CI: 0.08, 4.48). Among boys (n=72, 140 sMRIs), MEP (−2.97 cm3, 95% CI: −5.85, −0.09) and MiBP (−2.40 cm3, 95% CI: −4.64, −0.15) were also associated with lower GMV. Among girls (n=85, 229 MRIs), higher ∑DINCH exposure was associated with higher WMV (2.27 cm3, 95% CI: 0.29, 4.25). We observed significant sex interactions for ∑DEHP with GMV (p-interaction=0.03) and ∑DINCH with WMV (p-interaction=0.001).ConclusionEarly life phthalate/plasticizer exposure may differentially impact various brain region volumes in early childhood, with potential downstream consequences on functional development.
Estimating prevalence of immunocompromising conditions in Canada in 2022 using an administrative hospital database
Authors: Finès Philippe 
Published: February 2025

AbstractBackgroundImmunocompromising conditions (ICs) are conditions that may be present at different moments in a person’s life and affect their health. In individuals with ICs, the body’s ability to effectively fight infections or mount a robust response to vaccination is weakened. It is thus important to understand the burden of ICs in part to inform public health policies on the procurement of vaccines for this population. However, no estimates of prevalence rates of ICs exist in Canada.ObjectiveOur objective was to address this gap.InterventionWe defined our list of ICs using different published sources and expert opinion. Using diagnoses coded with ICD-10 over a period of 14 years in the Discharge Abstract Database, we were able to estimate prevalence rates of ICs.OutcomeFor all ICs combined and conservatively assuming a hospitalization rate of 0.1, general population prevalence rates is estimated at 1.8% for females and 1.9% for males. Inflammatory bowel disease, severe liver disease and severe cancers are among the most frequent ICs at all age groups and for both genders. Functional asplenia and Primary Immunodeficient conditions are mostly present at young ages. Transplantation and renal dialysis are also among the most frequent ICs.ConclusionThe prevalence of ICs estimated using DAD aligns with estimates obtained using other methods from other countries (2.7–6.6%) under certain assumptions for hospitalization rates. This work serves as the foundation for future investigation into obtaining more precise estimates of prevalence rates of ICs in Canada.
Sex differences in progressive multiple sclerosis brain gene expression in oligodendrocytes and OPCs
Authors: LaBarre Brenna A. , King Devin , Ploumakis Athanasios , Pinzon Alfredo Morales , Guttmann Charles R.G. , Patsopoulos Nikolaos , Chitnis Tanuja 
Published: February 2025

AbstractMultiple sclerosis is a neurological autoimmune disease with sex-imbalanced incidence; in the USA, the disease is more likely to effect females at a ratio of 3:1. In addition, males are more likely to have a more severe disease course at time of diagnosis. Questions about both causes and downstream effects of this disparity remain. We aim to investigate gene expression differences at a cellular level while considering sex to discover fine-scale sex disparities. These investigations could provide new avenues for treatment targeting, or treatment planning based on sex.Public single-nuclei RNA-sequencing data from three publications of progressive MS including control brains were analysed using the Seurat R package. Differential gene and pathway expression was looked at both within a specific data set which has sub-lesion level sample dissection and across all studies to provide a broader lens. This allowed for the consideration of cell types and spatial positioning in relation to the interrogated lesion in some of the calculations.Our analysis showed expression changes in the female MS oligodendrocytes and oligodendrocyte progenitor cells compared to healthy controls, which were not observed in the corresponding male affected cells. Differentially up-regulated genes in females include increased HLA-A in the oligodendrocytes, and increased clusterin in the oligodendrocyte progenitor cells. There are also several mitochondrial genes in both the oligodendrocytes and oligodendrocyte progenitors which are up-regulated in females, including several directly involved in electron transport and which have previously been associated with neurodegenerative diseases.These results point to altered states in oligodendrocyte progenitors and oligodendrocytes that in combination with known physiological dissimilarities between sexes may denote different programming in males and females in response to the onset of demyelinating lesions. The potential for increased debris clearance mediated by clusterin and availability of oligodendrocyte progenitors in females may indicate an environment more primed for repair, potentially including remyelination. This could contribute to the disparity in etiology in females versus males.
In the brain of the beholder: whole brain dynamics shape the perception during ambiguous motion
Authors: Pizzuti Alessandra , Acero Pousa Irene , Gulban Omer Faruk , Peters Judith , Deco Gustavo , Goebel Rainer 
Published: February 2025

AbstractVisual perception is typically based on a one-to-one mapping between stimuli and conscious experiences. However, under bistable conditions, identical sensory inputs can elicit alternating perceptions, requiring the brain to resolve ambiguity. The mechanisms underlying transitions between distinct perceptual states and their sustained maintenance remain poorly understood. In this ultra-high-field (7T) fMRI study, we investigated the neural dynamics of perception using a bistable motion stimulus (ambiguous motion quartet) that evoked endogenous alternations between horizontal and vertical motion, compared to a control condition (physical motion quartet) with unambiguous sensory input. Consistent with previous findings, the human motion complex (hMT+) played a central role in processing both physical and ambiguous motion conditions. By dissociating neural activity during perceptual transitions from sustained perceptions, we found that hMT+ mostly interacts dynamically with area 46 in the frontal cortex and PF/PFm within the inferior parietal lobe during transitions and with subregions of the superior parietal lobe during sustained perceptions. Beyond local activity, computational modeling revealed an increase in hierarchical organization across cortical networks during the ambiguous condition. In particular, the same frontal and parietal regions exhibited ascension within the functional hierarchy, likely reflecting their specific role in coordinating computations for resolving ambiguity.