bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlates of asymmetric venous drainage in resting state functional magnetic resonance imaging data
Authors: Schwarz Nastaran , Sundermann Benedikt , Mathys Christian 
Published: January 2025

AbstractFunctional magnetic resonance imaging (fMRI) is an indirect technique for measuring cerebral neural activity. It depends on the local cerebral vasculature and perfusion. It has thus been suggested that pathologies and normal variants of the cerebral vasculature can bias conclusions drawn from fMRI. The purpose of this study was to assess whether frequently observed asymmetries of the transverse sinuses are associated with apparent asymmetries of fMRI data timecourses. We re-analysed a publicly available resting state fMRI dataset (n = 135 healthy human subjects included in the main analysis). Voxel-mirrored homotopic connectivity (VMHC) was calculated as a measure of fMRI timecourse symmetry, reflecting the correlation of signal fluctuations in mirroring voxels in both cerebral hemispheres. Transverse sinus (TS) cross-sectional areas were measured in structural MRI data. In the main analysis, we assessed whether VMHC and TS asymmetry exhibited a negative linear association in brain areas near the transverse sinus. This was supplemented by exploratory whole brain analyses, including mapping of subthreshold effects. In the main hypothesis test, VMHC was not significantly associated with TS asymmetry in brain regions close to the transverse sinuses. In the whole brain analyses, VMHC was significantly negatively associated with TS asymmetry in more distant brain areas, and subthreshold effects resembled venous drainage patterns. The results suggest that part of the variance in resting state fMRI signal fluctuations might be explained by asymmetrical venous drainage. Thus, fMRI results might be confounded by the normal variability of the human intracranial venous system.
NutriSighT: Interpretable Transformer Model for Dynamic Prediction of Hypocaloric Enteral Nutrition in Mechanically Ventilated Patients
Authors: Jangda Mateen , Patel Jayshil , Gill Jaskirat , McCarthy Paul , Desman Jacob , Gupta Rohit , Patel Dhruv , Kavi Nidhi , Bakare Shruti , Klang Eyal , Freeman Robert , Manasia Anthony , Oropello John , Chan Lili , Suarez-Farinas Mayte , Charney Alexander W , Kohli-Seth Roopa , Nadkarni Girish N , Sakhuja Ankit 
Published: January 2025

AbstractAchieving adequate enteral nutrition among mechanically ventilated patients is challenging, yet critical. We developed NutriSighT, a transformer model using learnable positional coding to predict which patients would achieve hypocaloric nutrition between days 3-7 of mechanical ventilation. Using retrospective data from two large ICU databases (3,284 patients from AmsterdamUMCdb – development set, and 6,456 from MIMIC-IV – external validation set), we included adult patients intubated for at least 72 hours. NutriSighT achieved AUROC of 0.81 (95% CI: 0.81 – 0.82) and an AUPRC of 0.70 (95% CI: 0.70 – 0.72) on internal test set. External validation with MIMIC-IV data yielded a AUROC of 0.76 (95% CI: 0.75 – 0.76) and an AUPRC of (95% CI: 0.69 – 0.70). At a threshold of 0.5, the model achieved a 75.16% sensitivity, 60.57% specificity, 58.30% positive predictive value, and 76.88% negative predictive value. This approach may help clinicians personalize nutritional therapy among critically ill patients, improving patient outcomes.
Racial/Ethnic Differences in Neuropsychological Test Performance in Frontotemporal Degeneration
Authors: Matyi Melanie A. , Rhodes Emma , Emrani Sheina , Jin Hannah A. , Irwin David J. , McMillan Corey T. , Massimo Lauren 
Published: January 2025

AbstractRacial disparities in neuropsychological test performance are well documented in Alzheimer’s Disease (AD) but have received little attention in frontotemporal degeneration (FTD). Identification of potential disparities in neuropsychological performance is critical to identify ways to improve inclusivity in clinical research and care of representative FTD populations. We evaluated disparities in neuropsychological performance among individuals with clinically diagnosed FTD (behavioral variant FTD [bvFTD] or primary progressive aphasia [PPA]) using data from the National Alzheimer’s Coordinating Center (NACC) collected between September 2005 and November 2023. Only 10% of NACC FTD cases are from racially/ethnically minoritized groups. Black (n=56), Hispanic (n=77) and White (n=1301) individuals were evaluated in the cognitive domains of episodic memory, working memory, processing speed, cognitive flexibility, attention, category fluency and lexical retrieval, in addition to global cognition across Uniform Data Set versions 1 to 3. Linear regressions examined the association between racial/ethnic group and cognitive scores covarying for disease stage, age, sex, and education. After adjusting for age, sex, and education using NACC established normative correction, binary logistic regression examined group differences in the proportion of participants classified as impaired (<=-1.5 normative z-score) for each cognitive test. Minoritized individuals, on average, had lower scores and/or greater likelihood of impairment (odds ratio; OR) on measures of global cognition (Black: β = -3.63; OR = 2.74; Hispanic: β = -2.50), lexical retrieval (Black: β = -4.31; OR = 3.28; Hispanic: β = -2.90; OR = 3.81), processing speed (Black: β = 26.80; OR = 4.07; Hispanic: β = 21.31; OR = 2.37), cognitive flexibility (Black: β = 46.65; OR = 3.35), attention (Hispanic: β = -0.39), working memory (Black: β = -0.79; Hispanic: β = -0.42), episodic memory (Hispanic: β = -1.67), and category fluency (Hispanic: β = -1.28). We did not identify any neuropsychological tests where White individuals performed worse than minoritized individuals. These findings indicate racial/ethnic differences in neuropsychological test performance on measures of global cognition, executive function, and lexical retrieval. Critically, these tests are used in diagnosis and monitoring of FTD. Future efforts must focus on increasing research participation in underrepresented populations with FTD to support the diverse needs of individuals, and an understanding of social determinants of health in FTD to evaluate potential sources of the observed differences across racial and ethnic groups.
Metastatic spine disease alters spinal load-to-strength ratios in patients compared to healthy individuals
Authors: Anderson Dennis E. , Keko Mario , James Joanna , Allaire Brett T. , Kozono David , Doyle Patrick F , Kang Heejoo , Caplan Sarah , Balboni Tracy , Spektor Alexander , Huynh Mai Anh , Hackney David B. , Alkalay Ron N. 
Published: January 2025

AbstractPathologic vertebral fractures (PVF) are common and serious complications in patients with metastatic lesions affecting the spine. Accurate assessment of cancer patients’ PVF risk is an unmet clinical need. Load-to-strength ratios (LSRs) evaluated in vivo by estimating vertebral loading from biomechanical modeling and strength from computed tomography imaging (CT) have been associated with osteoporotic vertebral fractures in older adults.Here, for the first time, we investigate LSRs of thoracic and lumbar vertebrae of 135 spine metastases patients compared to LSRs of 246 healthy adults, comparable by age and sex, from the Framingham Heart Study under four loading tasks. Findings include: (1) Osteolytic vertebrae have higher LSRs than osteosclerotic and mixed vertebrae; (2). In patients’ vertebrae without CT observed metastases, LSRs were greater than healthy controls. (3) LSRs depend on the spinal region (Thoracic, Thoracolumbar, Lumbar). These findings suggest that LSRs may contribute to identifying patients at risk of incident PVF in metastatic spine disease patients. The lesion-mediated difference suggests that risk thresholds should be established based on spinal region, simulated task, and metastatic lesion type.
Intrastriatal delivery of a zinc finger protein targeting the mutant HTT gene obviates lipid phenotypes in zQ175DN HD mice
Authors: Iwanowicz Andrew , Boudi Adel , Seeley Connor , Sapp Ellen , Miller Rachael , Liu Sophia , Chase Kathy , Shing Kai , Batista Ana Rita , Siena-Esteves Miguel , Aronin Neil , DiFiglia Marian , Kegel-Gleason Kimberly B. 
Published: January 2025

AbstractReducing the burden of mutant Huntingtin (mHTT) protein in brain cells is a strategy for treating Huntington’s disease (HD). However, it is still unclear what pathological changes can be reproducibly reversed by mHTT lowering. We previously found that lipid changes that occur with HD progression could be prevented by attenuating HTT transcription of the mutant allele in a genetic mouse model (LacQ140) with inducible whole body lowering. Here, we tested whether intrastriatal injection of a therapeutic capable of repressing the mutantHTTallele with expanded CAG can provide similar protection against lipid changes in HD mice with a deletion of neo cassette (zQ175DN).MethodsWild-type or zQ175DN mice were injected with AAV9 bearing a cDNA for a zinc finger protein (ZFP) which preferentially targets mutant HTT (ZFP-HTT) to repress transcription (Zeitler et al., 2019). Proteins were analyzed using western blot, capillary electrophoresis, and nitrocellulose filtration methods. Lipid analyses were conducted by liquid chromatography and mass spectrometry (LC-MS). Somatic expansion index was assessed using capillary gel electrophoresis of PCR products.ConclusionsLowering mHTT levels by 43% for 4 months prevented numerous changes in lipids of caudate-putamen in zQ175DN mice. Our data support the idea that mHTT lowering can provide meaningful benefits and support brain health. Furthermore, our data demonstrate that analyzing lipid signatures is a valuable method for evaluating potential therapies in a preclinical model of HD.
Butyrolactol A is a phospholipid flippase inhibitor that potentiates the bioactivity of caspofungin against resistant fungi
Authors: Chen Xuefei , Duan H. Diessel , Hoy Michael J. , Koteva Kalinka , Spitzer Michaela , Guitor Allison K. , Puumala Emily , Hu Guanggan , Yiu Bonnie , Chou Sommer , Bian Zhuyun , Guo Amelia Bing Ya , Sun Sheng , Robbins Nicole , Cook Michael A. , Truant Ray , MacNeil Lesley T. , Brown Eric D. , Kronstad James W. , Cowen Leah E. , Heitman Joseph , Li Huilin , Wright Gerard D. 
Published: January 2025

SummaryFungal infections cause millions of deaths annually and are challenging to treat due to limited antifungal options and increasing drug resistance. Cryptococci are intrinsically resistant to the latest generation of antifungals, echinocandins, whileCandida auris, a notorious global threat, is also increasingly resistant. We performed a natural product extract screen for rescue of the activity of the echinocandin caspofungin againstCryptococcus neoformansH99, identifying butyrolactol A, which restores echinocandin efficacy against resistant fungal pathogens, includingC. auris. Mode of action studies revealed that butyrolactol A inhibits the phospholipid flippase Apt1–Cdc50, blocking phospholipid transport. Cryoelectron-microscopy analysis of the Apt1●butyrolactol A complex revealed that the flippase is locked in a dead-end state. Apt1 inhibition disrupts membrane asymmetry, vesicular trafficking, and cytoskeletal organization, thereby enhancing echinocandin uptake and potency. This study identifies flippases as promising antifungal targets and demonstrates the potential of revisiting natural products to expand the antifungal arsenal and combat resistance.
Amygdala GABA Neurons: Gatekeepers of Stress and Reproduction
Authors: Yu Junru , Farjami Saeed , Nechyporenko Kateryna , Li Xiao Feng , Yaseen Hafsa , Lin Yanyan , Ye Jinbin , Hollings Owen , de Burgh Ross , O’Byrne Kevin T. , Tsaneva-Atanasova Krasimira , Voliotis Margaritis 
Published: January 2025

AbstractStress can disrupt menstrual cycles, cause infertility, and lead to other reproductive disorders. The posterodorsal medial amygdala (MePD) processes stress signals and regulates the gonadotropin-releasing hormone (GnRH) pulse generator through GABAergic inhibitory projections to the hypothalamus. However, how stress is processed in the MePD - especially involving its dense GABAergic and Urocortin-3 (UCN3) neurons - remains poorly understood.In this study, we combinein vivoGRadient-INdex (GRIN) lens mini-endoscopic calcium imaging (to track neuronal activity), optogenetics, clustering analysis, and computational modeling to investigate MePD circuitry. Our findings reveal two anti-correlated GABAergic sub-populations in the MePD that dictate responses to both UCN3 neuron stimulation and restraint stress. Our computational modeling suggests that mutual inhibition between these GABAergic groups drives this anti-correlated activity and predicts how these interactions shape downstream responses to stimulation of GABAergic and UCN3 neurons.We test these predictions using optogenetics and confirm that GABAergic neurons operate downstream of the UCN3 population, playing a crucial role in transmitting UCN3 signals to regulate luteinizing hormone (LH) pulse frequency. Our study is the first to show how GABAergic neurons in the amygdala mediate stress effects on reproductive health, uncovering key neural mechanisms linking emotional and reproductive functions.
Polymerase mutations underlie early adaptation of H5N1 influenza virus to dairy cattle and other mammals
Authors: Dholakia Vidhi , Quantrill Jessica L. , Richardson Samuel , Pankaew Nunticha , Brown Maryn D. , Yang Jiayun , Capelastegui Fernando , Masonou Tereza , Case Katie-Marie , Aejian Jila , Staller Ecco , Sheppard Carol M. , Brown Ian H. , Smith Claire M. , Iqbal Munir , Digard Paul , Barclay Wendy S. , Pinto Rute M. , Peacock Thomas P. , Goldhill Daniel H. 
Published: January 2025

AbstractIn early 2024, an unprecedented outbreak of H5N1 high pathogenicity avian influenza was detected in dairy cattle in the USA. The epidemic remains uncontrolled, with spillbacks into poultry, wild birds and other mammals including humans. Here, we present molecular and virological evidence that the cattle B3.13 genotype H5N1 viruses rapidly accumulated adaptations in polymerase genes that enabled better replication in bovine cells, as well as cells of other mammalian species including humans and pigs. We find evidence of several mammalian adaptations gained early in the evolution of these viruses in cattle including PB2 M631L, which is found in all cattle sequences, and PA K497R, which is found in the majority. Structurally, PB2 M631L maps to the polymerase-ANP32 interface, an essential host factor for viral genome replication. We show this mutation adapts the virus to co-opt bovine ANP32 proteins and thereby enhances virus replication in bovine and primary human airway cells. Importantly, we show that ongoing evolution during 2024 in the PB2 gene, including a convergently arising D740N substitution, further increases polymerase activity in a range of mammalian cells. Thus, the continued circulation of H5N1 in dairy cattle allows virus adaption improving replicative ability in cattle and increasing zoonotic spillover risk.
A glycerol oxidase from Norway spruce (Picea abiesL. Karst.) expands biochemical and structural attributes of the GMC oxidoreductase superfamily
Authors: Paasela Tanja , Schwenner Naike , Zhao Hongbo , Sun Mengyi , Haataja Topi , Karppi Johanna , Vaattovaara Aleksia , Master Emma , Sandgren Mats , Kärkönen Anna , Tenkanen Maija 
Published: January 2025

SummaryInvestigations to uncover the versatility of carbohydrate active enzymes belonging to the auxiliary activity family 3 (AA3) have focused on microbial enzymes. Plant genomes also harbor AA3 encoding genes, and reverse genetics approaches have shown their importance in plant development. To date, however, detailed biochemical characterizations and structures of plant AA3 enzymes have not been reported.Here, we describe screening AA3 encoding genes from Norway spruce and the first in-depth biochemical and structural characterization of a plant AA3 oxidase,PaAOX1.PaAOX1 was crystallized, and the structure was solved by X-ray crystallography.PaAOX1 demonstrated highest oxidase activity against glycerol. It oxidized glycerol to glyceraldehyde, then further to glyceric acid, and showed preference for L-glyceraldehyde over D-glyceraldehyde. Despite the low sequence similarity with fungal alcohol oxidases, it had all the structural features of the typical AA3 enzyme.PaAOX1 has a novel activity among the characterized AA3s, and it showed a new structural arrangement of the region surrounding the catalytic center. Our findings contribute to a deeper understanding of the structural and functional aspects of enzymes in the GMC superfamily, and especially of alcohol oxidases, expanding the knowledge from fungi to plants.
Human milk-derived extracellular vesicles promote the heat shock response in polarized microglia
Authors: Storm Jasmyne A. , Lu Jueqin , Obtial Mon Francis , Wijenayake Sanoji 
Published: January 2025

AbstractProteotoxic stress induces microglia polarization and attenuates cytoprotective, pro-survival cellular cascades. Milk-derived extracellular vesicles (MEVs) are lipid-coated nanovesicles that combat pro-inflammation in peripheral cells and tissues; however, the cytoprotective potential of MEVs remains unknown in brain macrophages. We investigated whether MEVs reduce neuroinflammation in human microglia by activating the heat shock response (HSR). The HSR triggers the upregulation of molecular chaperones (heat shock proteins; HSPs) to restore proteostasis by refolding or degrading misfolded aggregates. MEVs were isolated from unpasteurized human donor milk. Human microglia clone 3 (HMC3) cells were primed with 10 ng/mL IFN-γ to induce polarization, and a subset of cells were supplemented with 200 µg of MEVs. The abundance of HSF1 and candidate HSPs (Hsp70, Hsp90, Hsp40, Hsp27) were analyzed via RT-qPCR and western immunoblotting at 6h, 12h, and 24h post-MEV supplementation. We found that MEV supplementation promoted the HSR in polarized microglia, compared to homeostatic cells. Furthermore, MEVs increased the duration of the HSR in response to pro-inflammatory stress, exerting robust and continued pro-survival benefits.
Rev-RRE activity modulates HIV-1 replication and latency reactivation: Implications for viral persistence and cure strategies
Authors: Dzhivhuho Godfrey A. , Jackson Patrick E. H. , Honeycutt Ethan S. , da Silva Mesquita Flavio , Huang Jing , Hammarskjold Marie-Louise , Rekosh David 
Published: January 2025

AbstractThe HIV-1 Rev-RRE regulatory axis plays a crucial role in viral replication by facilitating the nucleo-cytoplasmic export and expression of viral mRNAs with retained introns. In this study, we investigated the impact of variation in Rev-RRE functional activity on HIV-1 replication kinetics and reactivation from latency. Using a novel HIV-1 clone with an interchangeable Rev cassette, we engineered viruses with different Rev functional activities and demonstrated that higher Rev-RRE activity confers greater viral replication capacity while maintaining a constant level of Nef expression. In addition, a low Rev activity virus rapidly acquired a compensatory mutation in the RRE that significantly increased Rev-RRE activity and replication. In a latency model, proviruses with differing Rev-RRE activity levels varied in the efficiency of viral reactivation, affecting both initial viral release and subsequent replication kinetics. These results demonstrate that activity differences in the Rev-RRE axis among different viral isolates have important implications for HIV replication dynamics and persistence. Importantly, our findings indicate that bolstering Rev/RRE activity could be explored as part of latency reversal strategies in HIV cure efforts.Author SummaryThe activity of the HIV-1 Rev-RRE axis is essential for viral replication and varies among primary viral isolates. However, the role of this for viral fitness, evolution, and persistence has not previously been investigated. Our results show that duringin vitroreplication, there is a selective fitness advantage for viruses with higher Rev-RRE activity and that HIV has the ability to fine tune this regulatory system with minimal sequence changes. Additionally, the maintenance of Nef expression in low Rev activity viruses suggests a potential mechanism for balancing immune evasion and replication capacity in different selection landscapes within a host. We also show that viruses with low Rev-RRE activity are more difficult to reverse from latency than viruses with higher Rev-RRE activity. Thus, differences in provirus Rev-RRE activity may be a barrier to developing effective latency reversal strategies. These findings provide new insights into the complex roles that the Rev/RRE axis plays in functionality, viral fitness, evolution, and persistence.
Benchmark of Wide Range of Pairwise Distance Metrics for Automated Classification of Mouse Mutant Phenotypes from Flow Cytometry Data
Authors: May M. , Hewitt T. , Mashford B. , Hammill D. , Davies A. , Andrews T. D. 
Published: January 2025

AbstractPrecision medicine requires a comprehensive mapping of genotype to phenotype to provide patients with individually tailored treatment. However, when using flow cytometry to identify phenotypes, such as the quantity of various immune cell populations in tissue and blood used to identify autoimmune disorders, it is often unclear which cellular phenotypes are from healthy and disease individuals, especially when including the effects of population diversity, due to the high-dimensional nature of the data. To identify and segregate healthy phenotype from various disease phenotypes, we use pairwise distance metrics between each sample’s cell populations. By comparing distance metrics between C57BL/6 clone mice with mutations of known phenotype, we find that cosine similarity is best suited for segregating wildtype from mutant samples while respecting minute differences in already small cell populations, and that standardised Euclidean distance is best suited for machine-learning input due to its sensitivity. Both metrics outperform other tested metrics (including Aitchison, Euclidean, Manhattan, Earth-Movers Distance, and squared Euclidean). We demonstrate the utility of these different pairwise metrics through their application to a classification task of known mutant phenotypes: using an existing FACS phenotype dataset derived from X000 inbred C57BL/6 mice that harbour potentially phenotypic genetic variation introduced through ENU mutagenesis of individual pedigree-founding G0 male mice.