bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of TRIM21 drives UVB-induced systemic inflammation by regulating DNA-sensing pathways
Authors: Tumurkhuu Gantsetseg , Moore Richard , Perri Graziela , Huo Lihong , Kumar Arati Naveen , de los Santos Gabriela , Gibb David , Carriere Jessica , Yu Jeong Min , Abuav Rachel , Wallace Daniel J. , Ishimori Mariko , Shon Wonwoo , Dortfleutner Andrea , Stehlik Christian , Jefferies Caroline A. 
Published: April 2024

ABSTRACTBackgroundExposure of systemic lupus erythematosus (SLE) patients to ultraviolet light B (UVB) triggers local and systemic inflammation, with cytosolic DNA sensing and induction of type I interferons (IFNs) known to play a role. We previously identified TRIM21 as a negative regulator of DNA sensing and IFN expression.Here we explore the role of TRIM21 in regulating local and systemic responses following UVB exposure.MethodsWT (C57BL/6) andTrim21-/-mice were irradiated with UVB (100mJ/cm2) daily for 1 and 3 weeks, and UVB-induced inflammation in skin, blood, and spleen were analyzed by qPCR, histology, RNA sequencing and flow cytometry. Mechanistic studies were performed in bone marrow-derived macrophages (BMDMs) and mouse skin fibroblasts (MDF) from WT andTrim21-/-mice, andTRIM21-/-THP-1 cells.ResultsInfiltration of inflammatory cells and induction of type I IFN developed in UVB-exposed areas in both sets of mice, howeverTrim21-/-mice developed splenomegaly, enhanced total IgG levels and IFN-stimulated genes (ISG) in the blood and spleen. Enhanced basal and UVB-dependentIfnb1expression was observed inTrim21-/-BMDMs and MDFs, which was dependent on the cytosolic DNA sensing cGAS-STING pathway. Mechanistically, we found both degradation of DDX41 and STING levels were impaired in stimulatedTrim21-/-BMDMs.ConclusionTaken together, our results indicate that TRIM21 protects against IFN induction at local and systemic levels through restricting STING signaling. Our finding that reduced levels of TRIM21 are observed in SLE patients with cutaneous involvement indicates a potential role for TRIM21 in guarding against systemic flare in SLE patients.
The promise and challenge of spatial inference with the full ancestral recombination graph under Brownian motion
Authors: Deraje Puneeth , Kitchens James , Coop Graham , Osmond Matthew M. 
Published: April 2024

AbstractSpatial patterns of genetic relatedness among samples reflect the past movements of their ancestors. Our ability to untangle this history has the potential to improve dramatically given that we can now infer the ultimate description of genetic relatedness, the ancestral recombination graph (ARG). By extending spatial theory previously applied to trees, we generalize the common model of Brownian motion to full ARGs, thereby accounting for correlations in trees along a chromosome while efficiently computing likelihood-based estimates of dispersal rate and genetic ancestor locations, with associated uncertainties. We evaluate this model’s ability to reconstruct spatial histories using individual-based simulations and unfortunately find a clear bias in the estimates of dispersal rate and ancestor locations. We investigate the causes of this bias, pinpointing a discrepancy between the model and the true spatial process at recombination events. This highlights a key hurdle in extending the ubiquitous and analytically-tractable model of Brownian motion from trees to ARGs, which otherwise has the potential to provide an efficient method for spatial inference, with uncertainties, using all the information available in the full ARG.
Circadian rhythms tied to changes in brain morphology in a densely-sampled male
Authors: Murata Elle M. , Pritschet Laura , Grotzinger Hannah , Taylor Caitlin M. , Jacobs Emily G. 
Published: April 2024

AbstractCircadian, infradian, and seasonal changes in steroid hormone secretion have been tied to changes in brain volume in several mammalian species. However, the relationship between circadian changes in steroid hormone production and rhythmic changes in brain morphology in humans is largely unknown. Here, we examined the relationship between diurnal fluctuations in steroid hormones and multiscale brain morphology in a precision imaging study of a male who completed forty MRI and serological assessments at 7 A.M. and 8 P.M. over the course of a month, targeting hormone concentrations at their peak and nadir. Diurnal fluctuations in steroid hormones were tied to pronounced changes in global and regional brain morphology. From morning to evening, total brain volume, gray matter volume, and cortical thickness decreased, coincident with decreases in steroid hormone concentrations (testosterone, estradiol, and cortisol). In parallel, cerebrospinal fluid and ventricle size increased from A.M. to P.M. Global changes were driven by decreases within the occipital and parietal cortices. These findings highlight natural rhythms in brain morphology that keep time with the diurnal ebb and flow of steroid hormones.Significance StatementThough rhythmic changes in steroid hormone secretion have been tied to changes in brain volume in several mammalian species, this relationship has not been well characterized in humans. In this precision neuroimaging study, we found that global and regional brain morphology and steroid hormone levels exhibit tandem circadian rhythms. These findings provide high-resolution insight into the anatomical signature of diurnal changes in brain morphology and steroid hormone production in a human male and reveal the metronomic regularity of these rhythms over time.
A quantitative tumor–wide analysis of morphological heterogeneity of colorectal adenocarcinoma
Authors: Dragomir Mihnea P. , Popovici Vlad , Schallenberg Simon , Čarnogurská Martina , Horst David , Nenutil Rudolf , Bosman Fred , Budinská Eva 
Published: April 2024

AbstractMorphologic heterogeneity of colorectal adenocarcinoma (CRC) is poorly understood. Previously, we identified morphological patterns associated with CRC molecular subtypes, and showed that these patterns have distinct molecular motifs (Budinská et al., 2023). Here, we evaluated the heterogeneity of these patterns across CRC. Three pathologists evaluated dominant, secondary, and tertiary morphology on four different tissue blocks per tumor in a pilot set of 22 CRCs (n=88). An artificial intelligence (AI) image analysis tool was trained using the pathologist-rated tumors to assess the morphologic heterogeneity on an expanded set of 161 CRCs (644 images). Heterogeneity was expressed as a combination of morphology patterns (morphotypes) across slides and normalized Shannon’s index (NSI). All pathologists agreed that the majority of tumors had 2-3 different dominant morphotypes, and that the complex tubular (CT) morphotype was the most common. AI analysis confirmed these observations in the full set. CT morphotype combined with all other dominant morphotypes within a tumor. Desmoplastic (DE) morphotype was rarely dominant and rarely combined with other dominant morphotypes. Mucinous (MU) was most often combined with solid/trabecular (TB) and papillary (PP). Most tumors showed medium or high NSI, but without clinical consequence. The proportion of DE morphotype was associated with higher T-stage, N-stage, metastasis, AJCC-stage, and shorter relapse-free survival, and MU morphotype was associated with higher grade, right side, microsatellite instability, and shorter overall survival. In conclusion, we observed high intratumoral morphological heterogeneity of CRC, and that not heterogeneityper se, but the proportion of certain morphotypes showed associations with clinical outcome. This has implications for molecular profiling of CRC.
Spinal microcircuits go through multiphasic homeostatic compensations in a mouse model of motoneuron degeneration
Authors: Nascimento Filipe , Özyurt M. Görkem , Halablab Kareen , Bhumbra Gardave Singh , Caron Guillaume , Bączyk Marcin , Zytnicki Daniel , Manuel Marin , Roselli Francesco , Brownstone Rob , Beato Marco 
Published: April 2024

SummaryIn many neurological conditions, early-stage neural circuit adaption can preserve relatively normal behaviour. In some diseases, spinal motoneurons progressively degenerate yet movement is initially preserved. We therefore investigated whether these neurons and associated microcircuits adapt in a mouse model of progressive motoneuron degeneration. Using a combination ofin vitroandin vivoelectrophysiology and super-resolution microscopy, we found that, early in the disease, neurotransmission in a key pre-motor circuit, the recurrent inhibition mediated by Renshaw cells, is reduced by half due to impaired quantal size associated with decreased glycine receptor density. This impairment is specific, and not a widespread feature of spinal inhibitory circuits. Furthermore, it recovers at later stages of disease. Additionally, an increased probability of release from proprioceptive afferents leads to increased monosynaptic excitation of motoneurons. We reveal that in motoneuron degenerative conditions, spinal microcircuits undergo specific multiphasic homeostatic compensations that may contribute to preservation of force output.
Biophysical Profiling of Red Blood Cells from Thin-film Blood Smears using Deep Learning
Authors: Lamoureux Erik S. , Cheng You , Islamzada Emel , Matthews Kerryn , Duffy Simon P. , Ma Hongshen 
Published: April 2024

AbstractMicroscopic inspection of thin-film blood smears is widely used to identify red blood cell (RBC) pathologies, including malaria parasitism and hemoglobinopathies, such as sickle cell disease and thalassemia. Emerging research indicates that non-pathologic changes in RBCs can also be detected in images, such as deformability and morphological changes resulting from the storage lesion. In transfusion medicine, cell deformability is a potential biomarker for the quality of donated RBCs. However, a major impediment to the clinical translation of this biomarker is the difficulty associated with performing this measurement. To address this challenge, we developed an approach for biophysical profiling of RBCs based on cell images in thin-film blood smears. We hypothesize that subtle cellular changes are evident in blood smear images, but this information is currently undetectable by human cognition. To test this hypothesis, we developed a deep learning strategy to analyze Giemsa-stained blood smears to assess the subtle morphologies indicative of RBC deformability and storage-based degradation. Specifically, we prepared thin-film blood smears from 27 RBC samples (9 donors evaluated at 3 storage timepoints) and imaged them using high-resolution microscopy. Using this dataset, we trained a convolutional neural network to evaluate image-based morphological features related to cell deformability. The prediction of donor deformability is strongly correlated to the microfluidic scores and can be used to categorize images into specific deformability groups with high accuracy. We also used this model to evaluates differences in RBC morphology resulting from cold storage. Together, our results demonstrate that deep learning models can exceed the limits of human cognition to detect subtle cellular differences in morphology resulting from deformability and cold storage. This result suggests the potential to assess donor blood quality from thin-film blood smears, which can be acquired ubiquitously in clinical workflows.
The relationship between event boundary strength and pattern shifts across the cortical hierarchy during naturalistic movie-viewing
Authors: Lee Yoonjung , Chen Janice 
Published: April 2024

AbstractOur continuous experience is spontaneously segmented by the brain into discrete events. However, the beginning of a new event (an event boundary) is not always sharply identifiable: phenomenologically, event boundaries vary in salience. How are the response profiles of cortical areas at event boundaries modulated by boundary strength during complex, naturalistic movie-viewing? Do cortical responses scale in a graded manner with boundary strength, or do they merely detect boundaries in a binary fashion? We measured “cortical boundary shifts” as transient changes in multi-voxel patterns at event boundaries with different strengths (weak, moderate, and strong), determined by across-subject agreement. Cortical regions with different processing timescales were examined. In auditory areas, which have short timescales, cortical boundary shifts exhibited a clearly graded profile both in group-level and individual-level analyses. In cortical areas with long timescales, including the default mode network, boundary strength modulated pattern shift magnitude at the individual subject level. We also observed a positive relationship between boundary strength and the extent of temporal alignment of boundary shifts across different levels of the cortical hierarchy. Additionally, hippocampal activity was highest at event boundaries for which cortical boundary shifts were most aligned across hierarchical levels. Overall, we found that event boundary strength modulated cortical pattern shifts strongly in sensory areas and more weakly in higher-level areas, and that stronger boundaries were associated with greater alignment of these shifts across the cortical hierarchy.
Water Diffusion in the Live Human Brain is Gaussian at the Mesoscale
Authors: Magdoom Kulam Najmudeen , Avram Alexandru V. , Witzel Thomas E. , Huang Susie Y. , Basser Peter J. 
Published: April 2024

AbstractImaging the live human brain at the mesoscopic scale is a desideratum in basic and clinical neurosciences. Despite the promise of diffusion MRI, the lack of an accurate model relating the measured signal and the associated microstructure has hampered its success. The widely used diffusion tensor MRI (DTI) model assumes an anisotropic Gaussian diffusion process in each voxel, but lacks the ability to capture intravoxel heterogeneity. This study explores the extension of the DTI model to mesoscopic length scales by use of the diffusion tensor distribution (DTD) model, which assumes a Gaussian diffusion process in each subvoxel. DTD MRI has shown promise in addressing some limitations of DTI, particularly in distinguishing among different types of brain cancers and elucidating multiple fiber populations within a voxel. However, its validity in live brain tissue has never been established. Here, multiple diffusion-encoded (MDE) data were acquired in the living human brain using a 3 Tesla MRI scanner with large diffusion weighting factors. Two different diffusion times (Δ = 37, 74 ms) were employed, with other scanning parameters fixed to assess signal decay differences. In vivo diffusion-weighted signals in gray and white matter were nearly identical at the two diffusion times. Fitting the signals to the DTD model yielded indistinguishable results, except in the cerebrospinal fluid (CSF)-filled voxels likely due to pulsatile flow. Overall, the study supports the time invariance of water diffusion at the mesoscopic scale in live brain parenchyma, extending the validity of the anisotropic Gaussian diffusion model in clinical brain imaging.
Genomic epidemiology ofPlasmodium knowlesireveals putative genetic drivers of adaptation in Malaysia
Authors: Westaway Jacob A F , Diez Benavente Ernest , Auburn Sarah , Kucharski Michal , Aranciaga Nicolas , Nayak Sourav , William Timothy , Rajahram Giri S , Piera Kim A , Braima Kamil , Tan Angelica F , Alaza Danshy , Barber Bridget E , Drakeley Chris , Amato Roberto , Sutanto Edwin , Trimarsanto Hidayat , Anstey Nicholas M , Bozdech Zbynek , Field Matthew , Grigg Matthew J 
Published: April 2024

AbstractSabah, Malaysia, has amongst the highest burden of humanPlasmodium knowlesiinfection in the country, associated with increasing encroachment on the parasite’s macaque host habitat. However, the genomic make-up ofP. knowlesiin Sabah was previously poorly understood. To inform on local patterns of transmission and putative adaptive drivers, we conduct population-level genetic analyses ofP. knowlesihuman infections using 52 new whole genomes from Sabah, Malaysia, in combination with publicly available data. We identify the emergence of distinct geographical subpopulations within the macaque-associated clusters using IBD-based connectivity analysis. Secondly, we report on introgression events between the clusters, which may be linked to differentiation of the subpopulations, and that overlap genes critical for survival in human and mosquito hosts. Using village-level locations fromP. knowlesiinfections, we also identify associations between several introgressed regions and both intact forest perimeter-area ratio and mosquito vector habitat suitability. Our findings provide further evidence of the complex role of changing ecosystems and sympatric macaque hosts in Malaysia driving distinct genetic changes seen inP. knowlesipopulations. Future expanded analyses of evolvingP. knowlesigenetics and environmental drivers of transmission will be important to guide public health surveillance and control strategies.Author SummaryThe zoonoticP. knowlesiparasite is an emerging, yet understudied, cause of malaria in Southeast Asia. Sabah, Malaysia, has amongst the highest burden of human P. knowlesi infection in the country, however, the region is currently understudied. Thus, we produced a collection of high-qualityP. knowlesigenomes from Sabah, and in combination with publicly available data, performed an extensive population genetics analysis. Our work contributes novel insights forPlasmodium knowlesipopulation genetics and genetic epidemiology.
Synergistic Hypoxia and Apoptosis Conditioning Unleashes Superior Mesenchymal Stem Cells Efficacy in Acute Graft-versus-Host-Disease
Authors: Mendiratta Mohini , Mendiratta Meenakshi , Ganguly Shuvadeep , Rai Sandeep , Gupta Ritu , Kumar Lalit , Bakhshi Sameer , Dadhwal Vatsla , Pushpam Deepam , Malik Prabhat Singh , Pramanik Raja , Aggarwal Mukul , Gupta Aditya Kumar , Dhawan Rishi , Seth Tulika , Mahapatra Manoranjan , Nayak Baibaswata , Singh Thoudam Debraj , Singla Sachin Kumar , Singh Mayank , Prasad Chandra Prakash , Prakash Hridayesh , Mohanty Sujata , Sahoo Ranjit Kumar 
Published: April 2024

ABSTRACTMesenchymal stem cells (MSCs) have emerged as promising candidates for immune modulation in various diseases that are associated with dysregulated immune responses like Graft-versus-Host-Disease (GVHD). MSCs are pleiotropic and the fate of MSCs following administration is a major determinant of their therapeutic efficacy. In this context, we here demonstrate that hypoxia preconditioned apoptotic MSCs [bone marrow (BM), Wharton’s Jelly (WJ)] bear more immune programming ability in a cellular model of acute Graft-versus-Host-Disease (aGVHD). To this purpose, we programmed MSCs by exposing them to hypoxia and inducing apoptosis both sequentially as well as simultaneously. Our findings demonstrated that WJ MSCs that were conditioned with indicated approaches simultaneously induced the differentiation of CD4+T-cell towards Tregs, enhanced Th2 effector, and concomitantly mitigated Th1 and Th17, with polarization of M1 effector macrophages towards their M2 phenotype, and more interestingly enhanced efferocytosis by macrophages indicated Th2 programming ability of MSCs programmed by conjunctional approaches Overall, our study highlights the potential of WJ-MSCs conditioned with hypoxia and apoptosis concurrently, as a promising therapeutic strategy for aGVHD and underscores the importance of considering MSC apoptosis in optimizing MSCs-based cellular therapy protocols for enhanced therapeutic efficacy in aGvHD.GRAPHICAL ABSTRACT
Distinct communities of Bacteria and unicellular eukaryotes in the different water masses of Cretan Passage water column (Eastern Mediterranean Sea)
Authors: Charalampous Georgia , Kormas Konstantinos A. , Antoniou Eleftheria , Kalogerakis Nicolas , Gontikaki Evangelia 
Published: April 2024

AbstractUnderstanding the diversity and dynamics of marine microbiota holds significant importance due to their role in maintaining vital ecosystem functions and services including climate regulation and bioremediation. Here, we studied the diversity and associations between Bacteria and unicellular eukaryotes in the different water masses of the Cretan Passage water column in the Eastern Mediterranean Sea (EMS). Samples were collected from two stations in the Hellenic Exclusive Economic Zone (EEZ) at various depths down to 1000 m during two sampling expeditions in August 2019 and February 2020. Through high-throughput 16S and 18S rRNA gene analysis, we unveiled vertical variations in both bacterial and unicellular eukaryotes diversity respectively. Additionally, interspecies co-occurrence patterns were evaluated between the top and bottom water masses. Our results revealed species fluctuations indicative of seasonality in the surface water mass while the deepest water layers were enriched in heterotrophic taxa and grazers related to organic matter degradation and nutrient cycling. Finally, we found a higher number of microbial associations in surface waters indicating abundant ecological niches compared to the deepest layer, possibly related to the lack of bottom-up resources in the oligotrophic deep ocean.
Proteomic profile analysis of plasma and aqueous humor from glaucoma and non-glaucomatous patients
Authors: Pessuti Carmen L. , Huang Chia Ling , Banks Angela , Vo Nhi , Jennings Lori , Loureiro Joseph , Ribeiro Kleber S. , Costa Deise Fialho , Nascimento Heloisa , Muccioli Cristina , Tavares Ivan Maynart , Commodaro Alessandra G. , Belfort Rubens , Wilson Christopher W. , Chen Amy , Prasanna Ganesh , Raghunathan VijayKrishna 
Published: April 2024

AbstractPurposeGlaucoma, a multifactorial ocular neuropathic and age associated disease, can lead to irreversible vision loss. Diagnosis involves assessing optic cupping (increased cup-to-disc ratios) and structural changes (like retinal nerve fiber layer thinning) through clinical imaging. Elevated intraocular pressure (IOP) is commonly associated with glaucoma, but not always. However, understanding disease progression is hindered by limited access to donor ocular tissue and consistent clinical data. Our study focuses on live patient samples, analyzing their proteome for potential biomarkers to enhance precise diagnosis and monitor glaucoma progression.MethodsAqueous humor (AH) samples were collected from 36 glaucoma patients (17 male, 19 female), and 35 non-glaucomatous control patients (16 male, 19 female) undergoing cataract surgery. The protein profile was compared using the SOMAscan® assay system for proteome profiling. From glaucomatous donors, significant correlations between IOP and cup-to-disc ratios to proteome differences were identified.ResultsCorrelations in proteins between plasma and AH were identified. These proteins were enriched in pathways related to vascular integrity, inflammatory response, humoral & adaptive immune response, cell-cell & cell-matrix adhesion, and complement activation. Glaucomatous AH exhibited increased protein levels in general. Neurofilament light chain (NEFL) protein correlated with elevated IOP and inflammatory markers, but not with cup-to-disc ratios.ConclusionsTogether, our data demonstrate that the proteins identified in this study from glaucomatous donors correspond to both markers of neurodegeneration and those that may inhibit cell proliferation or disrupt vascular integrity.Translational RelevanceProteome analysis may lead to potential biomarker identification during disease progression.PrecisClinical glaucoma diagnosis is by assessing structure-function relationship which doesn’t yield molecular mechanisms underlying disease. Here, we analyzed proteome from aqueous and plasma of glaucomatous patients. Proteins correspond to markers of neurodegeneration, pressure and cup-to-disc-ratios.