bluuebunny/crossref_metadata_2025_split huggingface dataset:
Seasonal and environmental factors contribute to the variation in the gut microbiome: a large-scale study of a small bird
Authors: Liukkonen Martta , Muriel Jaime , Martínez-Padilla Jesús , Nord Andreas , Pakanen Veli-Matti , Rosivall Balázs , Tilgar Vallo , van Oers Kees , Grond Kirsten , Ruuskanen Suvi 
Published: December 2023

ABSTRACTEnvironmental variation can shape the gut microbiome, but majority of studies use captive-bred species, while data on large-scale variation in the gut microbiome and the associated environmental factors is lacking. Furthermore, previous studies have limited taxonomical coverage, and for example knowledge about avian gut microbiomes is still scarce. We investigated large-scale environmental variation in the gut microbiome of wild adult great tits across the species’ European distribution range. Our results show that gut microbiome diversity is higher during winter and that there are compositional differences between winter and summer gut microbiomes. During winter, individuals inhabiting mixed forest habitat show higher gut microbiome diversity, whereas there was no similar association during summer. Also, temperature was found to be a small contributor to compositional differences in the gut microbiome. We did not find significant differences in the gut microbiome among populations, nor any association between latitude, rainfall, and the gut microbiome. The results suggest that there is a seasonal change in wild avian gut microbiomes, but that there are still many unknown factors that shape the gut microbiome of wild bird populations.
Bias-corrected serum creatinine from UK Biobank electronic medical records generates an important data resource for kidney function trajectories
Authors: Gorski Mathias , Wiegrebe Simon , Burkhardt Ralph , Behr Merle , Küchenhoff Helmut , Stark Klaus J. , Böger Carsten A. , Heid Iris M. 
Published: December 2023

ABSTRACTBACKGROUNDLoss of kidney function is a substantial personal and public health burden. Kidney function is typically assessed as estimated glomerular filtration rate (eGFR) based on serum creatinine. Emerging electronic Medical Records (eMR) in UK Biobank present a promising resource to augment the data on longitudinal eGFR based on study center visits (SC; n=15,000). However, it is unclear whether eMR-based creatinine values can be used for research on eGFR trajectories.METHODSWe derived eMR-based serum creatinine values (various assays/labs, Jaffe or enzymatic) from UK Biobank “GP-clinical”. We compared these with SC-based creatinine in individuals with both measurements available in the same calendar year (n=70,231; 2007-2012).RESULTSWe found a multiplicative bias for eMR-based creatinine that was large, factor 0.84, for 2007, and decreased over time (0.97 for 2013). Deriving eGFR based on SC- and bias-corrected eMR-creatinine (CKD-Epi 2021) yielded 454,907 individuals with ≥1eGFR assessment (2,102,174 assessments). This included 206,063 individuals with ≥2 assessments (median=6.00 assessments) for a time between 1stand last assessment of up to 60.2 years (median time=8.7 years). We enriched the dataset with eMR-recorded kidney-relevant events from “GP-clinical” (Acute Kidney Injury, End stage Kidney Disease, Nephrectomy, Dialysis, Kidney Transplant, Pregnancy, and Diabetes). We illustrated the suitability of this data: e.g. we found an annual eGFR decline of 1.04 mL/min/1.73m²/year (95%-CI=1.03-1.05), in line with literature and a four-fold steeper decline following Acute Kidney Injury.CONCLUSIONSIn summary, our bias-correction of eMR-based creatinine values enabled a 4-fold increase in the number eGFR assessments in UK Biobank suitable for kidney function research.
A plasma peptidomic signature reveals extracellular matrix remodeling and predicts prognosis in alcohol-related hepatitis
Authors: Sayed Khaled , Dolin Christine E. , Wilkey Daniel W. , Li Jiang , Sato Toshifumi , Beier Juliane I , Argemi Josepmaria , Bataller Ramon , Wahed Abdus S , Merchant Michael L , Benos Panayiotis V , Arteel Gavin E 
Published: December 2023

ABSTRACTAlcohol-related hepatitis (AH) is plagued with high mortality and difficulty in identifying at-risk patients. The extracellular matrix undergoes significant remodeling during inflammatory liver injury that can be detected in biological fluids and potentially used for mortality prediction. EDTA plasma samples were collected from AH patients (n= 62); Model for End-Stage Liver Disease (MELD) score defined AH severity as moderate (12-20; n=28) and severe (>20; n=34). The peptidome data was collected by high resolution, high mass accuracy UPLC-MS. Univariate and multivariate analyses identified differentially abundant peptides, which were used for Gene Ontology, parent protein matrisomal composition and protease involvement. Machine learning methods were used on patient-specific peptidome and clinical data to develop mortality predictors. Analysis of plasma peptides from AH patients and healthy controls identified over 1,600 significant peptide features corresponding to 130 proteins. These were enriched for ECM fragments in AH samples, likely related to turnover of hepatic-derived proteins. Analysis of moderate versus severe AH peptidomes showed a shift in abundance of peptides from collagen 1A1 and fibrinogen A proteins. The dominant proteases for the AH peptidome spectrum appear to be CAPN1 and MMP12. Increase in hepatic expression of these proteases was orthogonally-validated in RNA-seq data of livers from AH patients. Causal graphical modeling identified four peptides directly linked to 90-day mortality in >90% of the learned graphs. These peptides improved the accuracy of mortality prediction over MELD score and were used to create a clinically applicable mortality prediction assay. A signature based on plasma peptidome is a novel, non-invasive method for prognosis stratification in AH patients. Our results could also lead to new mechanistic and/or surrogate biomarkers to identify new AH mechanisms.Lay summaryWe used degraded proteins found the blood of alcohol-related hepatitis patients to identify new potential mechanisms of injury and to predict 90 day mortality.
Electron-bifurcation and fluoride efflux systems inAcetobacteriumspp. drive defluorination of perfluorinated unsaturated carboxylic acids
Authors: Yu Yaochun , Xu Fengjun , Zhao Weiyang , Thoma Calvin , Che Shun , Richman Jack E. , Jin Bosen , Zhu Yiwen , Xing Yue , Wackett Lawrence , Men Yujie 
Published: December 2023

AbstractEnzymatic cleavage of C–F bonds in per- and polyfluoroalkyl substances (PFAS) is largely unknown but avidly sought to promote systems biology for PFAS bioremediation. Here, we report the reductive defluorination of α, β-unsaturated per- and polyfluorocarboxylic acids byAcetobacteriumspp. Two critical molecular features inAcetobacteriumspecies enabling reductive defluorination are (i) a functional fluoride efflux transporter (CrcB) and (ii) an electron-bifurcating caffeate reduction pathway (CarABCDE). The fluoride transporter was required for detoxification of released fluoride. Car enzymes were implicated in defluorination by the following evidence: (i) onlyAcetobacteriumspp. withcargenes catalyzed defluorination; (ii) caffeate and PFAS competedin vivo; (iii) models from the X-ray structure of the electron-bifurcating reductase (CarC) positioned the PFAS substrate optimally for reductive defluorination; (iv) products identified by19F-NMR and high-resolution mass spectrometry were consistent with the model. Defluorination biomarkers identified here were found in wastewater treatment plant metagenomes on six continents.
Targeted inCITE-Seq Analysis Identifies the Loss of Nuclear TDP-43 in Endothelium as a Mediator of Blood Brain Barrier Signaling Pathway Dysfunction in Neurodegeneration
Authors: Omar Omar M.F. , Kimble Amy L. , Cheemala Ashok , Tyburski Jordan D. , Pandey Swati , Wu Qian , Reese Bo , Jellison Evan R. , Li Yunfeng , Hao Bing , Yan Riqiang , Murphy Patrick A. 
Published: December 2023

AbstractDespite the importance of the endothelium in the regulation of the blood brain barrier (BBB) in aging and neurodegenerative disease, difficulties in extracting endothelial cell (EC) nuclei have limited analysis of these cells. In addition, nearly all Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Degeneration (FTD), and a large portion of Alzheimer’s Disease (AD) exhibit neuronal TDP-43 aggregation, leading to loss of nuclear function, but whether TDP-43 is similarly altered in human BBB ECs is unknown. Here we utilize a novel technique for the enrichment of endothelial and microglial nuclei from human cortical brain tissues, combined with inCITE-seq, to analyze nuclear proteins and RNA transcripts in a large cohort of healthy and diseased donors. Our findings reveal a unique transcriptional signature in nearly half of the capillary endothelial cells across neurodegenerative states, characterized by reduced levels of nuclear β-Catenin and canonical downstream genes, and an increase in TNF/NF-kB target genes. We demonstrate that this does not correlate with increased nuclear p65/NF-kB, but rather a specific loss of nuclear TDP-43 in these disease associated ECs. Comparative analysis in animal models with targeted disruption of TDP-43 shows that this is sufficient to drive these transcriptional alterations. This work reveals that TDP-43 is a critical governor of the transcriptional output from nuclear p65/NF-kB, which has paradoxical roles in barrier maintenance and also barrier compromising inflammatory responses, and suggests that disease specific loss in ECs contributes to BBB defects observed in the progression of AD, ALS and FTD.
Loss of Endothelial TDP-43 Leads to Blood Brain Barrier Defects in Mouse Models of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
Authors: Cheemala Ashok , Kimble Amy L. , Tyburski Jordan D. , Leclair Nathan K. , Zuberi Aamir R. , Murphy Melissa , Jellison Evan R. , Reese Bo , Hu Xiangyou , Lutz Cathleen M. , Yan Riqiang , Murphy Patrick A. 
Published: December 2023

AbstractLoss of nuclear TDP-43 occurs in a wide range of neurodegenerative diseases, and specific mutations in theTARDBPgene that encodes the protein are linked to familial Frontal Temporal Lobar Dementia (FTD), and Amyotrophic Lateral Sclerosis (ALS). Although the focus has been on neuronal cell dysfunction caused by TDP-43 variants,TARDBPmRNA transcripts are expressed at similar levels in brain endothelial cells (ECs). Since increased permeability across the blood brain barrier (BBB) precedes cognitive decline, we postulated that altered functions of TDP-43 in ECs contributes to BBB dysfunction in neurodegenerative disease. To test this hypothesis, we examined EC function and BBB properties in mice with either knock-in mutations found in ALS/FTLD patients (TARDBPG348CandGRNR493X) or EC-specific deletion of TDP-43 throughout the endothelium (Cdh5(PAC)CreERT2; Tardbpff) or restricted to brain endothelium (Slco1c1(BAC)CreERT2; Tardbpff). We found thatTARDBPG348Cmice exhibited increased permeability to 3kDa Texas Red dextran and NHS-biotin, relative to their littermate controls, which could be recapitulated in cultured brain ECs from these mice. Nuclear levels of TDP-43 were reducedin vitroandin vivoin ECs fromTARDBPG348Cmice. This coincided with a reduction in junctional proteins VE-cadherin, claudin-5 and ZO-1 in isolated ECs, supporting a cell autonomous effect on barrier function through a loss of nuclear TDP-43. We further examined two models ofTardbpdeletion in ECs, and found that the loss of TDP-43 throughout the endothelium led to systemic endothelial activation and permeability. Deletion specifically within the brain endothelium acutely increased BBB permeability, and eventually led to hallmarks of FTD, including fibrin deposition, microglial and astrocyte activation, and behavioral defects. Together, these data show that TDP-43 dysfunction specifically within brain ECs would contribute to the BBB defects observed early in the progression of ALS/FTLD.
Stable Cortical Body Maps Before and After Arm Amputation
Authors: Schone Hunter R. , Maimon Mor Roni O. , Kollamkulam Mathew , Szymanska Malgorzata A. , Gerrand Craig , Woollard Alexander , Kang Norbert V. , Baker Chris I. , Makin Tamar R. 
Published: December 2023

AbstractThe adult brain’s capacity for cortical reorganization remains debated. Using longitudinal neuroimaging in three adults, followed up to five years before and after arm amputation, we compared cortical activity elicited by movement of the hand (pre-amputation) versus phantom hand (post-amputation) and lips (pre/post-amputation). We observed stable representations of both hand and lips. By directly quantifying activity changes across amputation, we overturn decades of animal and human research, demonstrating amputation does not trigger large- scale cortical reorganization.
How demography shapes linkage disequilibrium with or without recombination
Authors: Kerdoncuff Elise , Lambert Amaury , Achaz Guillaume 
Published: December 2023

AbstractLinkage Disequilibrium (LD) is a measure of the statistical association, within a population, between alleles present at different loci. We first briefly explain how LD, and in particular its decay as a function of the genetic distance between the two loci, is expected to be affected by mutation, recombination, selection, drift and demography. We then focus on three specific, widely used measures of LD:D, |D′|, andr2, in three different contexts: absence of recombination, a single recombination event, and an infinite amount of recombination events. We produce detailed characterizations of these three statistics under different demographic scenarios, with simulations, and with analytic results forD. We classify recombination events into four types and rank them according to their respective frequencies and effects. Finally, we provide recommendations for the uses of the different statistics and suggest applications of LD measures in the absence of recombination.
Flexible decision-making is related to strategy learning, vicarious trial and error, and medial prefrontal rhythms during spatial set-shifting
Authors: Miles Jesse T. , Mullins Ginger L. , Mizumori Sheri J. Y. 
Published: December 2023

AbstractA hallmark of behavioral flexibility is the ability to update behavior in response to changes in context. Most studies tend to rely on error counting around reward contingency or rule switches to measure flexibility, but these measures are difficult to adapt in a way that allows shorter timescale flexibility estimates. Further, choice accuracy does not account for other markers of flexibility, such as the hesitations and decision reversals humans and other animals often exhibit as decisions unfold, a behavior often called vicarious trial and error (VTE). To relate observable information about decision-making to latent aspects like learning and behavioral flexibility, we quantified changes in decision-making strategy using a previously developed, recency-weighted Bayesian inference algorithm. By comparing models of strategy use with decision history to generate strategy likelihood estimates on a trial-by-trial basis, the algorithm enabled us to identify learning points, and served as the basis for the development of a behavioral flexibility score. Aligning flexibility scores to learning points showed that flexibility peaked around estimated learning points and near peaks in VTE rate. However, we occasionally observed VTE during periods of low flexibility, where it often led to incorrect choices, suggesting the likely existence of multiple VTE-types. Additionally, we built on the decades of research suggesting a prominent role for the medial prefrontal cortex in enabling behavioral flexibility by recording field potentials from the medial prefrontal cortex during task performance. We observed changes in different field potential frequency bands that varied with respect to the different behavioral measures we used to characterize learning and decision-making. Overall, we demonstrate the use of multiple measures that jointly assess relationships between learning, behavioral flexibility, and decision-making behaviors. Further, we used these complementary measures to demonstrate that a particular decision-making behavior, VTE, was likely to be a marker of deliberation at some times, and uncertainty at others. Finally, we validate these measures by showing that theta, beta, and gamma rhythms in the medial prefrontal cortex vary with respect to both observable and latent aspects of behavior.
Glucocerebrosidase deficiency leads to neuropathology via cellular immune activation
Authors: Vincow Evelyn S. , Thomas Ruth E. , Milstein Gillian , Pareek Gautam , Bammler Theo , MacDonald James , Pallanck Leo 
Published: December 2023

AbstractMutations inGBA(glucosylceramidase beta), which encodes the lysosomal enzyme glucocerebrosidase (GCase), are the strongest genetic risk factor for the neurodegenerative disorders Parkinson’s disease (PD) and Lewy body dementia. Recent work has suggested that neuroinflammation may be an important factor in the risk conferred byGBAmutations. We therefore systematically tested the contributions of immune-related genes to neuropathology in aDrosophilamodel of GCase deficiency. We identified target immune factors via RNA-Seq and proteomics on heads from GCase-deficient flies, which revealed both increased abundance of humoral factors and increased macrophage activation. We then manipulated the identified immune factors and measured their effect on head protein aggregates, a hallmark of neurodegenerative disease. Genetic ablation of humoral (secreted) immune factors did not suppress the development of protein aggregation. By contrast, re-expressingGba1bin activated macrophages suppressed head protein aggregation inGba1bmutants and rescued their lifespan and behavioral deficits. Moreover, reducing the GCase substrate glucosylceramide in activated macrophages also amelioratedGba1bmutant phenotypes. Taken together, our findings show that glucosylceramide accumulation due to GCase deficiency leads to macrophage activation, which in turn promotes the development of neuropathology.Author SummaryMutations in the geneGBAare the largest risk factor for developing Parkinson’s disease and Lewy body dementia, diseases in which important brain cells die. We know that the immune system can be involved in these diseases, and thatGBAmutations cause immune changes. We did experiments to learn how the immune system changes could make brain cells more likely to die. Using a fruit fly that was missing the fly version ofGBA, we found out that inappropriately activated immune cells, but not secreted immune proteins, were important in the development of brain problems. We also learned that the abnormal activation was triggered by the lack ofGBAfunction in the immune cells, not by signals from the brain or other parts of the body. We would like to find out next whether the immune cells get inside the brain or cause harm from a distance. What we learned matters because it could help us prevent or cure brain diseases associated withGBAmutations. Treating the abnormal activation of immune cells in people with these mutations might help prevent damage to the brain.
Examining the potential involvement of NONO in TDP-43 proteinopathy inDrosophila
Authors: Koch Rafael , Nagoshi Emi 
Published: December 2023

AbstractThe misfolding and aggregation of TAR DNA binding protein-43 (TDP-43), leading to the formation of cytoplasmic inclusions, emerge as a key pathological feature in a spectrum of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). TDP-43 shuttles between the nucleus and cytoplasm but forms nuclear bodies (NBs) in response to stress. These NBs partially colocalize with nuclear speckles and paraspeckles that sequester RNAs and proteins, thereby regulating many cellular functions. The laboratory of Steven Brown has recently found that the non-POU domain-containing octamer-binding protein (NONO), a component of paraspeckles, forms novel nuclear speckle-like structures in mouse cortical neurons in response to stress and sleep deprivation. These findings suggest the possibility of a functional link between NONO and TDP-43, potentially contributing to TDP-43 proteinopathy. Here, we demonstrate that loss of function in theDrosophilahomolog ofNONO, no on or off transient A(NonA), exacerbates pathological phenotypes caused byTDP-43gain of function, leading to locomotor defects and life span shortening. These results provide supporting evidence for the functional link between NONO and TDP-43 and lay the foundation for dissecting underlying mechanisms.
Battery-Free Optoelectronic Patch for Photodynamic and Light Therapies in Treating Bacteria-Infected Wounds
Authors: Xue Zhao , Chou Wenxin , Xu Yixuan , Cheng ZiYi , Ren Xuechun , Sun Tianzhen , Tong Wenbin , Xie Yang , Chen Junyu , Zhang Nuohan , Sheng Xing , Wang Yongtian , Zhao Hongyou , Yang Jian , Ding He 
Published: December 2023

AbstractLight therapy is an effective approach for the treatment of a variety of challenging dermatological conditions. In contrast to existing methods involving high doses and large areas of illumination, alternative strategies based on wearable designs that utilize a low light dose over an extended period provide a precise and convenient treatment. In this study, we present a battery-free, skin-integrated optoelectronic patch that incorporates a coil-powered circuit, an array of microscale violet and red light emitting diodes (LEDs), and polymer microneedles (MNs) loaded with 5-aminolevulinic acid (5-ALA). This polymer MNs, based on the biodegradable composite materials of polyvinyl alcohol (PVA) and hyaluronic acid (HA), serves as light waveguides for optical access and a medium for drug release into deeper skin layers. Unlike conventional clinical photomedical appliances with a rigid and fixed light source, this flexible design allows for a conformable light source that can be applied directly to the skin. In animal models with bacterial-infected wounds, the experimental group with the combination treatment of metronomic photodynamic and light therapies reduced 2.48 log10CFU mL−1in bactericidal level compared to the control group, indicating an effective anti-infective response. Furthermore, post-treatment analysis revealed the activation of proregenerative genes in monocyte and macrophage cell populations, suggesting enhanced tissue regeneration, neovascularization, and dermal recovery. Overall, this optoelectronic patch design broadens the scope for targeting deep skin lesions, and provides an alternative with the functionality of standard clinical light therapy methods.