bluuebunny/crossref_metadata_2025_split huggingface dataset:
The human microglia responsome: a resource to better understand microglia states in health and disease
Authors: Snijders Gijsje J.L.J. , de Paiva Lopes Katia , Sneeboer Marjolein A.M. , Muller Benjamin Z. , Gigase Frederieke A.J. , Vialle Ricardo A. , Missall Roy , Kubler Raphael , Raj Towfique , Humphrey Jack , de Witte Lot D. 
Published: October 2023

AbstractMicroglia, the immune cells of the brain, are increasingly implicated in neurodegenerative disorders through genetic studies. However, how genetic risk factors for these diseases are related to microglial gene expression, microglial function, and ultimately disease, is still largely unknown. Microglia change rapidly in response to alterations in their cellular environment, which is regulated through changes in transcriptional programs, which are as yet poorly understood. Here, we compared the effects of a set of inflammatory and restorative stimuli (lipopolysaccharide, interferon-gamma, resiquimod, tumor necrosis factor-alpha, adenosine triphosphate, dexamethasone, and interleukin-4) on human microglial cells from 67 different donors (N = 398 samples) at the gene and transcript level. We show that microglia from different anatomical brain regions show distinct responses to inflammatory stimuli. We observed a greater overlap between human stimulated microglia and human monocytes than with mouse microglia. We define specific microglial signatures across conditions which are highly relevant for a wide range of biological functions and complex human diseases. Finally, we used our stimulation signatures to interpret associations from Alzheimer’s disease (AD) genetic studies and microglia by integrating our inflammatory gene expression profiles with common genetic variants to mapcis-expression QTLs (eQTLs). Together, we provide the most comprehensive transcriptomic database of the human microglia responsome.HighlightsRNA-sequencing of 398 human microglial samples exposed to six different triggers.Microglia from different anatomical regions show distinct stimulation responses.Responses in human microglia show a greater overlap with human monocytes than murine microglia.Mapping of response Quantitative Trait Loci identifies interactions between genotype and effect of stimulation on gene expression.Our atlas provides a reference map for interpreting microglia signatures in health and disease.
Mesenchymal-specific Alms1 knockout in mice recapitulates key metabolic features of Alström Syndrome
Authors: McKay Eleanor J. , Luijten Ineke , Weng Xiong , Martinez de Morentin Pablo B. , De Frutos González Elvira , Gao Zhanguo , Kolonin Mikhail G. , Heisler Lora K. , Semple Robert K. 
Published: October 2023

AbstractBackgroundAlström Syndrome (AS), a multi-system disease caused by mutations in theALMS1gene, includes obesity with disproportionately severe insulin resistant diabetes, dyslipidemia, and hepatosteatosis. How loss of ALMS1 causes this phenotype is poorly understood, but prior studies have circumstancially implicated impaired adipose tissue expandability. We set out to test this by comparing the metabolic effects of selectiveAlms1knockout in mesenchymal cells including preadipocytes to those of globalAlms1knockout.MethodsGlobalAlms1knockout (KO) mice were generated by crossing floxedAlms1and CAG-Cre mice. APdgfrα-Cre driver was used to abrogate Alms1 function selectively in mesenchymal stem cells (MSCs) and their descendants, including preadipocytes. We combined metabolic phenotyping of global andPdgfrα+Alms1-KO mice on a 45% fat diet with measurements of body composition and food intake, and histological analysis of metabolic tissues.ResultsGlobalAlms1KO caused hyperphagia, obesity, insulin resistance, dyslipidaemia, and fatty liver.Pdgfrα-credriven KO ofAlms1(MSC KO) recapitulated insulin resistance, fatty liver, and dyslipidaemia in both sexes. Other phenotypes were sexually dimorphic: increased fat mass was only present in femaleAlms1MSC KO mice. Hyperphagia was not evident in maleAlms1MSC KO mice, but was found in MSC KO females, despite no neuronal Pdgfrαexpression.ConclusionsMesenchymal deletion ofAlms1recapitulates the metabolic features of AS, including severe fatty liver. This confirms a key role forAlms1in the adipose lineage, where its loss is sufficient to cause systemic metabolic effects and damage to remote organs. AS should be regarded as aforme frusteof lipodystrophy. Therapies should prioritise targeting positive energy balance.
New purifications reveal yeast and human stress granule cores are discrete particles with complex transcriptomes and proteomes
Authors: Demeshkina Natalia A. , Ferré-D’Amaré Adrian R. 
Published: October 2023

SUMMARYStress granules are a conserved response of eukaryotic cells to environmental insults. These cytoplasmic ribonucleoprotein condensates have hitherto been primarily studied by microscopy, which showed previously that they comprise dense ≈200 nm cores embedded in a diffuse shell. We have developed new purifications of budding yeast and mammalian (HEK293T cell) stress granule cores that do not rely on immunoprecipitation of candidate protein constituents. These unbiased preparations reveal that stress granule cores are discrete particles with variable size (mean, 135 nm and 225 nm, yeast and human, respectively) and shape. Proteomics and transcriptomics demonstrate complex composition. The results of hybrid chain reaction FISH analyses in HEK293T cells are consistent with stress granule cores having heterogeneous composition,i.e., each stress granule core particle contains only a limited number of mRNA species. Biochemical purification now opens the way to mechanistic analysis of the heterogeneity and complexity of stress granules.
COST AND UTILIZATION TRENDS OF PERCUTANEOUS KIDNEY BIOPSY IN KIDNEY TRANSPLANT PATIENTS: A 4-YEAR CLAIMS DATA ANALYSIS
Authors: Vilalta Adrian 
Published: October 2023

ABSTRACTObjectiveThis study evaluated patterns of utilization and costs of percutaneous kidney biopsies in kidney transplant patients.MethodsThe IBMTreatment Pathwaystool was used to interrogate cohorts selected from the IBMMarketScandataset. Analyses were done for both adult and pediatric patients. Differences in biopsy paid amounts and utilization patterns were assessed for commercial payers, Medicare, and Medicaid. Claims data were collected for the years 2016 to 2019.ResultsA total of 15,337 records for percutaneous kidney biopsy events performed between 2016 and 2019 were identified in the database. Out of these, 840 corresponded to pediatric patients.DiscussionAnalysis showed that the paid amount for the procedure increased by 10% from 2016 to 2019 for commercial payers for adult patients, with US $4,137 being the median paid amount in 2019. Median paid amounts by both Medicare and Medicaid remained essentially flat for the same time at US $2,063 for Medicare and US $865 for Medicaid in 2019. Median cost of the procedure in pediatric patients increased 17% between 2016 and 2019 for commercial payers being US $6,068 in 2019. Medicaid payments for the pediatric patient population showed little change between 2016 and 2019, being US $1,666 in 2019.
Demonstrating the Utility of Instrumented Gait Analysis in the Treatment of Children with Cerebral Palsy
Authors: Schwartz Michael H. , Ries Andrew J. , Georgiadis Andrew G. , Kainz Hans 
Published: October 2023

AbstractBackgroundInstrumented gait analysis (IGA) has been around for a long time but has never been shown to be useful for improving patient outcomes. In this study we demonstrate the potential utility of IGA by showing that machine learning models are better able to estimate treatment outcomes when they include both IGA and clinical (CLI) features compared to when they include CLI features alone.DesignWe carried out a retrospective analysis of data from ambulatory children diagnosed with cerebral palsy who were seen at least twice at our gait analysis center. Individuals underwent a variety of treatments (including no treatment) between sequential gait analyses. We fit Bayesian Additive Regression Tree (BART) models that estimated outcomes for mean stance foot progression to demonstrate the approach. We built two models: one using CLI features only, and one using CLI and IGA features. We then compared the models’ performance in detail. We performed similar, but less detailed, analyses for a number of other outcomes. All results were based on independent test data from a 70%/30% training/testing split.ResultsThe IGA model was more accurate than the CLI model for mean stance-phase foot progression outcomes (RMSEIGA= 11∘, RMSECLI= 13∘) and explained more than 1.5× as much of the variance (R2IGA= .45, R2CLI= .28). The IGA model outperformed the CLI model for every level of treatment complexity, as measured by number of simultaneous surgeries. The IGA model also exhibited superior performance for estimating outcomes of mean stance-phase knee flexion, mean stance-phase ankle dorsiflexion, maximum swing-phase knee flexion, gait deviation index (GDI), and dimensionless speed.InterpretationThe results show that IGA has thepotentialto be useful in the treatment planning process for ambulatory children diagnosed with cerebral palsy. We propose that the results of machine learning outcome estimators — including estimates of uncertainty — become the primary IGA tool utilized in the clinical process, complementing the standard medical practice of conducting a through patient history and physical exam, eliciting patient goals, reviewing relevant imaging data, and so on.
PCBP2 as an intrinsic aging factor regulates the senescence of hBMSCs through the ROS-FGF2 signaling axis
Authors: Chen Pengbo , Li Bo , Lu Zeyu , Xu Qingyin , Zheng Huoliang , Jiang Shengdan , Jiang Leisheng , Zheng Xinfeng 
Published: October 2023

AbstractBackgroundIt has been reported that loss of PCBP2 led to increased reactive oxygen species (ROS) production and accelerated cell aging. Knockdown of PCBP2 in HCT116 cells leads to significant down-regulation of fibroblast growth factor 2 (FGF2). Here, we tried to elucidate the intrinsic factors and potential mechanisms of BMSCs aging from the interactions among PCBP2, ROS and FGF2.MethodsUnlabeled quantitative proteomics were performed to show differentially expressed proteins in the replicative senescent human-derived bone marrow stromal cells (RS-hBMSCs). ROS and FGF2 were detected in the loss-and-gain cell function experiments of PCBP2. The function recovery experiments were performed to verify whether PCBP2 regulates cell function through ROS/FGF2-dependent ways.ResultsPCBP2 expression was significantly lower in P10-hBMSCs. Knocking down the expression of PCBP2 inhibited the proliferation while accentuated the apoptosis and cell arrest of RS-hBMSCs. PCBP2 silence could increase the production of ROS. On the contrary, overexpression of PCBP2 increased the viability of both P3-hBMSCs and P10-hBMSCs significantly. Meanwhile, over-expression of PCBP2 led to significantly reduced expression of FGF2. Overexpression of FGF2 significantly offset the effect of PCBP2 overexpression in P10-hBMSCs, leading to decreased cell proliferation, increased apoptosis and reduced G0/G1 phase ratio of the cells.ConclusionThis study initially elucidates that PCBP2 as an intrinsic aging factor regulates the replicative senescence of hBMSCs through the ROS-FGF2 signaling axis.
Atrial functional substrates for the prediction of atrial fibrillation recurrence after pulmonary vein isolation
Authors: Masuda Masaharu , Matsuda Yasuhiro , Uematsu Hiroyuki , Asai Mitsutoshi , Okamoto Shin , Ishihara Takayuki , Nanto Kiyonori , Tsujimura Takuya , Hata Yosuke , Higashino Naoko , Nakao Sho , Mano Toshiaki 
Published: October 2023

AbstractBackgroundLow-voltage areas have been used as atrial structural substrates in estimating fibrotic degeneration in patients with atrial fibrillation (AF). The high-resolution maps obtained by recently developed mapping catheters allow the visualization of several functional abnormalities.ObjectivesWe investigated the association between left atrial (LA) functional abnormal findings on a high-resolution substrate map and AF recurrence in patients who underwent pulmonary vein isolation without any additional LA substrate ablation.MethodsOne hundred consecutive patients who underwent second ablation for AF (paroxysmal, 48%; persistent, 52%) were considered for enrollment. Patients with extra-pulmonary-vein LA substrate ablation during the initial and second ablation were excluded. LA mapping was performed using a 64-pole mini-basket catheter on the Rhythmia mapping system. Patients were followed for 2 years.ResultsAF recurrence developed in 39 (39%) patients. On the high-resolution substrate map, AF recurrence was associated with the presence of the following findings: low-voltage areas (<1.0 mV, >5cm2; hazard ratio [HR]=2.53; 95% confidence interval [CI]=1.30-4.93; p<0.006), fractionated-electrogram areas (≥5 peaks, >5cm2; HR=2.15, 95%CI=1.10-4.19; p=0.025), LA conduction time of >130 msec (HR=3.11, 95%CI=1.65-5.88, p<0.0001), deceleration zone (≥5 isochrones/cm2; HR=1.97, 95%CI=1.04-3.37, p=0.039), and multiple septal breakout points (HR=3.27, 95%CI=1.50-7.16, p=0.003). Accumulation of these risk factors increased AF recurrence in a stepwise manner, with an HR=1.90, 95%CI=1.44-2.52, p<0.00001 for each additional risk factor.ConclusionA high-resolution map revealed new LA functional substrates associated with AF recurrence. Implementation of functional substrates may improve the prediction of AF recurrence after ablation, and possibly aid the development of tailored AF ablation strategies.Graphical abstractAbnormal LA substrates and accumulation of risk factorsStudy design, representative maps demonstrating abnormal substrates, and AF recurrence rates stratified by the number of risk factors are shown. Accumulation of these risk factors increased AF recurrence rates in a stepwise manner with an HR = 1.90, 95% CI = 1.44 - 2.52, p<0.00001, for 1 risk increase. AF indicates atrial fibrillation; HR, hazard ratio; CI, confidence interval.
Characterization ofRalstonia pseudosolanacearumdiversity and screening host resistance to manage bacterial wilt in South Asia
Authors: Subedi Nagendra , Cowell Tabitha , Cope-Arguello Matthew , Paul Pierce , Cellier Gilles , Bkayrat Hashem , Bonagura Nicolas , Cadatal Angela , Chen Rachel , Enriquez Ariana , Parasar Rama , Repetto Lisa , Hernandez Rivas Aracely , Shahbaz Mahnoor , White Kaitlin , Lowe-Power Tiffany M. , Miller Sally A. 
Published: October 2023

AbstractIn South Asia, bacterial wilt pathogens in theRalstonia solanacearumspecies complex (RSSC) impose major constraints on eggplant, tomato, and pepper production. To improve the efficacy of bacterial wilt management, the goals of this study were to (1) conduct a survey of RSSC pathogens in Bangladesh and Nepal, (2) characterize the genetic diversity of these isolates, and (3) screen 37 tomato, eggplant, and pepper accessions for resistance to six representative isolates from South Asia. We isolated 99 isolates from Bangladesh and 20 isolates from Nepal and determined that all are phylotype I isolates of theRalstonia pseudosolanacearumspecies. We sequenced and assembled draft genomes for 25 isolates. Phylogenomic analyses suggest that there is a wide diversity of endemic phylotype I isolates in South Asia, and possible introductions of two clonal phylotype I lineages into Bangladesh and Nepal. We contextualize our newly described isolates based on prior reports of RSSC diversity in South Asia and global reports of RSSC pathogens on eggplant and pepper. Greenhouse trials revealed multiple tomato, eggplant, and pepper accessions that exhibit promising levels of resistance to six phylotype I isolates from South Asia.
Super-resolution imaging of potassium channels with genetically encoded EGFP
Authors: Call Isabelle M. , Bois Julian L. , Hansen Scott B. 
Published: October 2023

ABSTRACTThe plasma membrane is a well-organized structure of lipids and proteins, segmented into lipid compartments under 200 nm in size. This specific spatial patterning is crucial for the function of proteins and necessitates super-resolution imaging for its elucidation. Here, we establish that the genetically encoded enhanced green fluorescent protein (EGFP), when combined with direct optical reconstruction microscopy (dSTORM), tracks shear- and cholesterol-induced nanoscopic patterning of potassium channels overexpressed in HEK293T cells. Leveraging EGFP in dSTORM (EGFP-STORM), our findings indicate that cholesterol directs the C-terminus of TWIK-related potassium channel (TREK-1) to ceramide-enriched lipid ganglioside (GM1) clusters. In the absence of the C-terminus, the channel associates with phosphatidylinositol 4,5-bisphosphate (PIP2) cluster. Similarly, cholesterol derived from astrocytes repositions EGFP-tagged inward-rectifying potassium (Kir) channels into GM1 clusters. Without cholesterol, the channel aligns with PIP2lipids. We deduce that cholesterol’s interaction with Kir sequesters the channel, separating it from its activating lipid PIP2. Fundamentally, a genetically encoded EGFP tag should make any protein amenable to dSTORM analysis.
Biosynthesis of the azoxy compound azodyrecin fromStreptomyces mirabilisP8-A2
Authors: Maleckis Matiss , Wibowo Mario , Gren Tetiana , Jarmusch Scott A. , Sterndorff Eva B. , Booth Thomas , Henriksen Nathalie N. S. E. , Whitford Christopher M. , Jiang Xinglin , Jørgensen Tue S. , Ding Ling , Weber Tilmann 
Published: October 2023

AbstractAzoxy compounds are a distinctive group of bioactive secondary metabolites, characterized by a unique RN=N+(O-)R moiety. The azoxy moiety is present in various classes of metabolites that exhibit various biological activities. The enzymatic mechanisms underlying azoxy bond formation remain enigmatic. Azodyrecins are cytotoxic azoxy metabolites produced byStreptomyces mirabilisP8-A2. Here we cloned and confirmed the putativeazdbiosynthetic gene cluster through CATCH cloning followed by expression and production of azodyrecins in two heterologous hosts,S. albidoflavusJ1074 andS. coelicolorM1146, respectively. We explored the function of 14 enzymes in azodyrecin biosynthesis through gene knock-out using CRISPR-Cas9 base editing in the native producer,S. mirabilisP8-A2. The key intermediates were analyzed in the mutants through MS/MS fragmentation studies, revealing azoxy bond formation via the conversion of hydrazine to azo compound; followed by further oxygenation. Additionally,N-oxygenase and dehydrogenase activities were confirmed among 8 core biosynthetic genes and five helper genes. Moreover, the distribution of the azoxy biosynthetic gene clusters acrossStreptomycesspp. genomes is explored, highlighting the presence of these clusters in over 20% of theStreptomycesspp. genomes and revealing that azoxymycin and valanimycin are scarce, while azodyrecin and KA57A like clusters are widely distributed across the phylogenetic tree.
The effects of genome size on cell size and the functional composition and morphology of leaves: a case study inRhododendron(Ericaceae)
Authors: Dastpak Arezoo , Williams Monica , Perkins Sally , Perkins John A. , Horn Charles , Thompson Patrick , Ryan Connor , Medeiros Juliana , An Yi-Dong , Jiang Guo-Feng , Simonin Kevin A. , Roddy Adam B. 
Published: October 2023

AbstractBackground and AimsDespite the predominance of scaling photosynthetic metabolism by two-dimensional leaf surface area, leaves are three-dimensional structures composed of multiple tissues that directly and indirectly influence photosynthetic metabolism. The structure of leaf surfaces for CO2diffusion and light transmission and the internal volume of tissues that process energy and matter work together to control rates of resource acquisition and turnover. Here we investigate the influence of cell size and packing density on resource acquisition as measured by surface conductance to CO2and water vapor and on resource turnover as measured by leaf water turnover time.MethodsWe sampled wild and cultivated congeneric species in the genusRhododendron(Ericaceae) and measured genome size, anatomical traits related to cell sizes and packing densities, and morphological traits related to water content and dry mass allocation.ResultsAmongRhododendron, anatomical traits related to cell size and morphological traits related to water content and dry mass investment varied largely orthogonally to each other, allowing for many combinations of leaf traits to exist. However, there was a strong, negative relationship between the leaf water residence time (τ) and the maximum leaf surface conductance per leaf volume (gmax,vol), both of which are influenced by cell size and cell packing densities.ConclusionsDespite leaf function being controlled by many potential combinations of leaf cell- and tissue-level traits, cell size has a pervasive effect on leaf function. Small cells allow for higher diffusion of CO2and water vapor per unit leaf volume (gmax,vol) even at constant leaf thickness, but small cells also result in shorter leaf water residence times (τ). The strong tradeoff betweengmax,voland (τ) illuminates how genome size-cell size allometry influences the fast-slow continuum of plant carbon and water economy.
EEG spectral attractors identify a geometric core of resting brain activity
Authors: Pourdavood Parham , Jacob Michael S. 
Published: October 2023

AbstractSpectral analysis of electroencephalographic (EEG) data simplifies the characterization of periodic band parameters but can obscure underlying dynamics. By contrast, reconstruction of neural activity in state-space preserves geometric complexity in the form of a multidimensional, global attractor. Here we combine these perspectives, inferring complexity and shared dynamics from eigen-time-delay embedding of periodic and aperiodic spectral parameters to yield unique dynamical attractors for each EEG parameter. We find that resting-state alpha and aperiodic attractors show low geometric complexity and shared dynamics with all other frequency bands, what we refer to as geometric cross-parameter coupling. Further, the geometric signatures of alpha and aperiodic attractors dominate spectral dynamics, identifying a geometric core of brain activity. Non-core attractors demonstrate higher complexity but retain traces of this low-dimensional signal, supporting a hypothesis that frequency specific information differentiates out of an integrative, dynamic core. Older adults show lower geometric complexity but greater geometric coupling, resulting from dedifferentiation of gamma band activity. The form and content of resting-state thoughts were further associated with the complexity of core dynamics. Thus, the hallmarks of resting-state EEG in the frequency domain, the alpha peak and the aperiodic backbone, reflect a dynamic, geometric core of resting-state brain activity. This evidence for a geometric core in EEG complements evidence for a regionally defined dynamic core from fMRI-based neuroimaging, further supporting the utility of geometric approaches to the analysis of neural data.