bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ras-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome-associated cardiac hypertrophy
Authors: Cuevas-Navarro Antonio , Wagner Morgan , Van Richard , Swain Monalisa , Allison Madeline R. , Cheng Alice , Messing Simon , Simanshu Dhirendra K. , Sale Matthew J. , McCormick Frank , Stephen Andrew G. , Castel Pau 
Published: November 2022

AbstractRIT1 belongs to the family of Ras guanosine triphosphatases (GTPases) that regulate many aspects of signal transduction and are drivers of cancer and congenital disorders.RIT1gain-of-function mutations are found in lung cancer, leukemia, and in the germline of Noonan syndrome individuals with an increased prevalence of cardiac hypertrophy and other congenital heart defects. Pathogenic RIT1 proteins evade proteasomal degradation and promote MEK/ERK mitogen-activated protein kinase (MAPK) hyperactivation, yet the mechanism remains poorly understood. Here we show that RAF kinases are putative mutant RIT1 effectors necessary for MAPK activation and characterize RIT1 association with plasma membrane lipids and interaction with RAF kinases. We identify critical residues present in the RIT1 hypervariable region that facilitate interaction with negatively charged membrane lipids and show that these are necessary for association with RAF kinases. Although mutant RIT1 binds to RAF kinases directly, it fails to activate RAF-MAPK signaling in the absence of classical Ras proteins. Consistent with aberrant RAF/MEK/ERK activation as a driver of disease, we show that MEK inhibition alleviates cardiac hypertrophy in a mouse model of RIT1-mutant Noonan syndrome. These data shed light on pathogenic RIT1 function and identify avenues for therapeutic intervention.One Sentence SummaryElectrostatic plasma membrane association facilitates RIT1-mediated Ras-dependent RAF kinase activation to promote pathogenic MAPK signaling.
High growing season temperatures limit winter recovery of grapevines fromXylella fastidiosainfection – implications for epidemiology in hot climates
Authors: Burbank Lindsey , Sisterson Mark S. , Wei Wei , Ortega Brandon , Luna Nathaniel , Naegele Rachel 
Published: November 2022

AbstractManagement of widespread plant pathogens is challenging as climatic differences among crop growing regions may alter key aspects of pathogen spread and disease severity.Xylella fastidiosais a xylem-limited bacterial pathogen that is transmitted by xylem sap feeding insects. Geographic distribution ofX. fastidiosais limited by winter climate and vines infected withX. fastidiosacan recover from infection when held at cold temperatures. California has a long history of research on Pierce’s disease, and significant geographic and climatic diversity among grape-growing regions. This background in combination with experimental disease studies under controlled temperature conditions can inform risk assessment forX. fastidiosaspread and epidemic severity across different regions and under changing climate conditions. California’s grape growing regions have considerable differences in summer and winter climate. In northern and coastal regions, summers are mild and winters cool, conditions favoring winter recovery of infected vines. In contrast, in inland and southern areas summers are hot and winters mild, reducing likelihood of winter recovery. Here, winter recovery of three table grape cultivars (Flame, Scarlet Royal, and Thompson seedless) and three wine grape cultivars (Sauvignon Blanc, Cabernet Sauvignon, and Zinfandel) were evaluated under temperature conditions representative of the San Joaquin Valley, an area with hot summers and mild winters that has been severely impacted by Pierce’s disease, and contains a large portion of California grape production. Mechanically inoculated vines were held in the greenhouse under one of three warming treatments to represent different seasonal inoculation dates prior to being moved into a cold chamber. Winter recovery under all treatments was generally limited, but with some cultivar variation. Given hot summer temperatures of many grape-growing regions worldwide, as well as increasing global temperatures overall, winter recovery of grapevines should not be considered a key factor affectingX. fastidiosaspread and epidemic severity in the majority of cases.
Single-cell transcriptomics reveals subset-specific metabolic profiles underpinning the bronchial epithelial response to flagellin
Authors: Ramirez-Moral Ivan , Schuurman Alex R. , Butler Joe M. , Yu Xiao , de Haan Karen , van Leeuwen Sarah , de Vos Alex F. , de Jong Menno D. , Vieira Braga Felipe A. , van der Poll Tom 
Published: November 2022

ABSTRACTRespiratory epithelial cells line the airways and represent the first line of defense against respiratory pathogens. The cellular heterogeneity of the airway wall has only recently been recognized by single-cell analyses. Here, we leveraged single-cell RNA sequencing of primary human bronchial epithelial cells growing in air-liquid interface to determine cell-specific changes evoked by flagellin, a protein driving the motility of many mucosal pathogens. We detected seven cell clusters in the human epithelium, including ciliated cells, ionocytes and several states of basal and secretory cells, of which only inflammatory basal cells and inflammatory secretory cells showed a proportional increase in response to flagellin. Only inflammatory secretory cells showed evidence of metabolic reprogramming toward aerobic glycolysis, and inhibition of the mTOR pathway specifically reduced this subset, prevented this metabolic shift, and reduced inflammatory gene transcription in these cells. This study expands our knowledge of the airway’s immune response to flagellated pathogens to single cell resolution and defines a novel target to modulate mucosal immunity during bacterial infections.
Functional validation of transposable element derivedcis-regulatory elements in Atlantic salmon
Authors: Sahlström Hanna M. , Datsomor Alex K. , Monsen Øystein , Hvidsten Torgeir R. , Sandve Simen Rød 
Published: November 2022

AbstractBackgroundTransposable elements (TEs) are hypothesized to play important roles in shaping genome evolution following whole genome duplications (WGD), including rewiring of gene regulation. In a recent analysis, duplicate gene copies that had evolved higher expression in liver following the salmonid WGD ~100 million years ago were associated with higher numbers of predicted TE-derivedcis-regulatory elements (TE-CREs). Yet, the ability of these TE-CREs to recruit transcription factors (TFs)in vivoand impact gene expression remains unknown.ResultsHere, we evaluated the gene regulatory functions of 11 TEs using luciferase promoter reporter assays in Atlantic salmon (Salmo salar) primary liver cells. Canonical Tc1-Marinerelements from intronic regions showed no or small repressive effects on transcription. However, other TE-derivedcis-regulatory elements upstream of transcriptional start sites increased expression significantly.ConclusionOur results question the hypothesis that TEs in the Tc1-Marinersuperfamily, which were extremely active following WGD in salmonids, had a major impact on regulatory rewiring of gene duplicates, but highlights the potential of other TEs in post-WGD rewiring of gene regulation in the Atlantic salmon genome.
Laurdan discerns lipid membrane hydration and cholesterol content
Authors: Orlikowska-Rzeznik Hanna , Krok Emilia , Chattopadhyay Madhurima , Lester Agnieszka , Piatkowski Lukasz 
Published: November 2022

ABSTRACTStudies of biological membrane heterogeneity particularly benefit from the use of the environment-sensitive fluorescent probe Laurdan, for which shifts in the emission, produced by any stimulus (e.g. fluidity variations), are ascribed to alterations in hydration near the fluorophore. Ironically, no direct measure of the influence of membrane hydration level on Laurdan spectra has been available. To address this, we investigated the fluorescence spectrum of Laurdan embedded in solid-supported lipid bilayers as a function of hydration and compared it with the effect of cholesterol – a major membrane fluidity regulator. The effects are illusively similar, hence the results obtained with this probe should be interpreted with caution. The dominant phenomenon governing the changes in the spectrum is the hindrance of the lipid internal dynamics. Furthermore, we unveiled the intriguing mechanism of dehydration-induced redistribution of cholesterol between domains in the phase-separated membrane which reflects yet another regulatory function of cholesterol.
Exact expressions and numerical evaluation of average evolvability measures for characterizing and comparing G matrices
Authors: Watanabe Junya 
Published: November 2022

AbstractTheory predicts that the additive genetic covariance (G) matrix determines a population’s short-term (in)ability to respond to directional selection—evolvability in the Hansen–Houle sense—which is typically quantified and compared via certain scalar indices called evolvability measures. Often, interest is in obtaining the averages of these measures across all possible selection gradients, but explicit formulae for most of these average measures have not been known. Previous authors relied either on approximations by the delta method, whose accuracy is generally unknown, or Monte Carlo evaluations (including the random skewers analysis), which necessarily involve random fluctuations. This study presents new, exact expressions for the average conditional evolvability, average autonomy, average respondability, average flexibility, average response difference, and average response correlation, utilizing their mathematical structures as ratios of quadratic forms. The new expressions are infinite series involving top-order zonal and invariant polynomials of matrix arguments, and can be numerically evaluated as their partial sums with, for some measures, known error bounds. Whenever these partial sums numerically converge within reasonable computational time and memory, they will replace the previous approximate methods. In addition, new expressions are derived for the average measures under a general normal distribution for the selection gradient, extending the applicability of these measures into a substantially broader class of selection regimes.
Aceandace-like genes of invasive redlegged earth mite: Copy number variation, target-site mutations, and their associations with organophosphate insensitivity
Authors: Thia Joshua A , Umina Paul A , Hoffmann Ary A 
Published: November 2022

AbstractBACKGROUNDInvasive Australian populations of redlegged earth mite,Halotydeus destructor(Tucker), are evolving increasing organophosphate resistance. In addition to the canonicalacegene, the target gene of organophosphates, theH. destructorgenome contains many radiatedace-like genes that vary in copy number and amino acid sequence. In this work, we characterise copy number and target-site mutation variation at the canonicalaceandace-like genes and test for potential associations with organophosphate insensitivity. This was achieved through comparisons of whole-genome pool-seq data from alive and dead mites following organophosphate exposure.RESULTSA combination of increased copy number and target-site mutations at the canonicalacewas associated with organophosphate insensitivity inH. destructor. Resistant populations were segregating for G119S, A201S, F331Y at the canonicalace. A subset of populations also had copy numbers of canonicalace>2, which potentially helps over-express proteins carrying these target-site mutations. Haplotypes possessing different copy numbers and target-site mutations of the canonicalacegene may be under selection acrossH. destructorpopulations. We also detected some evidence that increases in copy number of radiatedace-like genes are associated with organophosphate insensitivity, which might suggest potential roles in sequestration or breakdown of organophosphates.CONCLUSIONDifferent combinations of target-site mutations and (or) copy number variation in the canonicalaceandace-like genes may provide non-convergent ways forH. destructorto respond to organophosphate selection. However, these changes may only play a partial role in organophosphate insensitivity, which appears to have a polygenic architecture.
Presaccadic attention sharpens visual acuity
Authors: Kwak Yuna , Hanning Nina M. , Carrasco Marisa 
Published: November 2022

SummaryVisual perception is limited by spatial resolution, which declines with eccentricity and differs around polar angle locations. To compensate for poor peripheral resolution, we make rapid eye movements –saccades– to bring peripheral objects into high-acuity foveal vision. Already before saccade onset, visual attention shifts to the saccade target location and prioritizes visual processing. Thispresaccadic shift of attentionimproves performance in many visual tasks, but whether it changes resolution is unknown. Here, we investigated whether presaccadic attention sharpens peripheral spatial resolution; and if so, whether such effect interacts with polar angle locations. We measured acuity thresholds in an orientation discrimination task during fixation and saccade preparation around the visual field. The results revealed that presaccadic attention sharpens acuity, which can facilitate a smooth transition from peripheral to foveal representation. This acuity enhancement is similar across the four cardinal locations; thus, presaccadic attention does not change polar angle differences in resolution.
Sourmash Branchwater Enables Lightweight Petabyte-Scale Sequence Search
Authors: Irber Luiz , Pierce-Ward N. Tessa , Brown C. Titus 
Published: November 2022

AbstractWe introduce branchwater, a flexible and fast petabase-scale search for the 767,000 public metagenomes presently in the NCBI Sequence Read Archive. Our search is based on the FracMinHash k-mer sketching technique and can search all public metagenomes with 1000 query genomes in approximately 36 hours using 50 GB of RAM and 32 threads. Branchwater is a Rust-based multithreading front-end built on top of the sourmash library. We provide biological use cases, examine performance, and discuss design and performance considerations.
Spinal cord and brain concentrations of riluzole after oral and intrathecal administration: a potential new treatment route for amyotrophic lateral sclerosis
Authors: Keifer Orion P. , Gutierrez Juan Marco , Butt Mark T. , Cramer Sarah D. , Bartus Raymond , Tansey Malu , Deaver Daniel , Betourne Alexandre , Boulis Nicholas M 
Published: November 2022

SummaryRiluzole is the only treatment known to improve survival in patients with Amyotrophic Lateral Sclerosis (ALS). However, oral riluzole efficacy is modest at best, further it is known to have large inter-individual variability of serum concentration and clearance, is formulated as an oral drug in a patient population plagued with dysphagia, and has known systemic side-effects like asthenia (limiting patient compliance) and elevated liver enzymes. In this context, we postulated that continuous intrathecal (IT) infusion of low doses of riluzole could provide consistent elevations of the drug spinal cord (SC) concentrations at or above those achieved with oral dosing, without increasing the risk for adverse events associated with systemic drug exposure or off-target side effects in the brain. We developed a formulation of riluzole for IT delivery and conducted our studies in purpose-bred hound dogs. Our non-GLP studies revealed that IT infusion alone was able to increase SC concentrations above those provided by oral administration, without increasing plasma concentrations. We then conducted two GLP studies that combined IT infusion with oral administration at human equivalent dose, to evaluate SC and brain concentrations of riluzole along with assessments of safety and tolerability. In the 6-week study, the highest IT dose (0.2 mg/hr) was well tolerated by the animals and increased SC concentrations above those achieved with oral riluzole alone, without increasing brain concentrations. In the 6-month study, the highest dose tested (0.4 mg/hr) was not tolerated and yielded SC significantly above those achieved in all previous studies. Our data show the feasibility and safety profile of continuous IT riluzole delivery to the spinal cord, without concurrent elevated liver enzymes, and minimal brain concentrations creating another potential therapeutic route of delivery to be used in isolation or in combination with other therapeutics.”
Phylogenetic analysis of the MCL1 BH3 binding groove and rBH3 sequence motifs in the p53 and INK4 protein families
Authors: McGriff Anna , Placzek William J. 
Published: November 2022

AbstractB-cell lymphoma 2 (Bcl-2) proteins are central, conserved regulators of apoptosis. Bcl-2 family function is regulated by binding interactions between the Bcl-2 homology 3 (BH3) motif in pro-apoptotic family members and the BH3 binding groove found in both the pro-apoptotic effector and anti-apoptotic Bcl-2 family members. A novel motif, the reverse BH3 (rBH3), has been shown to interact with the anti-apoptotic Bcl-2 homolog MCL1 (Myeloid cell leukemia 1) and have been identified in the p53 homolog p73, and the CDK4/6 (cyclin dependent kinase 4/6) inhibitor p18INK4c, (p18, cyclin-dependent kinase 4 inhibitor c). To determine the conservation of rBH3 motif, we first assessed conservation of MCL1’s BH3 binding groove, where the motif binds. We then constructed neighbor-joining phylogenetic trees of the INK4 and p53 protein families and analyzed sequence conservation using sequence logos of the rBH3 locus. This showed the rBH3 motif is conserved throughout jawed vertebrates p63 and p73 sequences and in chondrichthyans, amphibians, mammals, and some reptiles in p18. Finally, a potential rBH3 motif was identified in mammalian and osteichthyan p19INK4d (p19, cyclin dependent kinase 4 inhibitor d). These findings demonstrate that the interaction between MCL1 and other cellular proteins mediated by the rBH3 motif may be conserved throughout jawed vertebrates.
QCR7affects the virulence ofCandida albicansand the uptake of multiple carbon sources present in different host niches
Authors: Zeng Lingbing , Huang Yongcheng , Tan Junjun , Peng Jun , Hu Niya , Liu Qiong , Cao YanLi , Zhang Yuping , Chen Junzhu , Huang Xiaotian 
Published: November 2022

AbstractBackgroundCandida albicansis a commensal yeast that may cause life-threatening infections. Studies have shown that the cytochrome b-c1 complex subunit 7 gene (QCR7) ofC. albicansencodes a protein that forms a component of the mitochondrial electron transport chain complex III, making it an important target for studying the virulence of this yeast. However, to the best of our knowledge, the functions ofQCR7have not yet been characterized.MethodsAQCR7knockout strain was constructed using SN152, and BALb/c mice were used as model animals to determine the role ofQCR7in the virulence ofC. albicans. Subsequently, the effects ofQCR7on mitochondrial functions and use of carbon sources were investigated. Next, its mutant biofilm formation and hyphal growth maintenance were compared with those of the wild type. Furthermore, the transcriptome of theqcr7Δ/Δmutant was compared with that of the WT strain to explore pathogenic mechanisms.ResultsDefectiveQCR7attenuated the virulence ofC. albicansinfection in vivo. Furthermore, the mutant influenced the use of multiple alternative carbon sources that exist in several host niches. Moreover, it led to mitochondrial dysfunction. Furthermore, theQCR7knockout strain showed defects in biofilm formation or the maintenance of filamentous growth. The overexpression of cell-surface-associated genes (HWP1, YWP1, XOG1, andSAP6) can restore defective virulence phenotypes and the carbon-source utilization ofqcr7Δ/Δ.ConclusionThis study provides new insights into the mitochondria-based metabolism ofC. albicans, accounting for its virulence and the use of variable carbon sources that promoteC. albicansto colonize host niches.
Astrocytes regulate spatial memory in a sex-specific manner
Authors: Meadows Samantha M. , Palaguachi Fernando , Licht-Murava Avital , Barnett Daniel , Zimmer Till S. , Zhou Constance , McDonough Samantha R. , Orr Adam L. , Orr Anna G. 
Published: November 2022

AbstractCognitive processes and neurocognitive disorders are regulated by astrocytes and have prominent sex differences. However, the contribution of astrocytes to sex differences is not known. We leveraged astrocyte-targeted gene editing and chemogenetics in adult mice to reveal that astrocytic glutamate receptors and other G protein-coupled receptors (GPCRs) modulate hippocampus-dependent cognitive function in a sexually dimorphic manner. In females, spatial memory was improved by increasing metabotropic glutamate receptor 3 (mGluR3) in astrocytes or stimulating astrocytic Gi/o-coupled signaling, whereas stimulating Gs-coupled signaling impaired memory. However, in males, memory was improved by reducing mGluR3 or stimulating Gs-coupled signaling, whereas stimulating Gi/o-coupled signaling impaired memory. Thus, memory requires a sex-specific balance of astrocytic Gs-coupled and Gi/o-coupled receptor activities, and disease-associated alterations or therapeutic targeting of these pathways may cause opposing sex-dependent effects on cognitive function.SummaryGlia cause sex-specific changes in cognition
Sharp-wave ripple associated activity in the medial prefrontal cortex supports spatial rule switching
Authors: den Bakker Hanna , Van Dijck Marie , Sun Jyh-Jang , Kloosterman Fabian 
Published: November 2022

ABSTRACTPrevious studies have highlighted an important role for hippocampal sharp-wave ripples in spatial alternation learning, as well as modulating activity in the medial prefrontal cortex (mPFC). However, no study so far has investigated the direct influence of hippocampal sharp-wave ripples on mPFC activity during spatial alternation learning. Long Evans rats were trained on a three-arm radial maze to perform a sequence of alternations. Three different alternation sequences needed to be learnt, and while learning a new sequence, the activity in the mPFC was inhibited either directly following sharp-wave ripples in the hippocampus (on-time condition) or with a randomized delay (delayed condition). In the on-time condition the behavioral performance was significantly worse compared to the same animals in the delayed inhibition condition, as measured by a lower correct alternation performance and more perseverative behavior. This indicates that the activity in the mPFC directly following hippocampal sharp-wave ripples is necessary for spatial rule switching.
Transport Pathways and Kinetics of Cerebrospinal Fluid Tracers in Mouse Brain Observed by Dynamic Contrast-Enhanced MRI
Authors: Zhu Yuran , Wang Guanhua , Kolluru Chaitanya , Gu Yuning , Gao Huiyun , Zhang Jing , Wang Yunmei , Wilson David L. , Zhu Xiaofeng , Flask Chris A. , Yu Xin 
Published: November 2022

AbstractRecent studies have suggested the glymphatic system as a key mechanism of waste removal in the brain. Dynamic contrast-enhanced MRI (DCE-MRI) using intracisternally administered contrast agents is a promising tool for assessing glymphatic function in the whole brain. In this study, we evaluated the transport kinetics and distribution of three MRI contrast agents with vastly different molecular sizes in mice. Our results demonstrate that oxygen-17 enriched water (H217O), which has direct access to parenchymal tissues via aquaporin-4 water channels, exhibited significantly faster and more extensive transport compared to the two gadolinium-based contrast agents (Gd-DTPA and GadoSpin). Time-lagged correlation and clustering analyses also revealed different transport pathways for Gd-DTPA and H217O. Furthermore, there were significant differences in transport kinetics of the three contrast agents to the lateral ventricles, reflecting the differences in forces that drive solute transport in the brain. These findings suggest the size-dependent transport pathways and kinetics of intracisternal contrast agents and the potential of DCE-MRI for assessing multiple aspects of solute transport in the glymphatic system.