bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cerebral ischemia induces TRPC6 in the glomerular podocytes: A novel role for HIF1α/ZEB2 axis in the pathogenesis of stroke-induced proteinuria
Authors: Nakuluri Krishnamurthy , Nishad Rajkishor , Mukhi Dhanunjay , Kumar Sireesh , Nakka Venkata P , Kolligundla Lakshmi P , Narne Parimala , Natuva Sai Sampath K , Phanithi Prakash Babu , Pasupulati Anil K 
Published: February 2019

AbstractGlomerular filtration apparatus (GFA) regulates the glomerular permselectivity and ultrafiltration of urine. Podocytes are specialized cells and a key component of the GFA. The mechanism by which the integrity of the GFA is compromised and manifest in proteinuria during ischemic stroke remains enigmatic. Hypoxia is a determining factor in the pathophysiology of ischemia. We investigated the mechanism of ischemic-hypoxia induced proteinuria in a middle cerebral artery occlusion (MCAO) model. Ischemic hypoxia resulted in the accumulation of HIF1α in the glomerular podocytes that resulted in the increased expression of ZEB2. ZEB2, in turn, induced TRPC6 (transient receptor potential cation channel, subfamily C, member 6), which has increased selectivity for calcium. Elevated expression of TRPC6 elicited increased calcium influx and aberrant activation of focal adhesion kinase (FAK) in podocytes. FAK activation resulted in the stress fibers reorganization and podocyte foot process effacement. Our study suggests overactive HIF1α/ZEB2 axis during ischemic-hypoxia induces intracellular calcium levels via TRPC6 and consequently altered podocyte integrity and permselectivity.
Cerebral Metabolic Changes during Visuomotor Adaptation Assessed using Quantitative FMRI
Authors: Foster Catherine , Steventon Jessica J , Helme Daniel , Tomassini Valentina , Wise Richard G. 
Published: February 2019

AbstractThe neural energetics underlying functional brain plasticity have not been thoroughly investigated in the healthy human brain. A better understanding of the blood flow and metabolism changes underlying plasticity will help us to address pathologies in which plasticity is compromised and, with interventions, could be enhanced for patient benefit.Calibrated fMRI was conducted in 20 healthy participants during performance of a serial reaction time task which induces rapid motor adaptation. Regions of interest (ROIs) were defined from areas showing linearly decreasing task-induced BOLD and CBF responses. BOLD, CBF and relative CMRO2 responses were calculated for each block of the task. The flow-metabolism coupling ratio, n, was also calculated for each ROI. Increases from baseline in BOLD, CBF and CMRO2 were observed in multiple brain regions including the motor and sensorimotor cortices, cerebellum and hippocampus during SRT task performance, as well as changes in the response amplitude from early to late task blocks reflecting task adaptation. CMRO2 responses on average decreased faster than BOLD or CBF responses, potentially due to rapid neural adaptation. However, the mean flow-metabolism coupling ratio was not significantly different between ROIs or across blocks.Calibrated fMRI can be used to study energetic changes during learning in the healthy brain and could be used to investigate the vascular and metabolic changes underlying reductions in plasticity in ageing and disease.
Mitochondrial-nuclear heme trafficking is regulated by GTPases that control mitochondrial dynamics
Authors: Martinez-Guzman Osiris , Dietz Jonathan V. , Bohovych Iryna , Medlock Amy E. , Khalimonchuk Oleh , Reddi Amit R. 
Published: February 2019

AbstractHeme is an essential cofactor and signaling molecule. All heme-dependent processes require that heme is trafficked from its site of synthesis in the mitochondria to hemoproteins in virtually every subcellular compartment. However, the mechanisms governing the mobilization of heme out of the mitochondria, and the spatio-temporal dynamics of these processes, are poorly understood. To address this, we developed a pulse-chase assay in which, upon the initiation of heme synthesis, heme mobilization into the mitochondrial matrix, cytosol and nucleus is monitored using fluorescent heme sensors. Surprisingly, we found that heme trafficking to the nucleus occurs at a faster rate than to the matrix or cytosol. Further, we demonstrate that GTPases in control of mitochondrial fusion, Mgm1, and fission, Dnm1, are positive and negative regulators of mitochondrial-nuclear heme trafficking, respectively. We also find that heme controls mitochondrial network morphology. Altogether, our results indicate that mitochondrial dynamics and heme trafficking are integrally coupled.
Cohesin occupancy and composition at enhancers and promoters are linked to DNA replication origin proximity inDrosophila
Authors: Pherson, Michelle , Misulovin Ziva , Gause Maria , Dorsett Dale 
Published: February 2019

AbstractCohesin consists of the Smc1-Smc3-Rad21 tripartite ring and the SA protein that interacts with Rad21. The Nipped-B protein loads cohesin topologically around chromosomes to mediate sister chromatid cohesion and facilitate long-range control of gene transcription. It is largely unknown how Nipped-B and cohesin associate specifically with gene promoters and transcriptional enhancers, or how sister chromatid cohesion is established. Here we use genome-wide chromatin immunoprecipitation inDrosophilacells to show that SA and the Fs(1)h (BRD4) BET domain protein help recruit Nipped-B and cohesin to enhancers and DNA replication origins, while the MED30 subunit of the Mediator complex directs Nipped-B and Rad21 to promoters. All enhancers and their neighboring promoters are close to DNA replication origins and bind SA with proportional levels of cohesin subunits. Most promoters are far from origins and lack SA, but bind Nipped-B and Rad21 with sub-proportional amounts of Smc1, indicating that they bind SA-deficient cohesin part of the time. Genetic data confirm that Nipped-B and Rad21 function together with Fs(1)h in vivo to facilitateDrosophiladevelopment. These findings demonstrate that Nipped-B and cohesin are differentially targeted to enhancers and promoters and suggest models for how SA and DNA replication help establish sister chromatid cohesion and facilitate enhancer-promoter communication. They indicate that SA is not an obligatory cohesin subunit but a factor that controls cohesin location on chromosomes.
2’3’-cGAMP is an immunotransmitter produced by cancer cells and regulated by ENPP1
Authors: Carozza Jacqueline A. , Böhnert Volker , Shaw Kelsey E. , Nguyen Khanh C. , Skariah Gemini , Brown Jenifer A. , Rafat Marjan , von Eyben Rie , Graves Edward E. , Glenn Jeffrey S. , Smith Mark , Li Lingyin 
Published: February 2019

Abstract2’3’-cyclic GMP-AMP (cGAMP) is characterized as an intracellular second messenger that is synthesized in response to cytosolic dsDNA and activates the innate immune STING pathway. Our previous discovery of its extracellular hydrolase ENPP1 hinted at the existence of extracellular cGAMP. Here, using mass spectrometry, we detected that cGAMP is continuously exported as a soluble factor by an engineered cell line but then efficiently cleared by ENPP1, explaining why it has escaped detection until now. By developing a potent, specific, and cell impermeable ENPP1 inhibitor, we detected cGAMP export in cancer cell lines commonly used for mouse tumor models. In tumors, depletion of extracellular cGAMP using neutralizing proteins decreased tumor-associated dendritic cells. Boosting extracellular cGAMP by genetic knockout and pharmacological inhibition of ENPP1 increased tumor-associated dendritic cells, shrunk tumors, and synergized with ionizing radiation and anti-CTLA-4 to cure tumors. In conclusion, cGAMP is an anti-cancer immunotransmitter released by tumors and detected by host innate immunity.
Deep motif deconvolution of HLA-II peptidomes for robust class II epitope predictions
Authors: Racle Julien , Michaux Justine , Rockinger Georg Alexander , Arnaud Marion , Bobisse Sara , Chong Chloe , Guillaume Philippe , Coukos George , Harari Alexandre , Jandus Camilla , Bassani-Sternberg Michal , Gfeller David 
Published: February 2019

AbstractCD4 T cells are key for priming and regulating immune recognition of infected and cancer cells, but predictions of class II epitopes have limited accuracy. We combined unbiased Mass Spectrometry-based HLA-II peptidomics with a novel motif deconvolution algorithm to profile and analyze a total of 99’265 unique HLA-II ligands. Our work demonstrates substantial improvement in the definition of HLA-II binding motifs and enhanced accuracy in class II epitope predictions.
Locus-coeruleus norepinephrine activity gates sensory-evoked awakenings from sleep
Authors: Hayat Hanna , Regev Noa , Matosevich Noa , Sales Anna , Paredes-Rodriguez Elena , Krom Aaron J , Bergman Lottem , Li Yong , Lavigne Marina , Kremer Eric J. , Yizhar Ofer , Pickering Anthony E , Nir Yuval 
Published: February 2019

AbstractA defining feature of sleep is reduced responsiveness to external stimuli, but the mechanisms gating sensory-evoked arousal remain unclear. We hypothesized that reduced locus-coeruleus norepinephrine (LC-NE) activity during sleep mediates unresponsiveness, and its action promotes sensory-evoked awakenings. We tested this using electrophysiological, behavioral, pharmacological, and optogenetic techniques alongside auditory stimulation in freely behaving rats. We found that systemic reduction of NE signaling lowered probability of sound-evoked awakenings (SEAs). The level of tonic LC activity during sleep anticipated SEAs. Optogenetic LC activation promoted arousal as evident in sleep-wake transitions, EEG desynchronization, and pupil dilation. Importantly, liminal LC excitation before sound presentation increased SEA probability. Optogenetic LC silencing using a soma-targeted anion-conducting channelrhodopsin (stGtACR2) suppressed LC spiking and constricted pupils. Brief periods of LC opto-silencing reduced the probability of SEAs. Thus, LC-NE activity determines the likelihood of sensory-evoked awakenings and its reduction during sleep constitutes a key factor mediating behavioral unresponsiveness.
Multiomic definition of generalizable endotypes in human acute pancreatitis
Authors: Neyton Lucile P. A. , Zheng Xiaozhong , Skouras Christos , Doeschl-Wilson Andrea , Gutmann Michael U. , Yau Christopher , Uings Iain , Rao Francesco V. , Nicolas Armel , Marshall Craig , Wilson Lisa-Marie , Baillie J. Kenneth , Mole Damian J. 
Published: February 2019

AbstractAcute pancreatitis (AP) is sudden onset pancreas inflammation that causes multiple organ dysfunction syndrome (MODS) and death in certain individuals who develop AP yet minimal systemic inflammation in others. Here, we show that this observed diversity in systemic response and outcome is accompagnied by diversity in molecular subtypes that can be identified using computational analysis of clinical and multiomic data. We integrated co-incident whole blood transcriptomic, plasma proteomic, and serum metabolomic data at serial time points from a cohort of patients presenting with AP and systematically evaluated four different metrics for patient similarity, using unbiased mathematical, biological and clinical measures of internal and external validity. Our results identify four distinct and stable AP endotypes that are characterized by pathway and biomarker combination stereotypes into hypermetabolic, hepatopancreaticobiliary, catabolic and innate immune endotypes. The catabolic endotype in AP strikingly recapitulates a disease endotype previously reported in acute respiratory distress syndrome, a recognized complication of AP. Our findings demonstrate that clinically-relevant and generalizable endotypes exist in AP.
Investigating the Association Between Body Fat and Depression via Mendelian Randomization
Authors: Speed Maria S. , Jefsen Oskar H. , Børglum Anders D. , Speed Doug , Østergaard Søren D. 
Published: February 2019

AbstractObesity and depression are major public health concerns that are both associated with substantial morbidity and mortality. There is a considerable body of literature linking obesity to the development of depression. Recent studies using Mendelian Randomization indicate that this relationship is causal. Most studies of the obesity-depression association have used body mass index as a measure of obesity. Body mass index is defined as weight (measured in kilograms) divided by the square of height (meters) and therefore does not distinguish between the contributions of fat and non-fat to body weight. To better understand the obesity-depression association, we conduct a Mendelian Randomization study of the relationship between fat mass, non-fat mass, height, and depression, using genome-wide association study results from the UK Biobank (n=332,000) and the Psychiatric Genomics Consortium (n=480,000). Our findings suggest that both fat mass and height (short stature) are causal risk factors for depression, while non-fat mass is not. These results represent important new knowledge on the role of anthropometric measures in the etiology of depression. They also suggest that reducing fat mass will decrease the risk of depression, which lends further support to public health measures aimed at reducing the obesity epidemic.
Therapeutic Targeting of Casein Kinase 1δ/ε in an Alzheimer’s Disease Mouse Model
Authors: Adler Paula , Mayne Janice , Walker Krystal , Ning Zhibin , Figeys Daniel 
Published: February 2019

SUMMARYSleep disturbances and memory impairment are common symptoms of Alzheimer’s disease (AD). Given that the circadian clock regulates sleep, hippocampal function, and neurodegeneration, it represents a therapeutic target against AD. Casein kinase 1δ/ε (CK1δ/ε) are clock regulators and overexpressed in AD brains, making them viable targets to improve sleep and cognition. We assessed the effects of a small molecule CK1δ/ε inhibitor (PF-670462) in a cellular model of circadian clocks and in 3xTg-AD mice. Mass spectrometry–based proteomic analyses revealed that PF-670462 treatmentin vitroupregulated multiple proteins that are downregulated in AD, while administration in 3xTg-AD mice reversed hippocampal proteomic alterations in diverse AD-associated and clock-regulated pathways, including synaptic plasticity and amyloid precursor protein processing. Furthermore, PF-670462 rescued working memory and normalized behavioural circadian rhythms in 3xTg-AD mice. Our study provides proof of concept for CK1δ/ε inhibition and direct clock modulation against AD-related proteomic changes, memory impairment, and circadian disturbances.
KAI2 regulates root and root hair development by modulating auxin distribution
Authors: Villaecija-Aguilar José Antonio , Hamon-Josse Maxime , Carbonnel Samy , Kretschmar Annika , Ljung Karin , Bennett Tom , Gutjahr Caroline 
Published: February 2019

ABSTRACTStrigolactones (SLs) are endogenous signalling molecules that play important roles in controlling plant development. SL perception is closely related to that of karrikins, smoke-derived compounds presumed to mimic endogenous signalling molecules (KLs). SLs have been suggested to regulate root development. However, perception of both molecules requires the F-box protein MAX2 and the use ofmax2mutants has hampered defining the exact role of SLs in roots. Here we dissect the role of SL and KL signalling inArabidopsisroot development using mutants defective in the α/β hydrolase receptors D14 and KAI2, which specifically perceive SLs and KLs, respectively. Both pathways together regulate lateral root density (LRD), but contrary to previous reports, KL signalling alone controls root hair density, root hair length and additionally root skewing, straightness and diameter. Members of the SMXL protein family are downstream targets of SL (SMXL6, 7, 8) and KL (SMAX1, SMXL2) signalling. We identified distinct and overlapping roles of these proteins in the regulation of root development. Both SMAX1/SMXL2 and SMXL6/SMXL7/SMXL8 regulate LRD, confirming that SL and KL signalling act together to regulate this trait, while the KL-signalling specific SMAX1 and SMXL2 regulate all other investigated root traits. Finally, we show that KL signalling regulates root hair development by modulating auxin distribution within the root.
Bingeing in rats: Persistence of high intakes of palatable solutions induced by 1-in-4 days intermittent access
Authors: Rehn Simone , Boakes Robert A. 
Published: February 2019

AbstractWhen animals are given access to a palatable food or drink on some days but not on others, the amount they consume can far exceed the daily amounts consumed by controls given daily access. In a previous study such bingeing was found when rats were given 4% sucrose solution; it also found that, following 1-in-4-days access for many weeks, intakes remained persistently higher than that of controls even when the conditions were changed to 1-in-2-days access for both groups. One aim of the three experiments reported here was to test whether such persistent bingeing could be found for other solutions. This was confirmed in rats for a saccharin solution and a highly palatable saccharin-plus-glucose solution. However, when a maltodextrin solution was used, initial increased intakes produced by the 1-in-4-days schedule were not maintained when this was changed to a 1-in-2-days schedule. These results suggested that the hedonic value of a solution is more important than its caloric content in determining whether it will support persistent bingeing. A second aim was to test for evidence that the 1-in-4-days procedure induced an addiction to the target solution. No such evidence was found using multiple measures including instrumental responding and anxiety-like behavior on the elevated plus-maze for craving and withdrawal respectively.
DETECTION OFFUSARIUM OXYSPORUMF. SP. ELAEIDIS CAUSING FUSARIUM WILT OF OIL PALM USING LOOP-MEDIATED ISOTHERMAL AMPLIFICATION (LAMP)
Authors: Adusei-Fosu Kwasi , Dickinson Matthew 
Published: February 2019

AbstractFusarium oxysporumf. sp.elaeidis(FOE) a pathogen that causes fusarium wilt disease in oil palm can be detected using polymerase chain reaction (PCR) but very time consuming. Loop-Mediated Isothermal Amplification (LAMP) was used to rapidly detectFusarium oxysporumf. sp.elaeidis(FOE) in oil palm seedlings. Eight additionalFusarium oxysporumisolates collected from symptomatic oil palm trees (i.e. presumed-FOE as their pathogenicity was not confirmed) and five other non-FOE isolates were sampled from symptomatic mature oil palm trees and tomato respectively to broaden the scope of the research. The identities of FOE, presumed-FOE and non-FOE were established via sequencing. LAMP primers designed for detecting FOE or presumed-FOE were based on partial sequences ofSecreted In Xylem(SIX8) andP-450cytochrome. The earliest detection time forSIX8andP-450cytochrome primers were 4:00 mins and 6:45 mins respectively with both recording late time for detection at 26:30 mins. Annealing derivative curves were used for assessing the level of specificity for bothSIX8andP-450cytochrome, but none of the LAMP primers could distinguish between FOE, presumed-FOE and non-FOE.
Streamlining and Cycle Time Reduction of the Start-up Phase of Clinical Trials
Authors: Abu-Shaheen Amani , Badr Ahmad Al , AlFayyad Isamme , Qutub Adel Al , Faqeih Eissa Ali , Altannir Mohamad 
Published: February 2019

AbstractObjectiveThe start-up phase of a clinical trial (CT) plays a vital role in execution of novel drug development. Hence, this study aims to identify the factors responsible for delaying the CT start-up phase. Further, it focuses on streamlining and reducing the cycle time of the start-up phase of newly sponsored CTs.MethodologyThirteen sponsored CTs conducted (between 2016 and 2017) in clinical research department at King Fahad Medical City, Riyadh were analyzed to identify the data specific start-up metrics usingFind an improvement area-Organize a team-Clarify current practices-Understand source of variation/problem-Select a Strategy-Plan-Do-Check-Act (FOCUS-PDCA) cycle. Five measures incorporated in the metrics were: date of initial contact with site to the signing of confidentiality agreement; date of receiving questionnaire from sponsor to date of its completion; time taken to review protocol and approve investigational drug service (IDS) form; time taken to review protocol and approve pharmacy and pathology and clinical laboratory medicine (PCLM) form and date of receipt of institutional review board (IRB) submission package to final IRB approval.Fishbone analysis was used to understand the potential causes of process variation. Mean time was calculated for each metrics prior to and post implementation of the intervention protocol to analyze and compare percentage reduction in the mean cycle time of CTs.ResultsOf the various potential factors of delay identified through Fishbone analysis, the two major ones were lack of well-defined timeline for approval and review of the study protocol; and inconsistent IRB meetings. Post introduction of the new intervention protocol, the entire CT lifecycle was reduced by 45.6% (24.8 weeks' vs 13 weeks, before and after intervention, respectively).ConclusionVaried factors are responsible for delay of the start-up phase of CTs and understanding the impact of each factor allows for optimization and faster execution of the start-up phase of CTs.
Optimal sample size calculation for null hypothesis significance tests
Authors: Mudge Joseph F. , Houlahan Jeffrey E. 
Published: February 2019

AbstractTraditional study design tools for estimating appropriate sample sizes are not consistently used in ecology and can lead to low statistical power to detect biologically relevant effects. We have developed a new approach to estimating optimal sample sizes, requiring only three parameters; a maximum acceptable average of α and β, a critical effect size of minimum biological relevance, and an estimate of the relative costs of Type I vs. Type II errors.This approach can be used to show the general circumstances under which different combinations of critical effect sizes and maximum acceptable combinations of α and β are attainable for different statistical tests. The optimal α sample size estimation approach can require fewer samples than traditional sample size estimation methods when costs of Type I and II errors are assumed to be equal but recommends comparatively more samples for increasingly unequal Type I vs. Type II errors costs. When sampling costs and absolute costs of Type I and II errors are known, optimal sample size estimation can be used to determine the smallest sample size at which the cost of an additional sample outweighs its associated reduction in errors. Optimal sample size estimation constitutes a more flexible and intuitive tool than traditional sample size estimation approaches, given the constraints and unknowns commonly faced by ecologists during study.