bluuebunny/crossref_metadata_2025_split huggingface dataset:
Astrocytic BDNF and TrkB regulate severity and neuronal activity in mouse models of temporal lobe epilepsy
Authors: Fernández-García Sara , Sancho-Balsells Anna , Longueville Sophie , Hervé Denis , Gruart Agnès , Delgado-García José María , Alberch Jordi , Giralt Albert 
Published: June 2020

AbstractAstrocytes have emerged as crucial regulators of neuronal network activity, synapse formation, and underlying behavioral and cognitive processes. Despite some pathways have been identified, the communication between astrocytes and neurons remains to be completely elucidated. Unraveling this communication is crucial to design potential treatments for neurological disorders like temporal lobe epilepsy (TLE). The BDNF and TrkB molecules have emerged as very promising therapeutic targets. However, their modulation can be accompanied by several off-target effects such as excitotoxicity in case of uncontrolled upregulation or dementia, amnesia, and other memory disorders in case of downregulation. Here, we show that BDNF and TrkB from astrocytes modulate neuronal dysfunction in TLE models. First, conditional overexpression of BDNF from astrocytes worsened the phenotype in the lithium-pilocarpine mouse model. Our evidences pointed out to the astrocytic pro-BDNF isoform as a major player of this altered phenotype. Conversely, specific genetic deletion of BDNF in astrocytes prevented the increase in the number of firing neurons and the global firing rate in an in vitro model of TLE. Regarding to the TrkB, we generated mice with a genetic deletion of TrkB specifically in hippocampal neurons or astrocytes. Interestingly, both lines displayed neuroprotection in the lithium-pilocarpine model but only the mice with genetic deletion of TrkB in astrocytes showed significantly preserved spatial learning skills. These data identify the astrocytic BDNF and TrkB molecules as promising therapeutic targets for the treatment of TLE.
Defective NADPH production in mitochondrial disease complex I causes inflammation and cell death
Authors: Balsa Eduardo , Perry Elizabeth A. , Bennett Christopher F. , Jedrychowski Mark , Gygi Steven P. , Doench John G. , Puigserver Pere 
Published: June 2020

AbstractElectron transport chain (ETC) defects occurring from mitochondrial disease mutations compromise ATP synthesis and render cells vulnerable to nutrient and oxidative stress conditions. This bioenergetic failure is thought to underlie pathologies associated with mitochondrial diseases. However, the precise metabolic processes resulting from a defective mitochondrial ETC that compromise cell viability under stress conditions are not entirely understood. We design a whole genome gain-of-function CRISPR activation screen using human mitochondrial disease complex I (CI) mutant cells to identify genes whose increased function rescue glucose restriction-induced cell death. The top hit of the screen is the cytosolic Malic Enzyme (ME1), that is sufficient to enable survival and proliferation of CI mutant cells under nutrient stress conditions. Unexpectedly, this metabolic rescue is independent of increased ATP synthesis through glycolysis or oxidative phosphorylation, but dependent on ME1-produced NADPH and glutathione (GSH). Survival upon nutrient stress or pentose phosphate pathway (PPP) inhibition depends on compensatory NADPH production through the mitochondrial one-carbon metabolism that is severely compromised in CI mutant cells. Importantly, this defective CI-dependent decrease in mitochondrial NADPH production pathway or genetic ablation of SHMT2 causes strong increases in inflammatory cytokine signatures associated with redox dependent induction of ASK1 and activation of stress kinases p38 and JNK. These studies find that a major defect of CI deficiencies is decreased mitochondrial one-carbon NADPH production that is associated with increased inflammation and cell death.
AcrIF9 tethers non-sequence specific dsDNA to the CRISPR RNA-guided surveillance complex
Authors: Hirschi Marscha , Lu Wang-Ting , Santiago-Frangos Andrew , Wilkinson Royce , Golden Sarah M. , Davidson Alan R. , Lander Gabriel C. , Wiedenheft Blake 
Published: June 2020

AbstractBacteria have evolved sophisticated adaptive immune systems, called CRISPR-Cas, that provide sequence-specific protection against phage infection. In turn, phages have evolved a broad spectrum of anti-CRISPRs that suppress these immune systems. Here we report structures of anti-CRISPR protein IF9 (AcrIF9) in complex with the type I-F CRISPR RNA-guided surveillance complex (Csy). In addition to sterically blocking the hybridization of complementary dsDNA to the CRISPR RNA, our results show that AcrIF9 binding also promotes non-sequence-specific engagement with dsDNA, potentially sequestering the complex from target DNA. These findings highlight the versatility of anti-CRISPR mechanisms utilized by phages to suppress CRISPR-mediated immune systems.
Integrated omics in Drosophila uncover a circadian kinome
Authors: Wang Chenwei , Shui Ke , Ma Shanshan , Lin Shaofeng , Zhang Ying , Wen Bo , Deng Wankun , Xu Haodong , Hu Hui , Guo Anyuan , Xue Yu , Zhang Luoying 
Published: June 2020

AbstractMost organisms on the earth exhibit circadian rhythms in behavior and physiology, which are driven by endogenous clocks. Phosphorylation plays a central role in timing the clock, but how this contributes to overt rhythms is unclear. Here we conduct phosphoproteomics in conjunction with transcriptomic and proteomic profiling using fly heads. By developing a pipeline for integrating multi-omics data, we identify 789 (~17%) phosphorylation sites with circadian oscillations. We predict 27 potential circadian kinases to participate in phosphorylating these sites, including 7 previously known to function in the clock. We screen the remaining 20 kinases for effects on circadian rhythms and find an additional 3 to be involved in regulating locomotor rhythm. We re-construct a signal web that includes the 10 circadian kinases and identify GASKET as a potentially important regulator. Taken together, we uncover a circadian kinome that potentially shapes the temporal pattern of the entire circadian molecular landscapes.
Dynamics of the 4D genome during in vivo lineage specification and differentiation
Authors: Oudelaar A. Marieke , Beagrie Robert A. , Gosden Matthew , de Ornellas Sara , Georgiades Emily , Kerry Jon , Hidalgo Daniel , Carrelha Joana , Shivalingam Arun , El-Sagheer Afaf H. , Telenius Jelena M. , Brown Tom , Buckle Veronica J. , Socolovsky Merav , Higgs Douglas R. , Hughes Jim R. 
Published: June 2020

AbstractMammalian gene expression patterns are controlled by regulatory elements, which interact within topologically associating domains (TADs). The relationship between activation of regulatory elements, formation of structural chromatin interactions and gene expression during development is unclear. Here, we present Tiled-C, a low-input chromosome conformation capture (3C) technique. We use this approach to study chromatin architecture at high spatial and temporal resolution through in vivo mouse erythroid differentiation. Integrated analysis of chromatin accessibility and single-cell expression data shows that regulatory elements gradually become accessible within pre-existing TADs during early differentiation. This is followed by structural re-organization within the TAD and formation of specific contacts between enhancers and promoters. Our high-resolution data show that these enhancer-promoter interactions are not established prior to gene expression, but formed gradually during differentiation, concomitant with progressive upregulation of gene activity. Together, these results provide new insight into the close, interdependent relationship between chromatin architecture and gene regulation during development.
Evidence for quark-matter cores in massive neutron stars
Authors: Annala Eemeli , Gorda Tyler , Kurkela Aleksi , Nättilä Joonas , Vuorinen Aleksi 
Published: June 2020

AbstractThe theory governing the strong nuclear force—quantum chromodynamics—predicts that at sufficiently high energy densities, hadronic nuclear matter undergoes a deconfinement transition to a new phase of quarks and gluons1. Although this has been observed in ultrarelativistic heavy-ion collisions2,3, it is currently an open question whether quark matter exists inside neutron stars4. By combining astrophysical observations and theoretical ab initio calculations in a model-independent way, we find that the inferred properties of matter in the cores of neutron stars with mass corresponding to 1.4 solar masses (M⊙) are compatible with nuclear model calculations. However, the matter in the interior of maximally massive stable neutron stars exhibits characteristics of the deconfined phase, which we interpret as evidence for the presence of quark-matter cores. For the heaviest reliably observed neutron stars5,6 with mass M ≈ 2M⊙, the presence of quark matter is found to be linked to the behaviour of the speed of sound cs in strongly interacting matter. If the conformal bound $${c}_{\rm{s}}^{2}\le 1/3$$

c

s

2

≤
1
/
3

(ref. 7) is not strongly violated, massive neutron stars are predicted to have sizable quark-matter cores. This finding has important implications for the phenomenology of neutron stars and affects the dynamics of neutron star mergers with at least one sufficiently massive participant.
Direct Visualization of Perm-Selective Ion Transportation
Authors: Kim Wonseok , Lee Jungeun , Yun Gunsu , Sung Gun Yong , Kim Sung Jae 
Published: June 2020

AbstractPerm-selective ion transportation in a nanoscale structure such as nanochannel, nanoporous membrane or nanojunction has been extensively studied with aids of nanofabrication technology for a decade. While theoretical and experimental advances pushed the phenomenon to seminal innovative applications, its basic observation has relied only on an indirect analysis such as current-voltage relation or fluorescent imaging adjacent to the nanostructures. Here we experimentally, for the first time, demonstrated a direct visualization of perm-selective ion transportation through the nanoscale space using an ionic plasma generation. A micro/nanofluidic device was employed for a micro bubble formation, plasma negation and penetration of the plasma along the nanojunction. The direct observation provided a keen evidence of perm-selectivity, i.e. allowing cationic species and rejecting anionic species. Furthermore, we can capture the plasma of lithium, which has lower mobility than sodium in aqueous state, passed the nanojunction faster than sodium due to the absence of hydrated shells around lithium. This simple, but essential visualization technique would be effective means not only for advancing the fundamental nanoscale electrokinetic study as well as interfacial ion transportation between liquid and plasma but also for providing the insight of new innovative engineering applications.
Comparison of Balloon Pulmonary Angioplasty and Pulmonary Vasodilators for Inoperable Chronic Thromboembolic Pulmonary Hypertension: A Systematic Review and Meta-Analysis
Authors: Kalra Rajat , Duval Sue , Thenappan Thenappan , Raveendran Ganesh , Pritzker Marc , Prisco Sasha Z. , Prins Kurt W. 
Published: June 2020

AbstractTreatment options for chronic thromboembolic pulmonary hypertension (CTEPH) that is not amenable to thromboendarterectomy or is recurrent/persistent after thromboendarterectomy (inoperable CTEPH) include pulmonary vasodilators or balloon pulmonary angioplasty (BPA). We compared efficacy and safety outcomes of BPA with or without pulmonary vasodilators to pulmonary vasodilator therapy alone in patients with inoperable CTEPH. Observational and randomized trial data reporting outcomes for >5 patients with inoperable CTEPH were sought. Single-arm random effects meta-analyses were performed. The primary outcome was change in six-minute walk distance (6MWD). Secondary outcomes included safety; World Health Organization functional class (WHO FC); and change in mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), and cardiac index. Thirty-four studies with 1604 patients were eligible for analyses. Both treatments resulted in significant improvement in 6MWD (71.0 meters, 95% CI: 47.4–94.5 meters with BPA versus 47.8 meters, 95% CI: 34.5–61.2 meters with pulmonary vasodilators), PVR [−3.1 Wood Units (WU), 95% CI: −4.9 to −1.4 WU versus −1.6 WU, 95% CI: −2.4 to −0.8 WU] and mPAP (−14.8 mmHg, 95% CI: −18.2 to −11.5 mmHg versus −4.9 mmHg, 95% CI: −6.9 to −2.8 mmHg). Cardiac index was similar and most patients were WHO FC II and III after their respective interventions. More complications occurred in the BPA arm. In conclusion, BPA and pulmonary vasodilators both improve 6MWD and hemodynamics in patients with inoperable CTEPH. While BPA may offer greater functional and hemodynamic improvements, this technique carries the accompanying risks of an invasive procedure.
Osteonecrosis of Femoral Head, An Overlooked Long-Term Complication after Paraquat Intoxication: A Retrospective Cohort Study
Authors: Chan Ming-Jen , Huang Chien-Chang , Hu Ching-Chih , Huang Wen-Hung , Hsu Ching-Wei , Yen Tzung-Hai , Weng Cheng-Hao 
Published: June 2020

AbstractWith increasing numbers of patients surviving acute intoxication phase, long-term complication after paraquat intoxication is a topic worth exploring, such as osteonecrosis (ON) of femoral head. We reviewed 86 paraquat-intoxicated survivors between 2000 and 2012 in Chang Gung Memorial Hospital, a 3700-bed tertiary hospital in Taiwan. With all the patients underwent same detoxification protocol in the acute stage, 17.4% of paraquat poisoning survivors developed ON of femoral head requiring surgery during follow up. Most of ON episodes occurred within 2 to 4 years after paraquat intoxication and then plateau after 6 years. ON patients exhibited higher SOFA scores than non-ON patients (2.80 ± 2.14 vs. 1.76 ± 1.52, p = 0.028). Furthermore, AKIN scores are also higher in the ON patients than non-ON patients (0.87 ± 1.13 vs. 0.38 ± 0.74, p = 0.040). Multivariate logistic regression showed higher AKIN score and higher partial pressure of carbon dioxide in the blood 48 hours after admission significantly predicted ON of femoral head after paraquat intoxication (p = 0.002 and p = 0.006 respectively). Larger studies with longer follow-up durations are warranted to confirm our finding.
Flavonoid epimers from custard apple leaves, a rapid screening and separation by HSCCC and their antioxidant and hypoglycaemic activities evaluation
Authors: Zhu Heng , Chen Long , Yu Jinqian , Cui Li , Ali Iftikhar , Song Xiangyun , Park Jeong Hill , Wang Daijie , Wang Xiao 
Published: June 2020

AbstractLeaves of custard apple are widely used in many places as a popular dietary supplement for the treatment of diabetes. Flavonoids are known to have anti-diabetic activity. In this study, the main flavonoid epimers were separated. The crude extract was first screened by HPLC-DAD before and after incubation with DPPH method to evaluate the antioxidants. An efficient extraction method was employed to remove non-flavonoid components. Subsequently, five main flavonoids with two pairs of epimers including quercetin-3-O-robinobioside, rutin, quercetin-3-O-β-D-glucoside, kaempferol-3-O-robinobioside, and kaempferol-3-O-rutinoside were successfully separated by high-speed counter-current chromatography with ethyl acetate/n-butanol/water (4:1:5, v/v) coupled with online-storage inner-recycling mode. The structures of the separated compounds were identified by spectral techniques. The purity of the separated flavonoid glycosides was over 98%, as determined by HPLC. The separated pure constituents were found to possess the antioxidant capacities following DPPH radical scavenging protocol. The compounds (1-3) exhibited better antioxidant activity. Furthermore, the glucose uptake of crude flavonoid extract had better results than the crude ethanol extract. The present study demonstrates that the efficacy of custard apple leaves in lowering glucose level, and antioxidant capacities of separated pure compounds probably appear to be predominantly responsible for hypoglycaemic properties on HepG2 cells.
A meta-analysis to assess long-term spatiotemporal changes of benthic coral and macroalgae cover in the Mexican Caribbean
Authors: Contreras-Silva Ameris I. , Tilstra Arjen , Migani Valentina , Thiel Andra , Pérez-Cervantes Esmeralda , Estrada-Saldívar Nuria , Elias-Ilosvay Xochitl , Mott Claudius , Alvarez-Filip Lorenzo , Wild Christian 
Published: June 2020

AbstractCoral reefs in the wider Caribbean declined in hard coral cover by ~80% since the 1970s, but spatiotemporal analyses for sub-regions are lacking. Here, we explored benthic change patterns in the Mexican Caribbean reefs through meta-analysis between 1978 and 2016 including 125 coral reef sites. Findings revealed that hard coral cover decreased from ~26% in the 1970s to 16% in 2016, whereas macroalgae cover increased to ~30% in 2016. Both groups showed high spatiotemporal variability. Hard coral cover declined in total by 12% from 1978 to 2004 but increased again by 5% between 2005 and 2016 indicating some coral recovery after the 2005 mass bleaching event and hurricane impacts. In 2016, more than 80% of studied reefs were dominated by macroalgae, while only 15% were dominated by hard corals. This stands in contrast to 1978 when all reef sites surveyed were dominated by hard corals. This study is among the first within the Caribbean region that reports local recovery in coral cover in the Caribbean, while other Caribbean reefs have failed to recover. Most Mexican Caribbean coral reefs are now no longer dominated by hard corals. In order to prevent further reef degradation, viable and reliable conservation alternatives are required.
Determining correlates of the average number of cigarette smoking among college students using count regression models
Authors: Sharareh Parami , Leili Tapak , Abbas Moghimbeigi , Jalal Poorolajal , Ali Ghaleiha 
Published: June 2020

AbstractCollege students, as a large part of young adults, are a vulnerable group to several risky behaviors including smoking and drug abuse. This study aimed to utilize and to compare count regression models to identify correlates of cigarette smoking among college students. This was a cross-sectional study conducted on students of Hamadan University of Medical Sciences. The Poisson, negative binomial, generalized Poisson, exponentiated-exponential geometric regression models and their zero-inflated counterparts were fitted and compared using the Vuong test (α = 0.05). A number of 1258 students participated in this study. The majority of students were female (60.8%) and their average age was 23 years. Most of the students were non-smokers (84.6%). Negative binomial regression was selected as the most appropriate model for analyzing the data (comparable fit and simpler interpretation). The significant correlates of the number of cigarettes smoked per day included gender (male: incident-rate-ratio (IRR = 9.21), birth order (Forth: IRR = 1.99), experiencing a break-up (IRR = 2.11), extramarital sex (heterosexual (IRR = 2.59), homosexual (IRR = 3.13) vs. none), and drug abuse (IRR = 5.99). Our findings revealed that several high-risk behaviors were associated with the intensity of smoking, suggesting that these behaviors should be considered in smoking cessation intervention programs for college students.
HDO production from [2H7]glucose Quantitatively Identifies Warburg Metabolism
Authors: Mahar Rohit , Donabedian Patrick L. , Merritt Matthew E. 
Published: June 2020

AbstractIncreased glucose uptake and aerobic glycolysis are striking features of many cancers. These features have led to many techniques for screening and diagnosis, but many are expensive, less feasible or have harmful side-effects. Here, we report a sensitive 1H/2H NMR method to measure the kinetics of lactate isotopomer and HDO production using a deuterated tracer. To test this hypothesis, HUH-7 hepatocellular carcinoma and AML12 normal hepatocytes were incubated with [2H7]glucose. 1H/2H NMR data were recorded for cell media as a function of incubation time. The efflux rate of lactate-CH3, lactate-CH2D and lactate-CHD2 was calculated as 0.0033, 0.0071, and 0.0.012 µmol/106cells/min respectively. Differential production of lactate isotopomers was due to deuterium loss during glycolysis. Glucose uptake and HDO production by HUH-7 cells showed a strong correlation, indicating that monitoring the HDO production could be a diagnostic feature in cancers. Deuterium mass balance of [2H7]glucose uptake to 2H-lactate and HDO production is quantitatively matched, suggesting increasing HDO signal could be used to diagnose Warburg (cancer) metabolism. Measuring the kinetics of lactate isotopomer and HDO production by 1H and 2H MR respectively are highly sensitive. Increased T1 of 2H-lactate isotopomers indicates inversion/saturation recovery methods may be a simple means of generating metabolism-based contrast.
The Krüppel-like factor 15-NFATc1 axis ameliorates podocyte injury: a novel rationale for using glucocorticoids in proteinuria diseases
Authors: Dou Caoshuai , Zhang Hong , Ke Guibao , Zhang Li , Lian Zhiwen , Chen Xueqin , Zhao Xingchen , Chen Yuanhan , Li Ruizhao , Ma Jianchao , Li Zhuo , Lin Ting , Wang Wenjian , Ye Zhi ming , Liang Xinling , Shi Wei , Zhang Bin , Liu Shuangxin 
Published: June 2020

Abstract
Podocyte injury and loss contribute to proteinuria, glomerulosclerosis and eventually kidney failure. Recent studies have demonstrated that the loss of Kruppel-like factor 15 (KLF15) in podocytes increases the susceptibility to injury; however, the mechanism underlying the protective effects on podocyte injury remains incompletely understood. Herein, we showed that KLF15 ameliorates podocyte injury through suppressing NFAT signaling and the salutary effects of the synthetic glucocorticoid dexamethasone in podocyte were partially mediated by the KLF15–NFATc1 axis. We found that KLF15 was significantly reduced in glomerular cells of proteinuric patients and in ADR-, LPS- or HG-treated podocyets in vitro. Overexpression of KLF15 attenuated podocyte apoptosis induced by ADR, LPS or HG and resulted in decreased expression of pro-apoptotic Bax and increased expression of anti-apoptotic Bcl-2. Conversely, the flow cytometry analysis and TUNEl assay demonstrated that loss of KLF15 accelerated podocyte apoptosis and we further found that 11R-VIVIT, a specific NFAT inhibitor, and NFATc1–siRNA rescued KLF15-deficient induced podocyte apoptosis. Meanwhile, Western blot and RT-qPCR showed that the expression of NFATc1 was up-regulated in KLF15 silenced podocytes and reduced in KLF15 overexpressed podocytes. Mechanistically, ChIP analysis showed that KLF15 bound to the NFATc1 promoter region -1984 to -1861base pairs upstream of the transcription start site and the binding amount was decreased after treatment with LPS. The dual-luciferase reporter assay indicated that NFATc1 was a direct target of KLF15. In addition, we found that in vitro treatment with dexamethasone induced a decrease of NFATc1 expression in podocytes and was abrogated by knockdown of KLF15. Hence, our results identify the critical role of the KLF15–NFATc1 axis in podocyte injury and loss, which may be involved in mediating the salutary effects of dexamethasone in podocytes.