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Fenofibrate-promoted hepatomegaly and liver regeneration are PPARα-dependent and partially related to the YAP pathw.y

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Acta Pharmaceutica Sinica B 2024年第7期14卷 2992-3008页

作者： Shicheng Fan Yue Gao Pengfei Zhao Guomin Xie Yanying Zhou Xiao Yang Xuan Li Shuaishuai Zhang frank JGonzalez Aijuan Qu Min Huangb Huichang Bi NMPA Key Laboratory for Research and Evaluation of Drug Metabolism&Guangdong Provincial Key Laboratory of New.Drug Screening&Guangdong-Hongkong-Macao Joint Laboratory for New.Drug Screening School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China Guangdong Provincial Key Laboratory of New.Drug Design and Evaluation School of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhou 510006China Department of Physiology and Pathophysiology School of Basic Medical SciencesCapital Medical UniversityBeijing 100069China Laboratory of Metabolism Center for Cancer ResearchNational Cancer InstituteNational Institutes of HealthBethesdaMD 20892USA The State Key Laboratory of Chemical Oncogenomics School of Chemical Biology and BiotechnologyShenzhen Graduate School of Peking UniversityShenzhen 518055China

Fenofibrate,a peroxisome proliferator-activated receptor α(PPARα)agonist,is w.dely prescribed for hyperlipidemia *** studies also show.d that it has therapeutic potential in various liver ***,its effects on hepatomegaly and liver regeneration and the involved mechanisms remain ***,the study show.d that fenofibrate significantly promoted liver enlargement and regeneration post-partial hepatectomy in mice,w.ich w.s dependent on hepatocyteexpressed PPARα.Yes-associated protein(YAP)is pivotal in manipulating liver grow.h and *** further identified that fenofibrate activated YAP signaling by suppressing its K48-linked ubiquitination,promoting its K63-linked ubiquitination,and enhancing the interaction and transcriptional activity of the YAP-TEAD *** inhibition of YAP-TEAD interaction using verteporfin or suppression of YAP using AAV Yap shRNA in mice significantly attenuated fenofibrate-induced *** factors,such as MYC,KRT23,RAS,and RHOA,might also participate in fenofibrate-promoted hepatomegaly and liver *** studies demonstrate that fenofibratepromoted liver enlargement and regeneration are PPARα-dependent and partially through activating the YAP signaling,w.th clinical implications of fenofibrate as a novel therapeutic agent for promoting liver regeneration.

关键词： Fenofibrate PPARa Hepatomegaly Partial hepatectomy Liver regeneration YAP TEAD Ubiquitination

Felsenstein＇s ＂one-allele model＂ of speciation： The role of philopatry in the initial stages of host plant mediated reproductive isolation in Enchenopa binotata

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Current Zoology 2013年第5期59卷 658-666页

作者： frank w. STEARNS Kelley J. TILMON Thomas K. w.OD Department of Biology Biology-Psychology Building University of Maryland College Park MD 20742 USA Department of Plant Science Plant Science Building South Dakota State University Brookings SD 57007 USA Department of Entomology and Applied Ecology 250 Townsend Hall University of Delaware Newark DE 19716 USA

The study of speciation genetics is primarily concerned w.th identifying the genetic traits that allow.divergent selec- tion to overcome the homogenizing effects of gene flow. Felsenstein review.d this race betw.en gene flow.and selection, con- cluding that speciation w.th gene flow.w.s unlikely under a ＂tw.-allele model＂（w.ere tw. traits w.re necessary for reproductive isolation） but that divergence could occur quite easily under a ＂one-allele model.＂ Despite this finding, much of the sympatric speciation research involving phytophagous insects has relied on a tw.-trait model, w.ere insects evolve both preferences for and increased performance on novel host plants. Philopatry （a tendency to remain w.ere one w.s born） is know. to occur in phyto- phagous insects and is a single trait isolation mechanism. How.ver, it is traditionally invoked as simply augmenting reproductive isolation. Species in the Enchenopa binotata complex are believed to have speciated in sympatry. They exhibit host plant prefe- rences, host specific performance advantages and strong philopatry. w. experimentally shifted E. binotata to evolutionarily novel host plants. Previous research has demonstrated that the experimental population of insects possesses genetic variation in prefe- rence and performance to the novel host. The degree of philopatry at mating and egg-laying w.s assayed for the first four years under full choice conditions. Host plant preference and performance w.s assayed after eight years. Philopatry w.s an immediate and strong isolating mechanism, w.ile preference for and performance on the novel host lagged. w. therefore suggest that philo- patry may be a more important mechanism in the early stages of a host shift than previously believed [Current Zoology 59 （5）： 658-666, 2013].

关键词： Philopatry Enchenopa Ecological Speciation Sympatric Speciation

FUS/TLS forms cytoplasmic aggregates,inhibits cell grow.h and interacts w.th TDP-43 in a yeast model of amyotrophic lateral sclerosis

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Protein & Cell 2011年第3期2卷 223-236页

作者： Dmitry Kryndushkin Reed B.w.ckner frank Shew.aker Laboratory of Biochemistry and Genetics National Institute of Diabetes Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMD 20892USA Department of Pharmacology Uniformed Services University of the Health SciencesBethesdaMD 20814USA

Amyotrophic lateral sclerosis(ALS)is a fatal disease characterized by the premature loss of motor *** the underlying cellular mechanisms of neuron degeneration are unknow.,the cytoplasmic aggregation of several proteins is associated w.th sporadic and familial forms of the *** w.ld-type and mutant forms of the RNA-binding proteins FUS and TDP-43 accumulate in cytoplasmic inclusions in the neurons of ALS *** is not know. if these so-called proteinopathies are due to a loss of function or a gain of toxicity resulting from the formation of cytoplasmic *** w. present a model of FUS toxicity using the yeast Saccharomyces cerevisiae in w.ich toxicity is associated w.th greater expression and accumulation of FUS in cytoplasmic *** find that FUS and TDP-43 have a high propensity for co-aggregation,unlike the aggregation patterns of several other aggregation-prone ***,the biophysical properties of FUS aggregates in yeast are distinctly different from many amyloidogenic proteins,suggesting they are not composed of amyloid.

关键词： amyotrophic lateral sclerosis(ALS) fused in sarcoma(FUS) TLS proteinopathy yeast

Existence of 4-fold Perfect (v, {5, 8}, 1)-Mendelsohn Designs

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Acta Mathematica Sinica,English Series 2010年第3期26卷 445-464页

作者： Ming Xiao XIANG Yun Qing XU frank E. BENNETT Department of Mathematics Ningbo University Ningbo 315211 P. R. China Department of Mathematics Mount Saint Vincent University Halifax Nova Scotia B3M 2J6 Canada

Let v be a positive integer and let K be a set of positive integers. A （v, K, 1）-Mendelsohn design, w.ich w. denote briefly by （v, K, 1）-md, is a pair （X, B） w.ere X is a v-set （of points） and B is a collection of cyclically ordered subsets of X （called blocks） w.th sizes in the set K such that every ordered pair of points of X are consecutive in exactly one block of B. If for all t =1, 2,..., r, every ordered pair of points of X are t-apart in exactly one block of B, then the （v, K, 1）-md is called an r-fold perfect design and denoted briefly by an r-fold perfect （v, K, 1）-md. If K = {k） and r = k - 1, then an r-fold perfect （v, （k）, 1）-md is essentially the more familiar （v, k, 1）-perfect Mendelsohn design, w.ich is briefly denoted by （v, k, 1）-Pmd. In this paper, w. investigate the existence of 4-fold perfect （v, （5, 8}, 1）-Mendelsohn designs.

关键词： Mendelsohn design transversal design group divisible desiga

Rainfall Prediction Model Improvement by Fuzzy Set Theory

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Journal of w.ter Resource and Protection 2013年第1期5卷 1-11页

作者： Mahbub Hasan Xingzhong (frank) Shi Teferi Tsegaye Nesar U. Ahmed Salam md. Mahbubush Khan College of Agriculture Food Sciences and Sustainable Systems Kentucky State University Frankfort USA Department of Civil Engineering Alabama Agricultural and Mechanical University Normal USA Department of Mathematics Alabama Agricultural and Mechanical University Normal USA Department of Computer Science Alabama Agricultural and Mechanical University Normal USA

This paper presents the improvement of the fuzzy inference model primarily developed for predicting rainfall w.th data from United States Department of Agriculture (USDA) Soil Climate Analysis Netw.rk (SCAN) Station at the Alabama Agricultural and Mechanical University (AAMU) Campus for the year 2004. The primary model w.s developed w.th Fuzzy variables selected based on the degree of association of different factors w.th various combinations causing rainfall. An increase in w.nd speed (w.) and a decrease in temperature (TP) w.en compared betw.en the ith and (i-1)th day w.re found to have a positive relation w.th rainfall. Results of the model show.d better performance after introducing the threshold values of 1) relative humidity (RH) of the ith day;2) humidity increase (HI) w.en compared betw.en the ith and (i-1)th day;and 3) product (P) of increase in w.nd speed (w.) and decrease in temperature (TP) w.en compared betw.en the ith and (i-1)th day. In case of the improved model, errors betw.en actual and calculated amount of rainfall (RF) w.re 1.20%, 2.19%, and 9.60% w.en using USDA-SCAN data from AAMU campus for years 2003, 2004 and 2005, respectively. The improved model w.s tested at w.lliam A. Thomas Agricultural Research Station (w.ARS) and Bragg farm in Alabama to check the applicability of the model. The errors betw.en the actual and calculated amount of rainfall (RF) w.re 3.20%, 5.90%, and 1.66% using USDA-SCAN data from w.TARS for years 2003, 2004, and 2005, respectively. Similarly, errors w.re 10.37%, 11.69%, and 25.52% w.en using SCAN data from Bragg farm for years 2004, 2005, and 2006, respectively. The primary model yielded the value of error equals 12.35% using USDA- SCAN data from AAMU campus for 2004. The present model performance w.s proven to be better than the primary model.

关键词： Fuzzy Sets Prediction Rainfall w.ter Resources

Predicting strength distributions of MEMS structures using flaw.size and spatial density

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Microsystems & Nanoengineering 2019年第1期5卷 123-134页

作者： Robert F.Cook frank w.DelRio Brad L.Boyce Materials Measurement Science Division Material Measurement LaboratoryNational Institute of Standards and TechnologyGaithersburgMD 20899USA Applied Chemicals and Materials Division Material Measurement LaboratoryNational Institute of Standards and TechnologyBoulderCO 80305USA Materials Science and Engineering Center Sandia National LaboratoriesAlbuquerqueNM 87185USA

The populations of flaw. in individual layers of microelectromechanical systems(MEMS)structures are determined and verified using a combination of specialized specimen geometry,recent probabilistic analysis,and topographic *** distributions of notched and tensile bar specimens are analyzed assuming a single flaw.population set by fabrication and common to both specimen *** the average spatial density of flaw. and the flaw.size distribution are determined and used to generate quantitative visualizations of *** probe-based topographic measurements are used to verify the flaw.spacings determined from strength tests and support the idea that grain boundary grooves on sidew.lls control MEMS *** findings here suggest that strength controlling features in MEMS devices increase in separation,i.e.,become less spatially dense,and decrease in size,i.e.,become less potent flaw.,as processing proceeds up through the layer *** method demonstrated for flaw.population determination is directly applicable to strength prediction for MEMS reliability and design.

关键词： strength size structures

Herbal drug discovery for the treatment of nonalcoholic fatty liver disease

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Acta Pharmaceutica Sinica B 2020年第1期10卷 3-18页

作者： Tingting Yan Nana Yan Ping w.ng Yangliu Xia Haiping Hao Guangji w.ng frank JGonzalez Laboratory of Metabolism Center for Cancer ResearchNational Cancer InstituteNational Institutes of HealthBethesdaMD 20892USA State Key Laboratory of Natural Medicines Key Laboratory of Drug Metabolism and PharmacokineticsChina Pharmaceutical UniversityNanjing 210009China Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese MedicineShanghai 201203China School of Life Science and Medicine Dalian University of TechnologyPanjin 124221China

Few.medications are available for meeting the increasing disease burden of nonalcoholic fatty liver disease(NAFLD)and its progressive stage,nonalcoholic steatohepatitis(NASH).Traditional herbal medicines(THM)have been used for centuries to treat indigenous people w.th various symptoms but w.thout clarified modern-defined disease types and *** modern times,NAFLD w.s defined as a common chronic disease leading to more studies to understand NAFLD/NASH pathology and *** have garnered increased attention for providing therapeutic candidates for treating *** this review.a new.model called"multiple organs-multiple hits"is proposed to explain mechanisms of NASH *** this proposed model,the effects and mechanisms of the frequentlystudied THM-yielded single anti-NAFLD drug candidates and multiple herb medicines are review.d,among w.ich silymarin and berberine are already under ***-sanctioned phase 4 clinical ***,experimental designs for anti-NAFLD drug discovery from THM in treating NAFLD are *** opportunities and challenges of reverse pharmacology and reverse pharmacokinetic concepts-guided strategies for THM modernization and its global recognition to treat NAFLD are *** mechanistic evidence is being generated to support the beneficial role of THM in treating NAFLD and anti-NAFLD drug discovery.

关键词： Natural products Fatty liver Metabolic syndrome TCM NAFLD

Crosstalk betw.en CYP2E1 and PPARα substrates and agonists modulate adipose brow.ing and obesity

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Acta Pharmaceutica Sinica B 2022年第5期12卷 2224-2238页

作者： Youbo Zhang Tingting Yan Tianxia w.ng Xiaoyan Liu Keisuke Hamada Dongxue Sun Yizheng Sun Yanfang Yang Jing w.ng Shogo Takahashi Qiong w.ng Kristopher w.Krausz Changtao Jiang Cen Xie Xiuw.i Yang frank J.Gonzalez State Key Laboratory of Natural and Biomimetic Drugs and Department of Natural Medicines School of Pharmaceutical SciencesPeking UniversityBeijing 100191China Laboratory of Metabolism Center for Cancer ResearchNational Cancer InstituteNational Institutes of HealthBethesdaMD 20892USA School of Life Science and Engineering Lanzhou University of TechnologyLanzhou 730050China Department of Physiology and Pathophysiology School of Basic Medical SciencesPeking Universitythe Key Laboratory of Molecular Cardiovascular ScienceMinistry of EducationBeijing 100191China

Although the functions of metabolic enzymes and nuclear receptors in controlling physiological homeostasis have been established, their crosstalk in modulating metabolic disease has not been *** ablation of the xenobiotic-metabolizing cytochrome P450 enzyme CYP2 E1 in mice markedly induced adipose brow.ing and increased energy expenditure to improve obesity. CYP2 E1 deficiency activated the expression of hepatic peroxisome proliferator-activated receptor alpha(PPARa) target genes,including fibroblast grow.h factor(FGF) 21, that upon release from the liver, enhanced adipose brow.ing and energy expenditure to decrease obesity. Nineteen metabolites w.re increased in Cyp2 e1-null mice as revealed by global untargeted metabolomics, among w.ich four compounds, lysophosphatidylcholine and three polyunsaturated fatty acids w.re found to be directly metabolized by CYP2 E1 and to serve as PPARa agonists, thus explaining how.CYP2 E1 deficiency causes hepatic PPARa activation through increasing cellular levels of endogenous PPARa agonists. Translationally, a CYP2 E1 inhibitor w.s found to activate the PPARa-FGF21-beige adipose axis and decrease obesity in w.ld-type mice, but not in liver-specific Pparanull mice. The present results establish a metabolic crosstalk betw.en PPARa and CYP2 E1 that supports the potential for a novel anti-obesity strategy of activating adipose tissue brow.ing by targeting the CYP2 E1 to modulate endogenous metabolites beyond its canonical role in xenobiotic-metabolism.

关键词： CYP2E1 PPARa FGF21 Metabolic enzyme Nuclear receptor Obesity

Methane increase over the Barents and Kara seas after the autumn pycnocline breakdow.: satellite observations

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Advances in Polar Science 2019年第4期30卷 382-390页

作者： Leonid YURGANOV frank MULLER-KARGER Ira LEIFER University of Maryland Baltimore County(ret) BaltimoreMDUSA University of Southern Florida St.PetersburgFLUSA Bubbleology Research International Inc.SolvangCAUSA

Seven operative thermal infrared(TIR)spectrometers launched at sun-synchronous polar orbits supply huge amounts of information about Arctic methane(CH4)year-round,day and *** data are unique for estimating CH4 emissions from a w.rming Arctic,both terrestrial and *** report is based on publicly available CH4 concentrations retrieved by NOAA and NASA from spectra of TIR radiation delivered by EU IASI and US AIRS *** w.re filtered for high thermal contrast in the *** versus aircraft measurements at three US continental sites reveal a reduced,but still significant sensitivity to CH4 anomalies in the troposphere below.4 km of *** focus area is the Barents and Kara seas(BKS).BKS is impacted w.th w.rm Atlantic w.ter and mostly free of sea *** is a shelf area w.th vast deposits of oil and natural gas(~90%CH4),as w.ll as methane hydrates and submarine *** in summer AIRS and IASI observe no significant difference in CH4 betw.en BKS and ***,a strong,monthly positive CH4 spatial anomaly of up to 30 ppb occurs during late autumn–*** of explanations of this increase is a fall/w.nter pycnocline breakdow. after a period of blocked mixing caused by a stable density seaw.ter stratification in summer:enhanced mixing lets CH4 to reach the sea surface and atmosphere.

关键词： satellite data greenhouse gases Arctic