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Alanine and aspartate aminotransferase and glutamine-cycling pathway:Their roles in pathogenesis of metabolic syndrome

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World journal of Gastroenterology 2012年第29期18卷 3775-3781页

作者： Silvia Sookoian carlos j Pirola Department of Clinical and Molecular Hepatology Institute of Medical Research A Lanari-IDIMUniversity of Buenos Aires-National Council of Scientific and Technological Research(CONICET)Ciudad Autónoma de Buenos Aires 1427Argentina Department of Molecular Genetics and Biology of Complex Diseases Institute of Medical Research A Lanari-IDIMUniversity of Buenos Aires-National Council of Scientific and Technological Research(CONICET)Ciudad Autónoma de Buenos Aires 1427Argentina

Although new research technologies are constantly used to look either for genes or biomarkers in the prediction of metabolic syndrome(MS),the pathogenesis and pathophysiology of this complex disease remains a major ***,Cheng et al recently investigated possible pathways underlying MS by high-throughput metabolite profiling in two large and well characterized community-based *** authors explored by liquid chromatography and mass spectrometry the plasma concentrations of 45 distinct metabolites and examined their relation to cardiometabolic risk,and observed that metabolic risk factors such as obesity,insulin resistance(IR),high blood pressure,and dyslipidemia were associated with several metabolites,including branched-chain amino acids,other hydrophobic amino acids,tryptophan breakdown products,and nucleotide *** addition,the authors found a significant association of IR traits with glutamine,glutamate and the glutamineto-glutamate *** data provide new insight into the pathogenesis of MS-associated phenotypes and introduce a crucial role of glutamine-cycling pathway as prominently involved in the development of metabolic *** consider that the hypothesis about the role of abnormal glutamate metabolism in the pathogenesis of the MS is certainly challenging and suggests the critical role of the liver in the global metabolic modulation as glutamate metabolism is linked with aminotransferase *** discuss here the critical role of the "liver metabolism" in the pathogenesis of the MS and IR,and postulate that before fatty liver develops,abnormal levels of liver enzymes,such as alanine and aspartate aminotransferases might reflect high levels of hepatic transamination of amino acids in the liver.

关键词： Alanine Aspartate Glutamine Glutamate 2-oxoglutarate Glycolysis Pyruvate

PNPLA3,the triacylglycerol synthesis/hydrolysis/storage dilemma,and nonalcoholic fatty liver disease

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World journal of Gastroenterology 2012年第42期18卷 6018-6026页

作者： Silvia Sookoian carlos j Pirola Department of Clinical and Molecular Hepatology Institute of Medical Research A Lanari-IDIMUniversity of Buenos AiresNational Council of Scientific and Technological Research(CONICET)Autonomous City of Buenos Aires 1427Argentina Department of Molecular Genetics and Biology of Complex Diseases Institute of Medical Research A Lanari-IDIMUniversity of Buenos AiresNational Council of Scientific and Technological Research(CONICET)Autonomous City of Buenos Aires 1427Argentina

Genome-wide and candidate gene association studies have identified several variants that predispose indi- viduals to developing nonalcoholic fatty liver disease （NAFLD）. However, the gene that has been consis- tently involved in the genetic susceptibility of NAFLD in humans is patatin-like phospholipase domain contain- ing 3 （PNPLA3, also known as adiponutrin）. A nonsyn- onymous single nucleotide polymorphism in PNPLA3 （rs738409 C/G, a coding variant that encodes an amino acid substitution I148M） is significantly associated with fatty liver and histological disease severity, not only in adults but also in children. Nevertheless, how PNPLA3 influences the biology of fatty liver disease is still an open question. A recent article describes new aspects about PNPLA3 gene/protein function and suggests that the I148M variant promotes hepatic lipid synthesis due to a gain of function. We revise here the published data about the role of the I148M variant in lipogen- esis/lipolysis, and suggest putative areas of future research. For instance we explored in silico whether the rs738409 C or G alleles have the ability to modify miRNA binding sites and miRNA gene regulation, and we found that prediction of PNPLA3 target miRNAs shows two miRNAs potentially interacting in the 3＇ UTR region （hsa-miR-769-3p and hsa-miR-516a-3p）. In addition, interesting unanswered questions remain to be explored. For example, PNPLA3 lies between two CCCTC-binding factor-bound sites that could be tested for insulator activity, and an intronic histone 3 lysine 4 trimethylation peak predicts an enhancer element, cor- roborated by the DNase I hypersensitivity site peak. Finally, an interaction between PNPLA3 and glycerol- 3-phosphate acyltransferase 2 is suggested by data miming.

关键词： Adiponutrin Nonalcoholic fatty liver disease miRNA Glycerol-3-phosphate acyltransferase 2 Sys-tems biology Rs738409 Epigenetics

Mechanical and hydraulic properties of carbonate rock:The critical role of porosity

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journal of Rock Mechanics and Geotechnical Engineering 2023年第4期15卷 814-825页

作者： Kam Ng j.carlos Santamarina Department of Civil and Architectural Engineering and Construction Management University of WyomingLaramieWY82071USA Physical Science and Engineering Division King Abdullah University of Science and TechnologyThuwal23955-6900Saudi Arabia

Carbonate rocks are extensively used in civil infrastructure and play a critical role in geoenergy geoengineering,either as hydrocarbon reservoirs or potential repositories for CO_(2)geological *** genesis and diagenetic overprint determine the properties of carbonate *** study combines recent data gathered from Madison Limestone and an extensive dataset compiled from published sources to analyze the hydraulic and mechanical properties of limestone carbonate *** models and data analyses recognize the inherently granular genesis of carbonate rocks and explain the strong dependency of physical properties on *** asymptotically-correct power model in terms of(1-Ф/Ф*)a is a good approximation to global trends of unconfined stiffness E and unconfined compressive strength UCS,cohesive intercept in Mohr-Coulomb failure envelopes,and the brittle-toductile transition *** power model is the analytical solution for the mechanical properties of percolating granular *** adopted a limiting granular porosityФ*=0.5 for all models,which was consistent with the loosest packing of monosize *** fitted power model has exponent(α=2)in agreement with percolation theory and highlights the sensitivity of mechanical properties to *** and models confirm a porosity-independent ratio between unconfined stiffness and strength,and the ratio follows a log-normal distribution with mean(E/UCS)≈*** high angle of internal shear strength measured for carbonate rocks reflects delayed contact failure with increased confinement,and it is not sensitive to *** spans more than six orders of *** size controls pore size and determines the reference permeability k^(*)at the limiting porosityФ*=*** a given grain size from fine to coarse-grained dominant carbonates,permeability is very sensitive to changes in porosity,suggesting preferential changes in the internal pore network during compaction.

关键词： Rock porosity Carbonate permeability Rock unconfined stiffness Unconfined compressive strength(UCS)

Repurposing drugs to target nonalcoholic steatohepatitis

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World journal of Gastroenterology 2019年第15期25卷 1783-1796页

作者： Silvia Sookoian carlos j Pirola Department of Clinical and Molecular Hepatology National Scientific and Technical Research Council (CONICET) University of Buenos Aires Institute of Medical Research (IDIM) Department of Molecular Genetics and Biology of Complex Diseases National Scientific and Technical Research Council (CONICET) University of Buenos Aires Institute of Medical Research (IDIM)

Nonalcoholic fatty liver disease(NAFLD) is a complex disorder that has evolved in recent years as the leading global cause of chronic liver damage. The main obstacle to better disease management pertains to the lack of approved pharmacological interventions for the treatment of nonalcoholic steatohepatitis(NASH) and NASH-fibrosis-the severe histological forms. Over the past decade,tremendous advances have been made in NAFLD research, resulting in the discovery of disease mechanisms and novel therapeutic targets. Hence, a large number of pharmacological agents are currently being tested for safety and efficacy. These drugs are in the initial pharmacological phases(phase 1 and 2),which involve testing tolerability, therapeutic action, and pharmacological *** is thus reasonable to assume that the next generation of NASH drugs will not be available for clinical use for foreseeable future. The expected delay can be mitigated by drug repurposing or repositioning, which essentially relies on identifying and developing new uses for existing drugs. Here, we propose a drug candidate selection method based on the integration of molecular pathways of disease pathogenesis into network analysis tools that use OMICs data as well as multiples sources, including text mining from the medical literature.

关键词： Drug discovery Drug repositioning Fibrosis Genetics Treatment Systems biology

An Efficient Real Space Method for Orbital-Free Density-Functional Theory

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Communications in Computational Physics 2007年第2期2卷 334-357页

作者： carlos j.Garcıa-Cervera Department of Mathematics University of CaliforniaSanta BarbaraCA 93106USA.

We consider the Thomas-Fermi-von Weizsacker energy functional,with the Wang-Teter correction,and present an efficient real space method for Orbital-Free Density Functional *** is proved that the energy minimizer satisfies a second order quasilinear elliptic equation,even at the points where the electron density *** information is used to construct an efficient energy minimization method for the resulting constrained problem,based on the truncated Newton method for unconstrained *** Wang-Teter kernel is analyzed,and its behavior in real space at short and far distances is determined.A second order accurate discretization of the energy is obtained using finite *** efficiency and accuracy of the method is illustrated with numerical simulations in an Aluminium FCC lattice.

关键词： Density functional theory truncated Newton method constrained optimization.

Liver enzymes,metabolomics and genome-wide association studies:From systems biology to the personalized medicine

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World journal of Gastroenterology 2015年第3期21卷 711-725页

作者： Silvia Sookoian carlos j Pirola Department of Clinical and Molecular Hepatology Institute of Medical Research A Lanari-IDIMUniversity of Buenos Aires-National Scientific and Technical Research Council Ciudad Autónoma de Buenos AiresBuenos Aires 1427Argentina Department of Molecular Genetics and Biology of Complex Diseases Institute of Medical Research A Lanari-IDIMUniversity of Buenos Aires-National Scientific and Technical Research CouncilCiudad Autónoma de Buenos AiresBuenos Aires 1427Argentina

For several decades,serum levels of alanine(ALT) and aspartate(AST) aminotransferases have been regarded as markers of liver injury,including a wide range of etiologies from viral hepatitis to fatty *** increasing worldwide prevalence of metabolic syndrome and cardiovascular disease revealed that transaminases are strong predictors of type 2 diabetes,coronary heart disease,atherothrombotic risk profile,and overall risk of metabolic ***,it is plausible to suggest that aminotransferases are surrogate biomarkers of "liver metabolic functioning" beyond the classical concept of liver cellular damage,as their enzymatic activity might actually reflect key aspects of the physiology and pathophysiology of the liver *** this study,we summarize the background information and recent findings on the biological role of ALT and AST,and review the knowledge gained from the application of genome-wide approaches and "omics" technologies that uncovered new concepts on the role of aminotransferases in human diseases and systemic regulation of metabolic *** of biomolecular interactions between the candidate genes recently discovered to be associated with plasma concentrations of liver enzymes showed interesting interconnectivity nodes,which suggest that regulation of aminotransferase activity is a complex and highly regulated ***,links between aminotransferase genes and metabolites are explored to understand the genetic contributions to the metabolic diversity.

关键词： Transaminases Aminotransferases Alanineaminotransf

Multiomics biomarkers for the prediction of nonalcoholic fatty liver disease severity

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World journal of Gastroenterology 2018年第15期24卷 1601-1615页

作者： carlos j Pirola Silvia Sookoian Department of Genetics and Molecular Biology of Complex Diseases. University of Buenos Aires Institute of Medical Research A Lanari Buenos Aires Argentina National Scientific and Technical Research Council-University of Buenos Aires. Institute of Medical Research (IDIM) Clinical and Molecular Hepatology University of Buenos Aires Institute of Medical Research A Lanari Buenos Aires Argentina National Scientific and Technical Research Council-University of Buenos Aires. Institute of Medical Research (IDIM)

This review intends to uncover how information from large-scale genetic profiling(whole genome sequencing, and whole exome sequencing) of nonalcoholic fatty liver disease(NAFLD), as well as information from circulating transcriptomics(cell-free mi RNAs) and metabolomics, contributes to the understanding of NAFLD pathogenesis. A further aim is to address the question of whether OMICs information is ready to be implemented in the clinics. The available evidence suggests that any new knowledge pertaining to molecular signatures associated with NAFLD and nonalcoholic steatohepatitis should be promptly translated into the clinical setting. Nevertheless, rigorous steps that must include validation and replication are mandatory before utilizing OMICs biomarkers in diagnostics to identify patients at risk of advanced disease, including liver cancer.

关键词： nonalcoholic steatohepatitis Fibrosis Liver biopsy Genetics PNPLA3 TM6SF2 Metabolomics Proteomics Transcriptomics nonalcoholic fatty liver disease miR122

Different canopy openings affect underground traits in herbaceous plants of a southern forest in Patagonia

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journal of Plant Ecology 2016年第5期9卷 542-552页

作者： Luciano j.Selzer carlos A.Busso CADIC-CONICET Houssay 200(9410)UshuaiaTierra del FuegoArgentina.Instituto de Ciencias PolaresAmbiente y Recursos Naturales.Universidad Nacional de Tierra del FuegoAlem 1036(9410)UshuaiaTierra del FuegoArgentina CERZOS-CONICET San Andrés 800(8000)Bahía BlancaBuenos AiresArgentina.Depto.de Agronomía-Universidad Nacional del SurSan Andrés 800(8000)Bahía BlancaBuenos AiresArgentina

Aims Forest canopy openings modify the natural environment,producing changes in light quality and intensity,precipitation and *** turn,these changes promote the acclimation of understory ***,little work has been done on underground responses to those environmental *** objective of this work was to determine how Osmorhiza depauperata,Phleum alpinum and Poa pratensis change its root length density and root colonization by mycorrhiza as a function of light availability in a Nothofagus pumilio(***)forest harvested following the variable retention *** We selected three microenvironments in an old growth forest harvested by the variable retention prescription:aggregated retention,dispersed retention with influence of aggregated retention and dispersed retention.A non-harvested primary forest(PF),similar to the harvested one,was used as a *** 2 months,from October 2008 to April 2009,we took soil cores from randomly selected *** these soil cores,root length density and colonization percentage(CP)by arbuscular mycorrhizae were *** Findings Light availability changed significantly among the *** general,root length density was significantly greater in *** than in *** and both species greater than in *** availability increased root length density in all species,although the magnitude of these increases difference among *** length density was 187%greater in ***,101%in *** and 94%in *** in the disperse retention system than in the *** CP was higher in *** than in *** and ***,it was lower in the PF than in the harvested *** were very low.

关键词： root length density mycorrhizal colonization light shade understory Tierra del Fuego

Role of ABCC2 common variants in intrahepatic cholestasis of pregnancy

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World journal of Gastroenterology 2008年第13期14卷 2126-2127页

作者： Silvia Sookoian Gustavo Castao carlos j Pirola Department of Molecular Genetics and Biology of Complex Diseases Institute of Medical Research A. Lanari University of Buenos Aires-CONICET Buenos Aires 1427 Argentina Research Council of GCBA Buenos Aires 1427 Argentina

The pathogenesis of intrahepatic cholestasis of pregnancy (ICP), a disorder that adversely affects maternal wellbeing and fetal outcome, is unclear. However, multiple factors probably interact along with a genetic predisposition. We would like to add some comments on a paper recently published concerning the role of ABCB11 and ABCC2 polymorphisms in both ICP and contraceptive-induced cholestasis, especially in the light of our recently published findings about a positive association between ICP and ABCC2 common variants.

关键词： Intrahepatic cholestasis of pregnancy ABCC2 MRP2 Gene variants