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Integrating Culture-based Antibiotic Resistance Profiles with Whole-genome Sequencing Data for 11,087 Clinical Isolates

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Genomics, Proteomics & Bioinformatics 2019年第2期17卷 169-182页

作者： Valentina Galata Cédric C. Laczny Christina Backes Georg Hemmrich-Stanisak Susanne Schmolke Andre Franke Eckart Meese Mathias Herrmann Lutz von Müller Achim Plum Rolf Mü ller Cord Stahler Andreas E. Posch Andreas Keller Chair for Clinical Bioinformatics Saarland University 66123 Saarbrücken Germany Helmholtz Center for Infection Research and Pharmaceutical Biotechnology (HZI) Saarland University 66123 Saarbrücken Germany Institute of Clinical Molecular Biology Christian-Albrechts University of Kiel 24105 Kiel Germany Siemens Healthcare gmbh Strategy and Innovation 91052 Erlangen Germany Department of Human genetics Saarland University 66421 Homburg Germany Institute of Medical Microbiology and Hygiene Saarland University 66421 Homburg Germany ares genetics gmbh 1030 Vienna Austria Curetis gmbh 71088 Holzgerlingen Germany Department of Pharmacy Pharmaceutical Biotechnology Saarland University 66123 Saarbrücken Germany Department of Microbial Natural Products Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS) Saarland University 66123 Saarbrücken Germany

Emerging antibiotic resistance is a major global health threat. The analysis of nucleic acid sequences linked to susceptibility phenotypes facilitates the study of genetic antibiotic resistance determinants to inform molecular diagnostics and drug development. We collected genetic data (11,087 newly-sequenced whole genomes) and culture-based resistance profiles (10,991 out of the 11,087 isolates comprehensively tested against 22 antibiotics in total) of clinical isolates including 18 main species spanning a time period of 30 years. Species and drug specific resistance patterns were observed including increased resistance rates for Acinetobacter baumannii to carbapenems and for Escherichia coli to fluoroquinolones. Species-level pan-genomes were constructed to reflect the genetic repertoire of the respective species,including conserved essential genes and known resis-tance factors. Integrating phenotypes and genotypes through species-level pan-genomes allowed to infer gene–drug resistance associations using statistical testing. The isolate collection and the analysis results have been integrated into GEAR-base,a resource available for academic research use free of charge at https://***.

关键词： Antibiotic resistance Whole-genome sequencing Bacteria Pan-genome

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Mapping theArabidopsis Metabolic Landscape by Untargeted Metabolomics at Different Environmental Conditions

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Molecular Plant 2018年第1期11卷 118-134页

作者： Si Wu Takayuki Tohge Alvaro Cuadros-lnostroza Hao Tong Hezi Tenenboim Rik Kooke Michael Meret Joost B. Keurentjes Zoran Nikoloski Alisdair R. Fernie Lothar Willmitzer Yariv Brotman 1 Max Planck Institute of Molecular Plant Physiology 14476 Potsdam-Golm Germany MetaSysX gmbh Am Muhlenberg 11 14476 Potsdam-Golm Germany Laboratory of genetics Wageningen University Droevendaalsesteeg 1 6708 PB Wageningen the Netherlands Department of Life Sciences Ben Gurion University of the Negev Beersheva Israel

Metabolic genome-wide association studies （mGWAS）, whereupon metabolite levels are regarded as traits, can help unravel the genetic basis of metabolic networks. A total of 309Arabidopsis accessions were grown under two independent environmental conditions （control and stress） and subjected to untargeted LC-MS- based metabolomic profiling; levels of the obtained hydrophilic metabolites were used in GWAS. Our two- condition-based GWAS for more than 3000 semi-polar metabolites resulted in the detection of 123 highly resolved metabolite quantitative trait loci （p ≤ 1.0E-08）, 24.39% of which were environment-specific. Interestingly, differently from natural variation in Arabidopsis primary metabolites, which tends to be controlled by a large number of small-effect loci, we found several major large-effect loci alongside a vast number of small-effect loci controlling variation of secondary metabolites. The two-condition-based GWAS was fol- lowed by integration with network-derived metabolite-transcript correlations using a time-course stress experiment. Through this integrative approach, we selected 70 key candidate associations between struc- tural genes and metabolites, and experimentally validated eight novel associations, two of them showing differential genetic regulation in the two environments studied. We demonstrate the power of combining large-scale untargeted metabolomics-based GWAS with time-course-derived networks both performed under different ablotic environments for identifying metabollte-gene associations, providing novel global insights into the metabolic landscape of Arabidopsis.

关键词： untargeted metabolomics GWAS network analysis different environments secondary metabolism

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Empagliflozin alleviates podocytopathy and enhances glomerular nephrin expression in db/db diabetic mice

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World Journal of Diabetes 2020年第12期11卷 596-610页

作者： Vadim V Klimontov Anton I Korbut Iuliia S Taskaeva Nataliya P Bgatova Maksim V Dashkin Nikolai BOrlov Anna S Khotskina Evgenii L Zavyalov Thomas Klein Laboratory of Endocrinology Research Institute of Clinical and Experimental Lymphology–Branch of the Institute of Cytology and GeneticsSiberian Branch of Russian Academy of Sciences(RICEL–Branch of IC&G SB RAS)Novosibirsk 630060Russia Laboratory of Ultrastructural Research Research Institute of Clinical and Experimental Lymphology–Branch of the Institute of Cytology and GeneticsSiberian Branch of Russian Academy of Sciences(RICEL–Branch of IC&G SB RAS)Novosibirsk 630060Russia Laboratory of Clinical Immunogenetics Research Institute of Clinical and Experimental Lymphology–Branch of the Institute of Cytology and GeneticsSiberian Branch of Russian Academy of Sciences(RICEL–Branch of IC&G SB RAS)Novosibirsk 630060Russia Center for Genetic Resources of Laboratory Animals Institute of Cytology and GeneticsSiberian Branch of Russian Academy of SciencesNovosibirsk 630090Russia Department of Cardiometabolic Diseases Research Boehringer Ingelheim Pharma GmbHBiberach 88397Germany

BACKGROUND Modern guidelines recommend sodium-glucose cotransporter-2(SGLT2)inhibitors as the preferred antihyperglycemic agents for patients with type 2 diabetes and chronic kidney ***,the mechanisms underlying the renal protective effect of SGLT2 inhibitors are not fully *** of podocytes and nephrin expression in glomeruli in db/db diabetic *** We treated 8-wk-old male db/db mice with EMPA(10 mg/kg/d)or vehicle for 8 ***-matched male db/+mice were included as non-diabetic *** of body composition,glycemic and lipid control,and plasma concentrations of leptin,insulin and glucagon were *** evaluated renal hypertrophy as kidney weight adjusted to lean mass,renal function as plasma levels of creatinine,and albuminuria as the urinary albumin-to-creatinine ratio(UACR).Renal structures were studied by light and transmission electron microscopy with a focus on mesangial volume and podocyte structure,*** nephrin and transforming growth factor beta(TGF-β)were assessed by *** Severe obesity and hyperglycemia developed in db/db mice prior to the start of the experiment;increased plasma concentrations of fructosamine,glycated albumin,cholesterol,leptin,and insulin,and elevated UACR were *** expansion,glomerular basement membrane thickening,and increased area of TGF-βstaining in glomeruli were revealed in vehicle-treated *** was manifested by effacement of foot processes;nephrin-positive areas in glomeruli were *** decreased the levels of glucose,fructosamine and glycated albumin,UACR,kidney hypertrophy,mesangial expansion,glomerular basement membrane thickening,and glomerular TGF-βstaining,alleviated podocytopathy and restored glomerular staining of *** These data indicate that EMPA attenuates podocytopathy in experimental diabetic kidney *** anti-albuminuric effect of EMPA could be attributed to mitigation o

关键词： Diabetes Chronic kidney disease Albuminuria Podocyte Sodium-glucose transporter 2 inhibitors Empagliflozin

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Update on pathogenesis and predictors of response of therapeutic strategies used in inflammatory bowel disease

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World Journal of Gastroenterology 2015年第44期21卷 12519-12543页

作者： Emilio G Quetglas Zlatan Mujagic Simone Wigge Daniel Keszthelyi Sebastian Wachten Ad Masclee Walter Reinisch Project Strategy and Science Grünenthal GmbH Internal Medicine University of Maastricht Medical Center Translational Science Grünenthal GmbH Molecular Pharmacology Grünenthal GmbH Internal Medicine. Mc Master University

The search for biomarkers that characterize specific aspects of inflammatory bowel disease(IBD), has received substantial interest in the past years and is moving forward rapidly with the help of modern technologies. Nevertheless, there is a direct demand to identify adequate biomarkers for predicting and evaluating therapeutic response to different therapies. In this subset, pharmacogenetics deserves more attention as part of the endeavor to provide personalized medicine. The ultimate goal in this area is the adjustment of medication for a patient's specific genetic background and thereby to improve drug efficacy and safety rates. The aim of the following review is to utilize the latest knowledge on immunopathogenesis of IBD and update the findings on the field of Immunology and genetics, to evaluate the response to the different therapies. In the present article, more than 400 publications were reviewed but finally 287 included based on design, reproducibility(or expectancy to be reproducible and translationable into humans) or already measured in humans. A few testshave shown clinical applicability. Other, i.e., genetic associations for the different therapies in IBD have not yet shown consistent or robust results. In the close future it is anticipated that this, cellular and genetic material, as well as the determination of biomarkers will be implemented in an integrated molecular diagnostic and prognostic approach to manage IBD patients.

关键词： Mucosal immunology Biomarkers Pharmacology Mode of

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1A6/DRIM, the human UTP20 functions in 28S and 5.8S rRNA processing

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Chinese Science Bulletin 2010年第17期55卷 1770-1776页

作者： KONG RuiRui HAN Wei ULRICH H. Weidle NING Tao DU XiaoJuan KE Yang Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education) Genetics Laboratory Peking University School of Oncology Beijing Cancer Hospital & Institute Beijing 100142 China Cancer Research Center Peking University Health Science Center Beijing 100191 China Roche Diagnostics gmbh Division Pharma 82372 Penzberg Germany Department of Cell Biology Peking University Health Science Center Beijing 100191 China

1A6/DRIM has been identified as UTP20, a small subunit processome component, functioning in 18S rRNA processing. In the present study, the maturation of 28S rRNA and 5.8S rRNA was inhibited when 1A6/DRIM was silenced in HeLa cells; and coincidently, an accumulation of 32S rRNA precursor was observed. Immunoprecipitation was performed with the anti-1A6/DRIM antibody, followed by Northern blot with the ITS2 probe. The results showed that 1A6/DRIM was associated with both 32S and 12S rRNA precursors in vivo. The expression profile of 1A6/DRIM during rRNA processing was investigated by sucrose density gradient fractionation in combination with Western blot analysis. The results demonstrated that 1A6/DRIM was involved in the pre-60S particles in addition to the pre-40S particles and co-sediment with the 32S and 12S rRNA precursors in the nucleolus. Furthermore, the interaction of U8 snoRNA with 1A6/DRIM was revealed by immunoprecipitation. These results demonstrated that 1A6/DRIM interacted with both 32S rRNA and U8 snoRNA, being involved in 28S rRNA and 5.8S rRNA processing.

关键词： rRNA基因加工过程 snoRNA 职能人类 HeLa细胞免疫印迹分析免疫沉淀

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Immunological and functional features of decellularized xenogeneic heart valves after transplantation into GGTA1-KO pigs

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Regenerative Biomaterials 2021年第5期8卷 25-36页

作者： Robert Ramm Tobias Goecke Peter Kohler Igor Tudorache Serghei Cebotari Anatol Ciubotaru Samir Sarikouch Klaus Hoffler Friederike Bothe Bjorn Petersen Axel Haverich Heiner Niemann Andres Hilfiker Leibniz Research Laboratories for Biotechnology and Artificial Organs(LEBAO) Hannover Medical SchoolCarl-Neuberg Str.1Hannover 30625Germany Department of Cardiac- Thoracic-Transplantation and Vascular SurgeryHannover Medical SchoolCarl-Neuberg Str.1Hannover 30625Germany Institute of Farm Animal genetics Friedrich-Loeffler-InstitutHoeltystr.1031535 Mariensee/Neustadt am RuebenbergeGermany Medimplant gmbh Bischofsholer Damm 15Hannover 30173Germany

Decellularization of xenogeneic heart valves might lead to excellent regenerative implants,from which many patients could ***,this material carries various xenogeneic epitopes and thus bears a considerable inherent immunological ***,we investigated the regenerative and immunogenic potential of xenogeneic decellularized heart valve implants using pigs deficient for the galactosyltransferase gene(GGTA1-KO)as novel large animal *** aortic and pulmonary heart valves obtained from sheep,wild-type pigs or GGTA1-KO pigs were implanted into GGTA1-KO pigs for 3,or 6 months,*** were analyzed histologically,immunhistologically(CD3,CD21 and CD172a)and anti-aGal antibody serum titers were determined by *** sheep derived implants exhibited a strong immune reaction upon implantation into GGTA1-KO pigs,characterized by massive inflammatory cells infiltrates,presence of foreign body giant cells,a dramatic increase of anti-aGal antibody titers and ultimately destruction of the graft,whereas wild-type porcine grafts induced only a mild reaction in GGTA1-KO *** implants,wild-type/wild-type and GGTA1-KO/GGTA1-KO valves did not induce a measurable immune ***,GGTA1-KO pigs developed a‘human-like’immune response toward decellularized xenogeneic implants showing that immunogenicity of xenogeneic implants is not sufficiently reduced by decellularization,which detracts from their regenerative potential.

关键词： aGal-KO pig decellularization heart valves xenoantibodies large animal model

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DNA Damage-Induced Transcription of Transposable Elements and Long Non-coding RNAs in Arabidopsis Is Rare and ATM-Dependent

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Molecular Plant 2016年第8期9卷 1142-1155页

作者： Zhenxing Wang Rainer Schwacke Reinhard Kunze institute of Biology - Applied genetics Dahlem Centre of Plant Sciences - DCPS Freie Universit~t Berlin Albrecht-Thaler-Weg 6 14195 Berlin Germany Forschungszentrum JQlich gmbh Institute of Bio- and Geosciences Plant Sciences (IBG-2) 52425 JQlich Germany

Induction and mobilization of transposable elements （TEs） following DNA damage or other stresses has been reported in prokaryotes and eukaryotes. Recently it was discovered that eukaryotic TEs are frequently associated with long non-coding RNAs （IncRNAs）, many of which are also upregulated by stress. Yet, it is unknown whether DNA damage-induced transcriptional activation of TEs and IncRNAs occurs sporadically or is a synchronized, genome-wide response. Here we investigated the transcriptome of Arabidopsis wild- type （WT） and ataxia telangiectasia mutated （atm） mutant plants 3 h after induction of DNA damage. In WT, expression of 5.2% of the protein-coding genes is 〉 2-fold changed, whereas in atm plants, only 2.6% of these genes are regulated, and the response of genes associated with DNA repair, replication, and cell cy- cle is largely lost. In contrast, only less than 0.6% of TEs and IncRNAs respond to DNA damage in WT plants, and the regulation of 〉95% of them is ATM-dependent. The ATM-downstream factors BRCA1, DRM1, JMJ30, AGO2, and the ATM-independent AGO4 participate in the regulation of individual TEs and IncRNAs. Remarkably, protein-coding genes located adjacent to DNA damage-responsive TEs and IncRNAs are frequently coexpressed, which is consistent with the hypothesis that TEs and IncRNAs located close to genes commonly function as controlling elements.

关键词： Arabidopsis thaliana ataxia telangiectasia mutated DNA damage response transposable element,long non-coding RNA

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The use of milk Fourier transform midinfrared spectra and milk yield to estimate heat production as a measure of efficiency of dairy cows

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Journal of Animal Science and Biotechnology 2020年第3期11卷 920-928页

作者： Sadjad Danesh Mesgaran Anja Eggert Peter Höckels Michael Derno Björn Kuhla Institute of Nutritional Physiology“Oskar Kellner ”Leibniz Institute for Farm Animal Biology(FBN)Wilhelm-Stahl-Allee 218196 DummerstorfGermany Institute of genetics and Biometry Leibniz Institute for Farm Anih8mal Biology(FBN)Wilhelm-Stahl-Allee 218196 DummerstorfGermany IfM gmbh&Co.KG-Institut für Milchuntersuchung(Milk Testing Services North Rhine-Westphalia) Bischofstraße 8547809 KrefeldGermany

Background:Transformation of feed energy ingested by ruminants into milk is accompanied by energy losses via fecal and urine excretions,fermentation gases and *** production may differ among dairy cows despite comparable milk yield and body ***,heat production can be considered an indicator of metabolic efficiency and directly measured in respiration *** latter is an accurate but time-consuming *** contrast,milk Fourier transform mid-infrared(FTIR)spectroscopy is an inexpensive high-throughput method and used to estimate different physiological traits in ***,this study aimed to develop a heat production prediction model using heat production measurements in respiration chambers,milk FTIR spectra and milk yield measurements from dairy ***:Heat production was computed based on the animal’s consumed oxygen,and produced carbon dioxide and methane in respiration *** production data included 16824-h-observations from 64 German Holstein and 20 dual-purpose Simmental *** were milked twice daily at 07:00 and 16:30 h in the respiration *** yield was determined to predict heat production using a linear *** samples were collected from each milking and FTIR spectra were obtained with MilkoScan FT *** average or milk yield-weighted average of the absorption spectra from the morning and afternoon milking were calculated to obtain a computed spectrum.A total of 288 wavenumbers per spectrum and the corresponding milk yield were used to develop the heat production model using partial least squares(PLS)***:Measured heat production of studied animals ranged between 712 and 1470 kJ/kg *** coefficient of determination for the linear regression between milk yield and heat production was 0.46,whereas it was 0.23 for the FTIR spectra-based PLS *** PLS prediction model using weighted average spectra and milk yield resulted in a cross-validation variance of 57%and a ro

关键词： Dairy cattle Heat production Milk spectra Partial least square regression Respiration chamber

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Plant adaptation to low phosphorus availability:Core signaling,crosstalks,and applied implications

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Molecular Plant 2022年第1期15卷 104-124页

作者： Javier Paz-ares Maria Isabel Puga Monica Rojas-Triana Iris Martinez-Hevia Sergio Diaz Cesar Poza-Carrión Miguel Mi(n)ambres Antonio Leyva Department of Plant Molecular genetics Centro Nacional de Biotecnología(CNB-CSIC)Darwin 3Campus Universidad Autónoma28049 MadridSpain Institute of Plant Biochemistry Institute of Synthetic Biology and CEPLASUniversity of Düsseldorf40225 DüsseldorfGermany

Phosphorus(P)is an essential nutrient for plant growth and *** preferentially absorb P as orthophosphate(Pi),an ion that displays low solubility and that is readily fixed in the soil,making P limita-tion a condition common to many soils and Pi fertilization an inefficient *** cope with Pi limitation,plants have evolved a series of developmental and physiological responses,collectively known as the Pi starvation rescue system(PSR),aimed to improve Pi acquisition and use efficiency(PUE)and protect from Pi-starvation-induced *** research has been carried out during the last 20 years to un-ravel the mechanisms underlying the control of the PSR in *** we review the results of this research effort that have led to the identification and characterization of several core Pi starvation signaling components,including sensors,transcription factors,microRNAs(miRNAs)and miRNA inhibitors,kinases,phosphatases,and components of the proteostasis *** also refer to recent results revealing the existence of intricate signaling interplays between Pi and other nutrients and antagonists,N,Fe,Zn,and As,that have changed the initial single-nutrient-centric view to a more integrated view of nutrient ***,we discuss advances toward improving PUE and future research priorities.

关键词： inositol pyrophosphate plant nutrient PHR1 transcription factor PUE(phosphorus acquisition and use efficiency) SPX sensor and STOP1 transcription factor

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Metabolic reprogramming as an emerging mechanism of resistance to endocrine therapies in prostate cancer

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Cancer Drug Resistance 2021年第1期4卷 143-162页

作者： Paolo Chetta Giorgia Zadra University of Milan Milan 20122Italy Current Address:Boehringer Ingelheim RCV gmbh&Co.KG Dr.-Boehringer-Gasse 5-11Vienna 1121Austria Department of Oncologic Pathology Dana-Farber Cancer Institute and Brigham Women’s HospitalHarvard Medical SchoolBostonMA 02215USA Current Address:Institute of Molecular genetics National Research CouncilPavia 27100Italy

Prostate cancer(PCa)is the second leading cause of cancer-related death in the *** receptor(AR)signaling is the driver of both PCa development and progression and,thus,the major target of current in-use ***,despite the survival benefit of second-generation inhibitors of AR signaling in the metastatic setting,resistance mechanisms inevitably ***,novel strategies are required to circumvent resistance occurrence and thereby to improve PCa *** the key cellular processes that are regulated by androgens,metabolic reprogramming stands out because of its intricate links with cancer cell *** this review,we discuss how cancer metabolism and lipid metabolism in particular are regulated by androgens and contribute to the acquisition of resistance to endocrine *** describe the interplay between genetic alterations,metabolic vulnerabilities and castration *** PCa cells adapt their metabolism to excess nutrient supply to promote cancer progression,we review our current knowledge on the association between diet/obesity and resistance to anti-androgen *** briefly describe the metabolic symbiosis between PCa cells and tumor microenvironment and how this crosstalk might contribute to PCa *** discuss how tackling PCa metabolic vulnerabilities represents a potential approach of synthetic lethality to endocrine ***,we describe how the continuous advances in analytical technologies and metabolic imaging have led to the identification of potential new prognostic and predictive biomarkers,and non-invasive approaches to monitor therapy response.

关键词： Metabolic reprogramming prostate cancer castration resistance endocrine therapies metabolomics metabolic imaging therapy respo nse

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