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Activating interactions of sulfanilamides with T cell receptors

Open j.urnal of Immunology 2013年第3期3卷 139-157页

作者： Stephan Watkins werner j. Pichler Department of Graduate Cell Biology and Biomedical Sciences University of Bern Bern Switzerland Department of Rheumatology Clinical Immunology and Allergology Inselspital/University Hospital of Bern Bern Switzerland

Activation and expansion of drug reactive T cells are key features in drug hypersensitivity reactions. Drugs may interact directly with immune receptors such as the human leukocyte antigens (HLA) or the T-cell receptors (TCR) itself, the pharmacological interaction [p-i] concept. To analyze whether the drug sulfamethoxazole (SMX) interacts directly with the TCR and thereby contributing to signaling and T cell activation, we analyze two SMX specific T cell clones (TCC “1.3”and “H13”). Proliferation to SMX and 11 related sulfanilamides, Ca++ influx in drug stimulated T-cells and the inhibitory effect of non-reactive sulfanilamides on SMX stimulation were analyzed. In silico docking of SMX and related sulfanilamide to the TCR were used to identify possible drug binding sites, and correlated to in vitro data to find the correct docking. In Ca++ influx assays, reactions occurred as early as 14 sec after adding SMX to TCC and APC. The broadly reactive clone (“H13”) was stimulated by 5 additional sulfanilamide, while one TCC (“1.3”) was reactive exclusively with SMX but not other sulfanilamides. Competition experiments with sulfanilamide inhibited SMX induced Ca++ influx and proliferation of the TCC1.3 ina dose dependent way. Docking experiments with SMX and related sulfanilamides confirmed and explained the in vitro data as docking localized binding sites for SMX and the 5 stimulating sulfanilamides on the CDR2β domain of the clone H13, while the 6 non-stimulatory SA failed to bind. In TCC 1.3, SMX could be docked on the CDR3α of the TCR. The other, non-stimulatory but inhibitory SA could also be docked to the same site. The combined analysis of in vitro and in silico data show that sulfanilamide can bind directly to TCRs. It shows that TCR, like other receptors, appear to be reamenable to manipulations by small molecules.

关键词： p-i Concept Drug Hypersensitivity Sulfamethoxazole TCR Signaling TCR Specificity TCR-Modelling T Cell Clones

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Will the traditional horticultural breeding and genetics research be fairly valued in academia?

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Horticulture Research 2015年第1期2卷 71-72页

作者： Zong-Ming(Max)Cheng Dennis j.werner Horticulture Research The Laboratory of Fruit Crop Systems Biology College of HorticultureNanjing Agricultural UniversityNanjing210095Jiangsu ProvinceThe People's Republic of China Department of Plant Sciences University of TennesseeKnoxville37996TNUSA Department of Horticultural Science North Carolina State UniversityBox 7609Raleigh27695-7609NCUSA

I wrote the inaugural Editorial when Horticulture Research was launched in j.nuary *** second Editorial was trigged by the manuscript that was submitted to Horticulture Research(HORTRES.2015.49,***/articles/hortres201... 详细信息

关键词： breeding culture submitted

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Primary care clinicians’ strategies to overcome financial barriers to specialty health care for uninsured patients

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Family Medicine and Community Health 2015年第3期3卷 18-24页

作者： j.mes j.werner Kitty K.Corbett Department of Family Medicine and Community Health Mandel School of Applied Social SciencesCase Western Reserve University11000 Cedar AvenueSuite 402ClevelandOH 44106USA School of Public Health and Health Systems University of Waterloo200 University Avenue WestWaterlooOntarioN2L 3G1Canada

Obj.ctive:This study describes strategies used by federally qualified health centers(FQHCs)to assist medically uninsured patients in obtaining specialty health care ***:Qualitative methods were used to study strategies for obtaining specialty health care for uninsured *** were gathered from 10 primary care clinicians at three FQHC clinics by means of 10 semistructured interviews,23 brief interviews,and 45 h of direct *** captured additional data by studying cases of referred uninsured ***:The following six strategies were identified:(1)quid pro quo-a specialist accept-ing the clinic’s medically uninsured patients was rewarded with referrals of the clinic’s insured patients;(2)over referral-clinicians referred insured patients whose needs could have been met at the FQHC;(3)brief hospitalization-when a specialist could not be obtained,high-risk patients were briefly hospitalized;(4)case building-diagnostic tests were conducted at the FQHC to j.stify a referral;(5)direct communication-communication between clinicians and specialists was neces-sary when requesting a referral;(6)specialty clinics-in return for conducting a specialty clinic at the FQHC,the specialist received all referrals of insured ***:Uninsured FQHC patients encountered difficulties accessing specialty health care,and in response,clinicians developed a range of innovative strategies.

关键词： Health services accessibility barriers to health care medically uninsured health care inequities access to specialty care qualitative methods

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Reply:Is the evolution of tumors Darwinian or non-Darwinian?

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National Science Review 2018年第1期5卷 17-19页

作者： Marc j.Williams Benj.min werner Chris P Barnes Trevor A Graham Andrea Sottoriva Evolution and Cancer Laboratory Barts CancerInstitute Queen Marry University of London Department of Cell and Developmental Biology University College London Centre for Mathematics and Physics in the Life Sciences and Experimental Biology (CoMPLEX) University College London Centre for Evolution and Cancer The Institute of Cancer Research Department of Genetics Evolution and EnvironmentUniversity College London

Wu and colleagues’letter discusses the limitations of the use of a single sample per tumor to investigate neutral evolution in human *** evolution describes the situation in which there is no differential clonal selection amongst the population of cells within a cancer:all mutations thataccrue during growth are passengers and all drivers were already present in the

关键词： Reply:Is the evolution of tumors Darwinian or non-Darwinian VAF

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The proton radius:from a puzzle to precision

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Science Bulletin 2020年第4期65卷 257-258页

作者： Hans-werner Hammer Ulf-GMeiBner Institut für Kernphysik Technische Universitat Darmstadt64289 DarmstadtGermany ExtreMe Matter Institute EMMI GSI Helmholtzzentrum für Schwerionenforschung GmbH64291 DarmstadtGermany Helmholtz Institut für Strahlen-und Kernphysik and Bethe Center for Theoretical Physics Universitat BonnD-53115 BonnGermany Institute for Advanced Simulation and Institut für Kernphysik Forschungszentrum JülichD-52425 JülichGermany Tbilisi State University 0186 TbilisiGeorgia

The proton charge radius rP is a fundamental quantity in particle physics,as it challenges our understanding of the so successful Standard Model in the non-perturbative regime of the strong *** is defined by the slope of the proton charge form factor GE p etT at zero momentum transfer,with t the invariant four-momentum transfer *** proton charge radius was first indirectly measured in the Nobel prize winning electron scattering experiments by Hofstadter et al.[1,2],who fitted the form factor data with a dipole form and extracted the radius from the slope of the dipole.

关键词： DISPERSION-THEORETICAL ANALYSIS FORM-FACTORS NUCLEON SCATTERING HYDROGEN SIZE

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Turning to myelin turnover

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Neural Regeneration Research 2019年第12期14卷 2063-2066页

作者： Tobias j.Buscham Maria A.Eichel Sophie B.Siems Hauke B.werner Department of Neurogenetics Max Planck Institute of Experimental Medicine

Neural plasticity in the adult central nervous system involves the adaptation of myelination, including the formation of novel myelin sheaths by adult-born oligodendrocytes. Yet, mature oligodendrocytes slowly but constantly turn over their pre-existing myelin sheaths, thereby establishing an equilibrium of replenishment and degradation that may also be subj.ct to adaptation with consequences for nerve conduction velocity. In this short review we highlight selected approaches to the normal turnover of adult myelin in vivo, from inj.cting radioactive precursors of myelin constituents in the 1960s to current strategies involving isotope labeling and tamoxifen-induced gene targeting.

关键词： oligodendrocyte myelin plasticity and turnover degradation tamoxifen metabolic labeling isotope labeling neural plasticity myelinoid bodies central nervous system

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Transforming growth factor-β1 induces intestinal myofibroblast differentiation and modulates their migration

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World j.urnal of Gastroenterology 2009年第12期15卷 1431-1442页

作者： j.lia Brenmoehl Sandra Nicole Miller Claudia Hofmann Daniela Vogl werner Falk j.rgen Schlmerich Gerhard Rogler Department of Internal Medicine Ⅰ University of Regensburg93055 Regensburg Germany Department of Internal Medicine Ⅱ University of Jena07747 Jena Germany Clinic of Gastroenterology and Hepatology Department of Internal MedicineUniversity Hospital of Zurich8091 ZurichSwitzerland

AIM： To investigate the effects of transforming growth factor β1 （TGF-β1） on the differentiation of colonic lamina propria fibroblasts （CLPF） into myofibroblasts in vitro.METHODS： Primary CLPF cultures were incubated with TGF-β1 and analyzed for production of m-smooth muscle actin （α-SMA）, fibronectin （FN） and FN isoforms. Migration assays were performed in a modified 48-well Boyden chamber. Levels of total and phosphorylated focal adhesion kinase （FAK） in CLPF were analyzed after induction of *** not change α-SMA levels, while TGF-β1 treatment for 6 d significantly increased α-SIVlA production. Short term incubation （6 h） with TGF-β1 enhanced CLPF migration, while long term treatment （6 d） of CLPF with TGF-β1 reduced migration to 15%-37% compared to untreated cells. FN and FN isoform mRNA expression were increased after short term incubation with TGF-β1 （2 d） in contrast to long term incubation with TGF-β1 for 6 d. After induction of migration, TGF-β1-preincubated CLPF showed higher amounts of FN and its isoforms and lower levels of total and phosphorylated FAK than untreated cells.CONCLUSION： Long term incubation of CLPF with TGF-β1 induced differentiation into myofibroblasts with enhanced α-SMA, reduced migratory potential and FAK phosphorylation, and increased FN production. In contrast, short term contact （6 h） of fibroblasts with TGF-β1 induced a dose-dependent increase of cell migration and FAK phosphorylation without induction of α-SMA production.

关键词： Transforming growth factor β1 Colonicfibroblasts Myofibroblasts Migration Fibronectin

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Metabolic regulation of immune responses to cancer

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Cancer Biology & Medicine 2022年第11期19卷 1528-1542页

作者： j.nnis WiBfeld Anke werner Xin Yan Nora ten Bosch Guoliang Cui Helmholtz Institute for Translational Oncology(HI-TRON) Mainz 55131Germany T Cell Metabolism Group(D192) German Cancer Research Center(DKFZ)Heidelberg 69120Germany Faculty of Biosciences Heidelberg UniversityHeidelberg 69120Germany

The tumor microenvironment is an ecosystem composed of multiple types of cells, such as tumor cells, immune cells, and cancerassociated fibroblasts. Cancer cells grow faster than non-cancerous cells and consume larger amounts of nutrients. The rapid growth characteristic of cancer cells fundamentally alters nutrient availability in the tumor microenvironment and results in reprogramming of immune cell metabolic pathways. Accumulating evidence suggests that cellular metabolism of nutrients, such as lipids and amino acids, beyond being essential to meet the bioenergetic and biosynthetic demands of immune cells, also regulates a broad spectrum of cellular signal transduction, and influences immune cell survival, differentiation, and anti-tumor effector function. The cancer immunometabolism research field is rapidly evolving, and exciting new discoveries are reported in high-profile j.urnals nearly weekly. Therefore, all new findings in this field cannot be summarized within this short review. Instead, this review is intended to provide a brief introduction to this rapidly developing research field, with a focus on the metabolism of two classes of important nutrients-lipids and amino acids-in immune cells. We highlight recent research on the roles of lipids and amino acids in regulating the metabolic fitness and immunological functions of T cells, macrophages, and natural killer cells in the tumor microenvironment. Furthermore, we discuss the possibility of “editing” metabolic pathways in immune cells to act synergistically with currently available immunotherapies in enhancing anti-tumor immune responses.

关键词： Lipids amino acids cancer anti-tumor immunity T cells NK cells metabolism immunometabolism

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Multi-walled Carbon Nanotubes with π-Conj.gated Metal-free Phthalocyanine Moieties:Preparation and Optical Limiting Properties

Multi-walled Carbon Nanotubes with π-Conjugated Metal-free ...

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全国第八届有机固体电子过程暨华人有机光电功能材料学术讨论会

作者： werner j.Blau School of Physics Trinity CollegeUniversity of Dublin

Aside from numerous civilian applications of lasers,they have evolved to numerous modern battlefield weapons. Some are designed to dazzle or permanently disable humans by blinding,while others are used to destroy optical sensors,missiles,and other *** the past decade,significant research effort has been invested into optical limiting materials and processes in an attempt to achieve some measure of protection from such laser beams.

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Prodromal Parkinson’s disease: hype or hope for disease-modification trials?

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Translational Neurodegeneration 2022年第1期11卷 777-789页

作者： Philipp Mahlknecht Kathrin Marini Mario Werkmann werner Poewe Klaus Seppi Department of Neurology Innsbruck Medical University6020 InnsbruckAustria

The ultimate goal in Parkinson’s disease (PD) research remains the identification of treatments that are capable of slowing or even halting the progression of the disease. The failure of numerous past disease-modification trials in PD has been attributed to a variety of factors related not only to choosing wrong interventions, but also to using inadequate trial designs and target populations. In patients with clinically established PD, neuronal pathology may already have advanced too far to be modified by any intervention. Based on such reasoning, individuals in yet prediagnostic or prodromal disease stages, may provide a window of opportunity to test disease-modifying strategies. There is now sufficient evidence from prospective studies to define diagnostic criteria for prodromal PD and several approaches have been studied in observational cohorts. These include the use of PD-risk algorithms derived from multiple established risk factors for disease as well as follow-up of cohorts with single defined prodromal markers like hyposmia, rapid eye movement sleep behavior disorders, or PD gene carriers. In this review, we discuss recruitment strategies for disease-modification trials in various prodromal PD cohorts, as well as potential trial designs, required trial durations, and estimated sample sizes. We offer a concluding outlook on how the goal of implementing disease-modification trials in prodromal cohorts might be achieved in the future.

关键词： Neuroprotection Preclinical Prevention Epidemiology Probability Randomized controlled trial Preventive Neuroprotective

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