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Characterization of colonic dendritic cells in normal and colitic mice

World journal of Gastroenterology 2005年第40期11卷 6338-6347页

作者： Sheena M Cruickshank nicholas r English Peter j Felsburg Simon r Carding Institute of Molecular and Cellular Biology Antigen Presentation research Group Department of Clinical Science

AIM： recent studies demonstrating the direct involvement of dendritic cells （DC） in the activation of pathogenic T cells in animal models of inflammatory bowel disease identify DC as important antigen presenting cells in the colon. However, very little is known about the properties of colonic DC. METHODS： Using immunohistochemistry, electron microscopy and flow cytometry we have characterized and compared colonic DC in the colon of healthy animals and interleukin-2-deficient （IL2-/-） mice that develop colitis. rESULTS： In the healthy colon, DC resided within the lamina propria and in close association with the basement membrane of colonic villi. Type i myeloid （CD11c^＋, CD11b^＋, B220, CD8） DC made up the largest （40-45%） population and all DC expressed low levels of CD80, CD86, and CD40, and had high endooltic activity consistent with an immature phenotype. In colitic IL2-/- mice, colonic DC numbers increased four- to five-fold and were localized within the epithelial layer and within aggregates of T and B cells. They were also many more DC in mesenteric lymph nodes （MLN）. The majority （〉85%） of DC in the colon and MLN of IL2./ mice were type 1 myeloid, and expressed high levels of MHC class II, CD80, CD86, CD40, DEC 205, and CCr5 molecules and were of low endocytic activity consistent with mature DC. CONCLUSION： These findings demonstrate striking changes in the number, distribution and phenotype of DC in the inflamed colon. Their intimate association with lymphocytes in the colon and draining lymph nodes suggest that they may contribute directly to the ongoing inflammation in the colon.

关键词： Colonic dendritic cells Interleukin 2 Colitis

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Signaling from T cell receptors (TCrs) and chimeric antigen receptors (CArs) on T cells

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Cellular & Molecular Immunology 2020年第6期17卷 600-612页

作者： Ling Wu Qianru Wei joanna Brzostek nicholas r.j.gascoign. Department of Microbiology and Immunology Yong Loo Lin School of MedicineNational University of Singapore5 Science Drive 2Singapore 117545Singapore Immunology Programme Life Sciences InstituteNational University of SingaporeSingaporeSingapore

T cells react to foreign or self-antigens through T cell receptor(TCr)*** decades of research have delineated the mechanism of TCr signal transduction and its impact on T cell *** knowledge provides the foundation for chimeric antigen receptor T cell(CAr-T cell)technology,by which T cells are redirected in a major histocompatibility complex-unrestricted *** and CAr signaling plays a critical role in determining the T cell state,including exhaustion and *** its artificial nature,CArs might affect or rewire signaling differently than TCrs.A better understanding of CAr signal transduction would greatly facilitate improvements to CAr-T cell technology and advance its usefulness in clinical ***,we systematically review the knowns and unknowns of TCr and CAr signaling,from the contact of receptors and antigens,proximal signaling,immunological synapse formation,and late signaling *** through different T cell subtypes and how signaling is translated into practice are also discussed.

关键词： CAr-T TCr Signaling T cell Immunological synapse

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Themis regulates metabolic signaling and effector functions in CD4^(+) T cells by controlling NFAT nuclear translocation

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Cellular & Molecular Immunology 2021年第9期18卷 2249-2261页

作者： Mukul Prasad joanna Brzostek Namrata Gautam renu Balyan Vasily rybakin nicholas r.j.gascoign. Translational Immunology Programme Yong Loo Lin School of MedicineNational University of Singapore5 Science Drive 2Singapore 117545Singapore Department of Microbiology and Immunology Yong Loo Lin School of MedicineNational University of Singapore5 Science Drive 2Singapore 117545Singapore H.Lee Moffitt Cancer Center and research Institute TampaFLUSA Torque Therapeutics CambridgeMAUSA

Themis is a T cell lineage-specific molecule that is involved in TCr signal *** effects of germline Themis deletion on peripheral CD4^(+)T cell function have not been described *** this study,we found that Themis-deficient CD4^(+)T cells had poor proliferative responses,reduced cytokine production in vitro and weaker inflammatory potential,as measured by their ability to cause colitis in *** T cells are quiescent,whereas activated T cells have high metabolic *** of these metabolic demands depends upon nutrient availability and upregulation of nutrient intake channels after efficient TCr signal transduction,which leads to metabolic reprogramming in T *** tested whether defects in effector functions were caused by impaired metabolic shifts in Themis-deficient CD4^(+)T cells due to inefficient TCr signal transduction,in turn caused by the lack of *** found that upon TCr stimulation,Themis-deficient CD4^(+)T cells were unable to upregulate the expression of insulin receptor(Ir),glucose transporter(GLUT1),the neutral amino acid transporter CD98 and the mTOr pathway,as measured by c-Myc and pS6 *** analysis of activated Themis-deficient CD4^(+)T cells showed more oxidative phosphorylation(OXPHOS)than aerobic glycolysis,indicating defective metabolic ***,we found reduced NFAT translocation in Themis-deficient CD4^(+)T cells upon TCr *** previously reported ChIP-seq and rNA-seq data,we found that NFAT nuclear translocation controls Ir gene ***,our results describe an internal circuit between TCr signal transduction,NFAT nuclear translocation,and metabolic signaling in CD4^(+)T cells.

关键词： Immunometabolism NFAT nuclear translocation Insulin receptor mTOr Mitochondria

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Heart healthy equals prostate healthy and statins, aspirin, and/or metformin （S.A.M.） are the ideal recommendations for prostate cancer prevention

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Asian journal of Andrology 2015年第5期17卷 783-791,I0008页

作者： Mark A Moyad nicholas j Vogelzang Department of Urology University of Michigan Medical Center Ann Arbor Michigan USA Developmental Therapeutics Committee and Genitourinary Committee for US Oncology research Comprehensive Cancer Centers of Nevada Las Vegas Nevada USA

Cardiovascular disease （CVD） has been the number one cause of death in the U.S. for 114 of the last 115 years. Lifestyle factors that promote CVD also appear to increase prostate cancer risk and those that reduce CVD risk also appear to reduce the risk of prostate cancer. The largest randomized trials utilizing dietary supplements or pharmacologic agents for prostate cancer prevention （Selenium and Vitamin E Cancer Prevention Trial [SELECT]） have also shed light on the problems and future solutions in this area. Dietary supplements that have not been found to be CVD protective, such as selenium and Vitamin E have not been found to be prostate protective. In addition, over exposure to specific anti-oxidants in nutritionally replete populations may be encouraging cancer growth. Futuretrials of dietary supplements to prevent prostate cancer could be problematic because by the time a definitive trial is initiated the participants will no longer be ＂deficient＂ in the nutrient being tested, which arguably occurred in the SELECT trial. It is also interesting that statins, aspirin, and/or metformin （S.A.M.） are 3 generic, low-cost, heart healthy agents derived from natural sources with separate mechanism of actions, which all appear to have the best benefit to risk ratio compared to any other agent available for prostate cancer prevention, especially aggressive disease, or as an ancillary agent （s） to conventional cancer treatment. It is time to focus on the forest over the trees and recommend proven CVD protective measures for men concerned about their risk of prostate cancer.

关键词： aspirin diet lifestyle metformin prostate cancer statins

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Teleseismic waves reveal anisotropic poroelastic response of wastewater disposal reservoir

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Earth and Planetary Physics 2021年第6期5卷 547-558页

作者： Andrew j Barbour nicholas M Beeler u.s.geological survey earthquake science centerusa

Connecting earthquake nucleation in basement rock to fluid injection in basal,sedimentary reservoirs,depends heavily on choices related to the poroelastic properties of the fluid-rock system,thermo-chemical effects *** constraints on these parameters outside of laboratory settings are rare,and it is commonly assumed that the rock layers are *** the Arbuckle wastewater disposal reservoir in Osage County,Oklahoma,high-frequency formation pressure changes and collocated broadband ground velocities measured during the passing of large teleseismic waves show a poroelastic response of the reservoir that is both azimuthally variable and anisotropic;this includes evidence of static shifts in pressure that presumably relate to changes in local *** azimuthal dependence in both the static response and shear coupling appears related to tectonic stress and strain indicators such as the orientations of the maximum horizontal stress and faults and *** dynamic strains from a nearby borehole strainmeter,we show that the ratio of shear to volumetric strain coupling is~0.41 which implies a mean Skempton's coefficient of A=0.24 over the plausible range of the undrained Poisson's *** these observations are made at relatively low confining pressure and differential stress,we suggest that the hydraulically conductive fracture network is a primary control on the coupling between pore pressure diffusion and elastic stresses in response to natural or anthropogenic sources.

关键词： poroelasticity dynamic strain anisotropy wastewater disposal Oklahoma induced seismicity

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So you aspire to be a Professor?

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World journal of Gastroenterology 2009年第44期15卷 5626-5627页

作者： nicholas j Talley Department of Internal Medicine Mayo Clinic Jacksonville Professor of Medicine and EpidemiologyDivision of Gastroenterology & HepatologyMayo Clinic College of Medicine Consultant200 First Street S.W.PL-6-56Rochester MN 55905United States

＂The truth is that life is delicious, horrible, charming, frightful, sweet, bitter, and that is everything.＂ Anatole France （Francois-Anatole Thibault, 1844-1924）.

关键词：胃疾病临床治疗疗效

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Single and multiplexed gene repression in solventogenic Clostridium via Cas12a-based CrISPr interference

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Synthetic and Systems Biotechnology 2023年第1期8卷 148-156页

作者： rochelle Carla joseph nicholas r.Sandoval Department of Chemical and Biomolecular Engineering Tulane UniversityNew OrleansLA70118United States

The Gram-positive,spore-forming,obligate anaerobic firmicute species that make up the Clostridium genus have broad feedstock consumption capabilities and produce value-added metabolic products,but genetic manipulation is difficult,limiting their broad ***-Cas systems have recently been applied to Clostridium species,primarily using Cas9 as a counterselection marker in conjunction with plasmid-based homologous *** interference is a method that reduces gene expression of specific genes via precision targeting of a nuclease deficient Cas effector ***,we develop a dCas12a-based CrISPr interference system for transcriptional gene repression in multiple mesophilic Clostridium *** show the Francisella novicida Cas12a-based system has a broader applicability due to the low GC content in Clostridium species compared to CrISPr Cas systems derived from other *** demonstrate>99%reduction in transcript levels of targeted genes in Clostridium acetobutylicum and>75%reduction in Clostridium *** also demonstrate multiplexed repression via use of a single synthetic CrISPr array,achieving 99%reduction in targeted gene expression and elucidating a unique metabolic profile for their reduced ***,this work builds a foundation for high throughput genetic screens without genetic editing,a key limitation in current screening methods used in the Clostridium community.

关键词： CrISPr Cas12a Clostridium CrISPri

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Electrospun fibers:a guiding scaffold for research and regeneration of the spinal cord

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Neural regeneration research 2016年第11期11卷 1764-1765页

作者： nicholas j.Schaub National Institute of Standards & Technology Biosystems and Biomaterials Division

The challenge to regenerating the nervous system compared to other tissues in the body is the complexity of the tissue. For example, a small amount of scar tissue formation after an injury to the skin may have few negative side effects, but any scar tissue in the central nervous system is a major physical and chemical barrier to nerve regeneration （Sofroniew, 2009）.

关键词： Electrospun fibers

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Predicting flows through microfluidic circuits with fluid walls

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Microsystems & Nanoengineering 2021年第6期7卷 119-127页

作者： Cyril Deroy nicholas Stovall-Kurtz Federico Nebuloni Cristian Soitu Peter r.Cook Edmond j.Walsh Department of Engineering Science Osney Thermo-Fluids LaboratoryUniversity of OxfordOxford OX20ESUK Sir William Dunn School of Pathology University of OxfordOxford OX13REUK Cold Spring Harbor Laboratory Cold Spring HarborNYUSA

The aqueous phase in traditional microfluidics is usually confined by solid walls;flows through such systems are often predicted *** solid walls limit access,open systems are being developed in which the aqueous phase is partly bounded by fluid walls(interfaces with air or immiscible liquids).Such fluid walls morph during flow due to pressure gradients,so predicting flow fields remains *** recently developed a version of open microfluidics suitable for live-cell biology in which the aqueous phase is confined by an interface with an immiscible and bioinert fluorocarbon(FC40).Here,we find that common medium additives(fetal bovine serum,serum replacement)induce elastic no-slip boundaries at this interface and develop a semi-analytical model to predict flow *** experimentally validate the model’s accuracy for single conduits and fractal vascular trees and demonstrate how flow fields and shear stresses can be controlled to suit individual applications in cell biology.

关键词： walls flows flow

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The challenge to improve the response of biomaterials to the physiological environment

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regenerative Biomaterials 2016年第2期3卷 67-71页

作者： nicholas A.Peppas john r.Clegg McKetta Department of Chemical Engineering College of PharmacyUniversity of Texas at Austin Department of Biomedical Engineering College of PharmacyUniversity of Texas at Austin Institute for Biomaterials Drug Delivery and Regenerative MedicineCollege of PharmacyUniversity of Texas at Austin Department of Surgery and Perioperative Care Dell Medical SchoolCollege of PharmacyUniversity of Texas at Austin Division of Pharmaceutics College of PharmacyUniversity of Texas at Austin.

New applications of biomaterials often require advanced structures containing synthetic and natural components that are tuned to provide properties unique to a specific *** discuss how structural characteristics of biomaterials,especially hydrophilic ones,can be used in conjunction with non-ideal thermodynamics to develop advanced medical *** show a number of examples of biocompatible,intelligent biomaterials that can be used for organ replacement,biosensors,precise drug delivery over days or weeks,and regenerative medicine.

关键词： drug delivery nanobiomaterials regenerative mechanism materials structure

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