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TCR-pMHC:Envisioning the specialized dynamics of the target 5-component complex

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Cellular & Molecular Immunology 2022年第6期19卷 657-659页

作者： joseph s.murray Xenolaüs Genetics LLC Los AngelesCA90024USA

The mechanosensor theory of TCR function holds theα/βcomponent of the T-cell antigen receptor complex ultimately responsible for adaptive immunity[1,2,3].T-cell motility is envisioned to provide a force necessary to slow TCR dynamics as it sits on the pMHC ligand of an antigen presenting cell[1],which theoretically allows the TCR to discriminate different pMHC structures,principally by the so-called catch bonds(mostly H-bonds)at the interfaces of the 5-component complex(i.e.,TCRα/TCRβ/peptide/MHC-IIα(or,MHC-heavy-chain)/MHC-IIβ(or MHC-light-chain)[1,2,3,4].

关键词： component TCR complex

Differential effects of oilseed protein hydrolysates in attenuating inflammation in murine macrophages

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Food Bioscience 2022年第5期49卷 196-205页

作者： Ruixian Han Alan JHern´andez´Alvarez Joanne Maycock Brent s.murray Christine Boesch Nutritional sciences and Epidemiology School of Food Science and NutritionUniversity of LeedsLS29JTLeedsUK Food Colloids and Bioprocessing School of Food Science and NutritionUniversity of LeedsLS29JTLeedsUK

Proteins from underutilized defatted oilseed meals have been proposed as promising sources of bioactive peptides. This study was conducted to determine the anti-inflammatory activities of five oilseed proteins (flaxseed, rapeseed, sunflower, sesame and soybean) hydrolysed via alcalase, pepsin (at pH 1.3 and pH 2.1), respectively, and to compare these against two dairy proteins (whey, casein). The potential of protein hydrolysates of three different molecular weight fractions (Mw > 10 kDa, 3-10 kDa, signalling was screened via RAW-Blue™ reporter cells. Fractions with Mw sin (pH 1.3)-treated protein hydrolysates were subsequently selected to validate anti-inflammatory properties in RAW 264.7 macrophages. Rapeseed fractions showed greatest potency to attenuate inflammation, via efficiently down-regulating the expression of IL-6 (-49.1%), IL-1β (-58.6%), iNOs (-41.9%) and COX-2 (-58.7%) and up-regulating the IL- 10 (+47.2%) mRNA level at 2000 μg peptides/mL. Rapeseed, sesame and casein demonstrated marked repression of NF-κB pathway, through down-regulating NF-κB1, p65 and/or IκBα mRNA levels. In addition, rapeseed, sesame and soybean reduced the expression of TLR4 and/or CD14 associated with attenuated LPs recognition. In addition, it was confirmed that rapeseed and soybean hydrolysates showed capabilities to bind 43.9 and 52.4% of LPs in solution, thereby weakening inflammatory response;an effect that could at least partially be related to the presence of hydrophobic amino acids. To summarize, current data demonstrate differing capacity of plant protein hydrolysates to interact with inflammatory signalling, indicating the need for further research into the molecular mechanisms of peptide action.

关键词： Oilseeds Ultrafiltration Protein hydrolysate Bioactive peptide Inflammation Anti-inflammatory properties LPs binding

Development of drugs for celiac disease:review of endpoints for Phase 2 and 3 trials

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Gastroenterology Report 2015年第2期3卷 91-102页

作者： Klaus Gottlieb Jill Dawson Fez Hussain joseph A.murray Immunology Internal Medicine-Medical Strategy&ScienceQuintilesDurhamNCUSA Corporate Communications QuintilesDurhamNCUSA Division of Gastroenterology and Hepatology Mayo ClinicRochesterMNUSA

Celiac disease is a lifelong disorder for which there is currently only one known,effective treatment:a gluten-free *** treatment approaches have recently emerged;several drugs are in Phase 2 trials and results appear promising;however,discussion around regulatory endpoints is in its *** will briefly discuss the drugs that are under development and then shift our attention to potential trial endpoints,such as patient-reported outcomes,histology,serology,gene expression analysis and other *** will outline the differing requirements for proof-of-concept Phase 2 trials and Phase 3 registration trials,with a particular emphasis on current thinking in regulatory *** conclude our paper with recommendations and a glossary of regulatory terms,to enable readers who are less familiar with regulatory language to take maximum advantage of this review.

关键词： celiac disease clinical trials endpoints

Complex role for the immune system in initiation and progression of pancreatic cancer

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World Journal of Gastroenterology 2014年第32期20卷 11160-11181页

作者： Kristin s Inman Amanda A Francis Nicole R murray Department of Cancer Biology Mayo Clinic Jacksonville FL 32224United States

The immune system plays a complex role in the development and progression of pancreatic cancer. Inflammation can promote the formation of premalignant lesions and accelerate pancreatic cancer development. Conversely, pancreatic cancer is characterized by an immunosuppressive environment, which is thought to promote tumor progression and invasion. Here we review the current literature describing the role of the immune response in the progressive development of pancreatic cancer, with a focus on the mechanisms that drive recruitment and activation of immune cells at the tumor site, and our current understanding of the function of the immune cell types at the tumor. Recent clinical and preclinical data are reviewed, detailing the involvement of the immune response in pancreatitis and pancreatic cancer, including the role of specific cytokines and implications for disease outcome. Acute pancreatitis is characterized by a predominantly innate immune response, while chronic pancreatitis elicits an immune response that involves both innate and adaptive immune cells, and often results in profound sys-temic immune-suppression. Pancreatic adenocarcinoma is characterized by marked immune dysfunction driven by immunosuppressive cell types, tumor-promoting immune cells, and defective or absent inflammatory cells. Recent studies reveal that immune cells interact with cancer stem cells and tumor stromal cells, and these interactions have an impact on development and progression of pancreatic ductal adenocarcinoma(PDAC). Finally, current PDAC therapies are reviewed and the potential for harnessing the actions of the immune response to assist in targeting pancreatic cancer using immunotherapy is discussed.

关键词： Immune system Pancreatitis Pancreatic ductal adenocarcinoma Immunosuppression Immunotherapy Inflammation

Competitive effects of humic acid and wastewater on adsorption of Methylene Blue dye by activated carbon and non-imprinted polymers

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Journal of Environmental sciences 2018年第4期30卷 310-317页

作者： Audrey murray Banu Ormeci Department of Civil and Environmental Engineering Carleton UniversityOttawa ON K1S 5B6 Canada

Natural organic matter（NOM）, present in natural waters and wastewater, decreases adsorption of micropollutants, increasing treatment costs. This research investigated mechanisms of competition for non-imprinted polymers（NIPs） and activated carbon with humic acid and wastewater. Three different types of activated carbons（Norit PAC 200,Darco KB-M, and Darco s-51） were used for comparison with the NIP. The lower surface area and micropore to mesopore ratio of the NIP led to decreased adsorption capacity in comparison to the activated carbons. In addition, experiments were conducted for single-solute adsorption of Methylene Blue（MB） dye, simultaneous adsorption with humic acid and wastewater, and pre-loading with humic acid and wastewater followed by adsorption of MB dye using NIP and Norit PAC 200. Both the NIP and PAC 200 showed significant decreases of 27% for NIP（p = 0.087） and 29% for PAC 200（p = 0.096） during simultaneous exposure to humic acid and MB dye. There was no corresponding decrease for NIP or PAC 200 pre-loaded with humic acid and then exposed to MB. In fact, for PAC 200, the adsorption capacity of the activated carbon increased when it was pre-loaded with humic acid by 39%（p = 0.0005）. For wastewater, the NIP showed no significant increase or decrease in adsorption capacity during either simultaneous exposure or pre-loading. The adsorption capacity of PAC 200 increased by 40%（p = 0.001） for simultaneous exposure to wastewater and MB. Pre-loading with wastewater had no effect on MB adsorption by PAC 200.

关键词： Molecularly imprinted polymer Non-imprinted polymer Water treatment Wastewater treatment Activated carbon Micropollutants Pore-blocking Adsorption

High strength and ductility of titanium matrix composites by nanoscale design in selective laser melting

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Journal of Materials science & Technology 2022年第23期118卷 114-127页

作者： joseph A.Otte Jin Zou Matthew s.Dargusch school of Mechanical and Mining Engineering The University of QueenslandBrisbaneQLD 4072Australia Center for Microscopy and Microanalysis The University of QueenslandBrisbaneQLD 4072Australia

The use of selective laser melting(sLM)to produce titanium matrix composites(TMCs)with high strength while retaining sufficient tensile ductility suitable for structural applications is emerging as an attractive opportunity in the field of advanced ***,the presence of coarse ceramic reinforcements as well as difficulties in optimizing the sLM process is a barrier to the application of *** this study,we demonstrated the production of TMCs reinforced with in situ high aspect ratio Ti B nanowhiskers by selective laser melting using nanosized BN powder *** Ti with 2.5 vol.%nanosized BN powder showed promise for producing high performance TMCs with retained *** acted to produce Ti B nanowhiskers with diameterst process furnace annealing Ti B retained a low diameter but exhibited a high aspect ratio,up to *** addition to Ti B refinement,nanosized BN addition promoted grain refinement during sLM,both acting as a solute to induce nucleation events and,as Ti B is formed,providing nucleation sites leading to an ultrafine grain structure in as printed samples and after *** produced TMCs exhibit high tensile yield strength,up to1392 MPa,while retaining tensile ductility up to 10%.This study has shown how nanoscale design in powder bed fusion additive manufacturing techniques can be used to produce high performance TMCs through a combination of refined grain structure and high aspect ratio Ti B leading to TMCs with significant improvement in strength,isotropic properties and retained tensile ductility.

关键词： Additive manufacturing selective laser melting Metal matrix composite Mechanical properties Nanostructure Nanowires

Comparative analyses of current three-dimensional numerical solar wind models

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science China Earth sciences 2015年第6期58卷 839-858页

作者： shi Tsan WU murray DRYER Center for space Plasma and Aeronomic Research the University of Alabama in Huntsville space Weather Predictions Center National Weather Service National Oceanic and Atmospheric Administration

We present a comparative study of the most advanced three-dimensional time-dependent numerical simulation models of solar wind. These models can be classified into two categories：（I） theoretical, empirical and numerically based models and （Ⅱ） self-consistent multi-dimensional numerical magnetohydrodynamic （MHD） models. The models of Category I are used to sep- arately describe the solar wind solution in two plasma flows regions： transonic/trans-Alfvrnic and supersonic/super-Alfvenic, respectively. Models of Category II construct a complete, single, numerical solar wind solution through subsonic/sub-Alfvrnic region into supersonic/super-Alfvrnic region. The Wang-sheeley-Arge （WsA）/ENLIL in CIsM is the most successful space weather model that belongs to Category I, and the Block-Adaptive-Tree-solarwind-Roe-Upwind-scheme （BATs-R-Us） code in sWMF （space Weather Modeling Framework） and the solar-interplanetary conservative element solution element MHD （sIP-CEsE MHD） model in sWIM （space Weather Integrated Model） are the most commonly-used models that belong to Category II. We review the structures of their frameworks, the main results for solar wind background studies that are essential for solar transient event studies, and discuss the common features and differences between these two categories of solar wind models. Finally, we conclude that the transition of these two categories of models to operational use depends on the availability of computational resources at reasonable cost and point out that the models＇ prediction capabilities may be improved by employing finer computational grids, incorporating more observational data and by adding more physical constraints to the models.

关键词： space weather solar wind models comparative analyses

Correlation analysis of celiac sprue tissue transglutaminase and deamidated gliadin IgG/IgA

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World Journal of Gastroenterology 2009年第7期15卷 845-848页

作者： Eric V Marietta shadi Rashtak joseph A murray Department of Immunology Mayo Clinic College of Medicine Department of Gastroenterology and Hepatology Mayo Clinic College of Medicine

AIM:To indirectly determine if tissue transglutaminase(tTG)-specific T cells play a crucial role in the propagation of celiac ***:Anti-deamidated gliadin peptide(DGP) and anti-tTG IgA and IgG were measured in the sera of celiac patients(both untreated and treated).The correlations were determined by spearman's rank correlation ***:In celiac patients,we found a very significant correlation between the production of DGP IgA and IgG(r = 0.75),indicating a simultaneous and ongoing production of these two isotypes reminiscent of oral vaccination ***,there was far less association between the production of tTG IgA and tTG IgG in celiac patients(r = 0.52).While tTG IgA was significantly correlated with DGP IgA(r = 0.80) and DGP IgG(r = 0.67),there was a weak correlation between production of anti-tTG IgG and the production of anti-DGP IgA(r = 0.38) and anti-DGP IgG(r = 0.43).CONCLUsION:These data demonstrate that the production of anti-tTG IgA is directly correlated to the production of anti-DGP IgG and IgA,whereas anti-tTG IgG is only weakly *** result therefore supports the hapten-carrier theory that in well-established celiac patients anti-tTG IgA is produced by a set of B cells that are reacting against the complex of tTG-DGP in the absence of a tTG-specific T cell.

关键词： Celiac disease Tissue transglutaminase Deamidated gliadin peptide Correlation IgG IgA

A statistical procedure to assess the significance level of barriers to gene flow

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Journal of Genetics and Genomics 2009年第11期36卷 685-693页

作者： sébastien Rioux Paquette Franois-joseph Lapointe Allan Wilson Centre for Molecular Ecology & school of Biological sciences Victoria University of Wellington Département de sciences Biologiques Université de Montréal

Although several methods are available to study the extent of isolation by distance （IBD） among natural populations, comparatively few exist to detect the presence of sharp genetic breaks in genetic distance datasets. In recent years, Monmonier＇s maximum-difference algorithm has been increasingly used by population geneticists. However, this method does not provide means to measure the statistical significance of such barriers, nor to determine their relative contribution to population differentiation with respect to IBD. Here, we propose an approach to assess the significance of genetic boundaries. The method is based on the calculation of a multiple regression from distance matrices, where binary matrices represent putative genetic barriers to test, in addition to geographic and genetic distances. simulation results suggest that this method reliably detects the presence of genetic barriers, even in situations where IBD is also significant. We also illustrate the methodology by analyzing previously published datasets. Conclusions about the importance of genetic barriers can be misleading if one does not take into consideration their relative contribution to the overall genetic structure of species.

关键词： genetic barriers genetic distances isolation by distance multiple regression on distance matrices partial regression coefficients