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CD8+T cell metabolic flexibility elicited by CD28-ARS2 axisdriven alternative splicing of PKM supports antitumor immunity

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Cellular & Molecular Immunology 2024年第3期21卷 260-274页

作者： G.Aaron Holling colin A.Chavel Anand P.Sharda Mackenzie M.Lieberman Caitlin M.James Shivana M.Lightman Jason H.Tong Guanxi Qiao Tiffany R.Emmons Thejaswini Giridharan Shengqi Hou Andrew M.Intlekofer Richard M.Higashi Teresa W.M.Fan Andrew N.Lane Kevin H.Eng Brahm H.Segal Elizabeth A.Repasky Kelvin P.Lee Scott H.Olejniczak Department of Immunology Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Department of Medicine Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer CenterNew YorkNY 10065USA Center for Environmental Systems Biochemistry Department of Toxicology and Cancer Biology and Markey Cancer CenterLexingtonKY 40536USA Department of Cancer Genetics and Genomics Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Present address:University of Colorado Boulder BoulderCO 80309USA Present address:Dana Farber Cancer Institute BostonMA 02215USA Present address:Massachusetts Institute of Technology BostonMA 02139USA Present address:Melvin and Bren Simon Comprehensive Cancer Center Indiana University School of MedicineIndianapolisIN 46202USA

Metabolic flexibility has emerged as a critical determinant of CD8+T-cell antitumor activity,yet the mechanisms driving the metabolic flexibility of T cells have not been *** this study,we investigated the influence of the nuclear cap-binding complex(CBC)adaptor protein ARS2 on mature T *** doing so,we discovered a novel signaling axis that endows activated CD8+T cells with flexibility of glucose ***2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing *** these effects,the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2,a key determinant of CD8+T-cell glucose utilization,interferon gamma production,and antitumor effector ***,PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation,revealing a novel means by which costimulation reprograms glucose metabolism in CD8+T cells.

关键词： Immunometabolism mRNA splicing CD8 T cells ARS2 PKM2

Coupler force and fatigue assessments with stochasticdraft gear frictions

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Journal of Traffic and Transportation Engineering(English Edition) 2023年第1期10卷 1-12页

作者： Qing Wu colin Cole Maksym Spiryagin Centre for Railway Engineering Central Queensland UniversityRockhamptonQLD 4701Australia

Train dynamics and component fatigue assessments are important steps towards successful operations of long heavy haul *** train dynamics(LTD)simulation is an effective and efficient approach in this *** gear friction has been known to have a strong stochastic ***,relevant train dynamics simulations have not been reported in open *** paper uses experimental data to extract the stochastic feature of draft gear *** stochastic feature is then introduced into LTD *** force and fatigue damage assessments were conducted by simulating a heavy haul train that has 244 vehicles and weighs nearly 30,000 *** results show that average in-train force variations due to stochastic friction were 55 and 40 kN for the traction and air brake cases respectively;maximum force variations were 207 and 98 kN for the traction and air brake cases *** fatigue calculations are even more sensitive to stochastic draft gear friction;the largest variations can be up to 700 times different due to the strong nonlinearity of fatigue calculation *** friction is an unavoidable nature in friction draft *** using stochastic draft gear friction can deliver results that are more robust and reliable.

关键词： Stochastic friction Draft gear Train dynamics Coupler fatigue Laboratory testing

Localization and possible role of membrane type metallo-proteinase and tissue inhibitors of metalloproteinase-1 in early stages of placentation

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Chinese Science Bulletin 2000年第16期45卷 1484-1489页

作者： Ockleford colin D. Department of Pre-Clinical Sciences University of LeicesterLeicester LEI 7RHUK

Human placental tissues from the first and second trimesters of gestation have been investigated using riboprobe in situ hybridisation of mRNA sequences coding for membrane type metalloproteinase (MT-1-MMP) and tissue inhibitors of metalloproteinase-1 (TIMP-1). Results show that (i) both mRNAs express at a relatively high level in the chorion laeve trophoblast cells and the adjacent decidual cells of fetal membrane; (ii) the most abundant expression of the two mRNAs was found in the extravillous trophoblast between Rohrs and Nitabuch striae of basal plate, trophoblast shell and gland cells of the decidua; (iii) isolated or small groups of cytotrophoblast cells in the chorionic villi and in the cells lining arterioles in decidua and stem villi also expressed both MT-1-MMP and TIMP-1 at defferent extents. The data suggest that the coordinated expression of the MT-MMP and its inhibitor TIMP in defferent cells of the placental tissue may play an essential role in trophoblast invasion and angiogenesis

关键词： placenta trophoblast basal plate fetal membrane MT-l-MMP TIMP-1 in situ hybridization.

Hoare logic-based genetic programming

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Science China(Information Sciences) 2011年第3期54卷 623-637页

作者： JOHNSON colin G. Computing Laboratory University of Kent

Almost all existing genetic programming systems deal with fitness evaluation solely by testing. In this paper, by contrast, we present an original approach that combines genetic programming with Hoare logic with the aid of model checking and finite state automata, henceby proposing a brand new verification-focused formal genetic programming system that makes it possible to evolve reliable programs with mathematically-verified properties.

关键词： genetic programming program verification Hoare logic model checking finite state automata

Refining spatial neighbourhoods to capture terrain effects

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Ecological Processes 2012年第1期1卷 98-108页

作者： Trisalyn A Nelson colin Robertson Spatial Pattern Analysis and Research Lab Department of GeographyUniversity of VictoriaPO Box 3060VictoriaBritish ColumbiaV8W 3R4SCanada Department of Geography and Environmental Studies Wilfrid Laurier UniversityWaterlooOntarioN2L 3C5Canada

Introduction:Spatially explicit ecological research has increased substantially in the past 20 *** spatial approaches require the definition of a spatial neighbourhood or the region over which spatial relationships are modelled or *** neighbourhood definitions impact analysis results,and there are benefits in considering neighbourhood definitions that better capture ecological *** goal of this research is to present a simple and flexible approach in constraining ecological spatial neighbourhoods using terrain ***:Using watershed boundaries,we can restrict spatial neighbourhoods from combining populations or processes that should be separated by terrain *** demonstrate the need for ecological constraints by way of a simulation study and highlight our approach with a case study examining mountain pine beetle(Dendroctonus ponderosae,Coleoptera;Hopkins)infestation hot ***:Our results demonstrate how failure to constrain neighbourhoods can lead to errors when the spatial signals from unrelated populations are ***,unconstrained spatial neighbourhoods can unintentionally detect spatial relationships across many ***:There will be benefits to studies that develop new,ecology-based approaches in defining spatial neighbourhoods that better illuminate ecological function of phenomena under study.

关键词： spatial weights spatial analysis spatial ecology hot spots topography

What are universities for?

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Chinese Science Bulletin 2011年第23期56卷 2506-2517页

作者： Geoffrey BOULTON colin LUCAS The University of Edinburgh University of Oxford

Governments worldwide rightly regard universities as fundamental to the achievement of many national priorities. But it is the paper’s contention that many misunderstand their true benefit to society. Investments in universities are increasingly based on the belief that the science labs in particular of research-intensive universities can be the source of a continuous stream of people and ideas that will spawn innovative and fast growing companies to form the nexus of the knowledge-based economy. This belief is a source of misconceived policies that offer only ultimate disillusion. It is the totality of the university enterprise that is important, as the only place where that totality of ourselves and our world is brought together, and which makes it the strongest provider of the rational explanation and meaning that societies need. In research, universities create new possibilities; in teaching, they shape new people. Its graduates learn to seek the true meaning of things: to distinguish between the true and the merely seemingly true, to verify for themselves what is stable in that very unstable compound that often passes for knowledge. It is the complex, interacting whole of the university that is the source of the separate economic, social, cultural and utilitarian benefits valued by society. It needs to be understood, valued and managed as a whole. These perceptions are a direct challenge to not only to governments but to university administrators who have been either cowed or seduced into the slipshod thinking that is leading to demands that universities cannot satisfy, whilst obscuring their most important contributions. The challenge to both is to permit autonomy without oppressive accountability, and to give staff and students the freedom to think, speculate and research. These are the very conditions of the personal and collective creativity that are the sources of a university’s deepest benefits to its society.

关键词：研究型大学社会需要经济关系工作人员社会根源不稳定管理员实验室

Modeling grammatical evolution by automaton

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Science China(Information Sciences) 2011年第12期54卷 2564-2573页

作者： colin G.JOHNSON School of Computing University of Kent

Twelve years have passed since the advent of grammatical evolution (GE) in 1998, but such issues as vast search space, genotypic readability, and the inherent relationship among grammatical concepts, production rules and derivations have remained untouched in almost all existing GE researches. Model-based approach is an attractive method to achieve different objectives of software engineering. In this paper, we make the first attempt to model syntactically usable information of GE using an automaton, coming up with a novel solution called model-based grammatical evolution (MGE) to these problems. In MGE, the search space is reduced dramatically through the use of concepts from building blocks, but the functionality and expressiveness are still the same as that of classical GE. Besides, complex evolutionary process can visually be analyzed in the context of transition diagrams.

关键词： genetic programming grammatical evolution finite state automaton model

The k-Nacci Sequences in Some Special Modular Groups

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Algebra Colloquium 2014年第1期21卷 59-66页

作者： Omur Deveci colin M. Campbell Department of Mathematics Faculty of Science and Letters Katlms University 36100 Kars Turkey School of Mathematics and Statistics -University of St Andrews North Haugb St Andrews Fife KY16 9SS Scotland

A k-nacci （k-step Fibonacci） sequence in a finite group is a sequence of group elements x0,x1,x2,...,xn,.., for which, given an initial （seed） set x0,x1,x2,...,xj-1, each element is defined by xn{x0x1…xn-1 forj≤n〈k xn-kxn-k＋1 …xn-1 for n≥kFrom the definition, it is clear that the period of the k-nacci sequence in a group depends on the chosen generating set and the order in which the assignments of x0, x1, x2,…~, xj-1 are made. In this paper we examine the periods of the k-nacci sequences in the groups m2, m2＋ and R2, where each term of the sequence is reduced modulo 2.

关键词： k-nacci sequence period modular group

Lifespan Modulation in Mice and the Confounding Effects of Genetic Background

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Journal of Genetics and Genomics 2014年第9期41卷 497-503页

作者： Lorna Mulvey Amy Sinclair colin Selman Institute of Biodiversity Animal Health and Comparative MedicineCollege of MedicineVeterinary and Life SciencesGraham Kerr BuildingUniversity of Glasgow

We are currently in the midst of a revolution in ageing research, with several dietary, genetic and pharmacological interventions now known to modulate ageing in model organisms. Excitingly, these interventions also appear to have beneficial effects on late-life health. For example, dietary restriction （DR） has been shown to slow the incidence of age-associated cardiovascular disease, metabolic disease, cancer and brain ageing in non-human primates and has been shown to improve a range of health indices in humans. While the idea thai DR＇s ability to extend lifespan is often thought of as being universal, studies in a range of organisms, including yeast, mice and monkeys, suggest that this may not actually be the case. The precise reasons underlying these differential effects of DR on lifespan are currently unclear, but genetic background may be an important factor in how an individual responds to DR. Similarly, recent findings also suggest that the responsiveness of mice to specific genetic or pharmacological interventions that modulate ageing may again be influenced by genetic background. Consequently, while there is a clear driver to develop interventions to improve late-life health and vitality, under- standing precisely how these act in response to particular genotypes is critical if we are to translate these findings to humans. We will consider of the role of genetic background in the efficacy of various lifespan interventions and discuss potential routes of utilising genetic heterogeneity to further understand how particular interventions modulate lifespan and healthspan.

关键词： Ageing Dietary restriction Genotype Longevity