33,326 research outputs found
DNA fusion gene vaccination mobilizes effective anti-leukemic cytotoxic T lymphocytes from a tolerized repertoire
No full textThe majority of known human tumor-associated antigens derive from non-mutated self proteins. T cell tolerance, essential to prevent autoimmunity, must therefore be cautiously circumvented to generate cytotoxic T cell responses against these targets. Our strategy uses DNA fusion vaccines to activate high levels of peptide-specific CTL. Key foreign sequences from tetanus toxin activate tolerance-breaking CD4+ T cell help. Candidate MHC class Ibinding tumor peptide sequences are fused to the C terminus for optimal processing and presentation. To model performance against a leukemia-associated antigen in a tolerized setting, we constructed a fusion vaccine encoding an immunodominant CTL epitopederived from Friend murine leukemia virus gag protein (FMuLVgag) and vaccinated tolerant FMuLVgag-transgenic (gag-Tg) mice. Vaccination with the construct induced epitopespecificIFN-c-producing CD8+ T cells in normal and gag-Tg mice. The frequency and avidity of activated cells were reduced in gag-Tg mice, and no autoimmune injury resulted. However, these CD8+ T cells did exhibit gag-specific cytotoxicity in vitro and in vivo. Also, epitope-specific CTL killed FBL-3 leukemia cells expressing endogenous FMuLVgag antigen and protected against leukemia challenge in vivo. These results demonstrate a simple strategy to engage anti-microbial T cell help to activate epitope-specific polyclonal CD8+ T cell responses from a residual tolerized repertoire
The maternal immune system during pregnancy and its influence on fetal development
No full textThe maternal immune system plays a critical role in the establishment, maintenance, and completion of a healthy pregnancy. However, the specific mechanisms utilized to achieve these goals are not well understood. Various cells and molecules of the immune system are key players in the development and function of the placenta and the fetus. Effector cells of the immune system act to promote and yet limit placental development. The T helper 1 (Th1)/T helper 2 (Th2) immune shift during pregnancy is well established. A fine balance between proinflammatory and anti-inflammatory influences is required. We herein review the evidence regarding maternal tolerance of fetal tissues and the underlying cell-mediated immune and humoral (hormones and cytokines) mechanisms. We also note the many unanswered questions in our understanding of these mechanisms. In addition, we summarize the clinical manifestations of an altered maternal immune system during pregnancy related to susceptibility to common viral, bacterial, and parasitic infections, as well as to autoimmune diseases.Peer reviewe
Heterogeneous and tissue-specific regulation of effector T cell responses by IFN-gamma during Plasmodium berghei ANKA infection.
No full textIFN-γ and T cells are both required for the development of experimental cerebral malaria during Plasmodium berghei ANKA infection. Surprisingly, however, the role of IFN-γ in shaping the effector CD4(+) and CD8(+) T cell response during this infection has not been examined in detail. To address this, we have compared the effector T cell responses in wild-type and IFN-γ(-/-) mice during P. berghei ANKA infection. The expansion of splenic CD4(+) and CD8(+) T cells during P. berghei ANKA infection was unaffected by the absence of IFN-γ, but the contraction phase of the T cell response was significantly attenuated. Splenic T cell activation and effector function were essentially normal in IFN-γ(-/-) mice; however, the migration to, and accumulation of, effector CD4(+) and CD8(+) T cells in the lung, liver, and brain was altered in IFN-γ(-/-) mice. Interestingly, activation and accumulation of T cells in various nonlymphoid organs was differently affected by lack of IFN-γ, suggesting that IFN-γ influences T cell effector function to varying levels in different anatomical locations. Importantly, control of splenic T cell numbers during P. berghei ANKA infection depended on active IFN-γ-dependent environmental signals--leading to T cell apoptosis--rather than upon intrinsic alterations in T cell programming. To our knowledge, this is the first study to fully investigate the role of IFN-γ in modulating T cell function during P. berghei ANKA infection and reveals that IFN-γ is required for efficient contraction of the pool of activated T cells
Letter from X. N. Steeves to Carl Hayden
No full textLetter from X. N. Steeves to Carl T. Hayden describing road conditions around the Grand Canyon National Par
Letter from Carl Hayden to X. N. Steeves
No full textLetter with red pencil corrections from Carl T. Hayden to X. N. Steeves about the construction of an approach road to the canyo
Identification of Immune Gene Signature Associated with T Cells and Natural Killer Cells in Type 1 Diabetes [Corrigendum]
No full textWang N, Wang G, Feng X, Yang T. Diabetes Metab Syndr Obes. 2024;17:2983—2996.
The authors have advised the affiliation callouts in the author list on page 2983 are incorrect. The correct author callouts should read as follows:
Na Wang1, Guofeng Wang1,2, Xiuli Feng1, Teng Yang
Ratio of n-6/n-3 in the diets of beef cattle
No full textEffects of feeding heat-treated canola (C), soybean (S) and flax (F) or mixtures on growth and slaughter characteristics, taste and fatty acid (FA) composition of beef tissue were investigated using 128 crossbred steers to determine the potential of improving the nutritional quality of beef for humans. For Trial 1 (48 steers), dietary treatments were: roasted C, extruded C, roasted S, extruded S, roasted F and extruded F. For Trial 2 (80 steers), the dietary treatments were: S:F (1:1), S:C (1:1), C:F (1:1) and S:F:C (1:1:1), and the oilseeds were processed either by roasting or extruding before mixing. Soybean meal and soybean oil were used to give equivalent lipid and protein contents to each experimental diet. The basal diet consisted of grass silage, barley grain, vitamins and minerals. Steers were fed for a minimum of 100d then slaughtered at a uniform degree of finish. Growth and slaughter characteristics of the steers were only slightly affected by dietary treatment in that the soybean-fed steers consumed more feed and had a higher average daily gain than the canola or flax-fed animals in Trial 1. There was no difference in taste panel parameters for any of the treatments. Inclusion of flax in the diet increased the total n-3 content of meat. Similar results were found for canola and C18:1n-9 although this was not the case for soybean and the n-6 FA. For the n-6 FA in the PL and neutral lipid fractions of the meat samples, levels were correlated with high dietary levels of n-6 or n-9 with low levels of n-3 while for the n-3 FA, levels were correlated with high dietary n-3 levels and low n-6 levels. Oilseed processing method did not have an effect on any fatty acid levels. It is possible to modify the FA composition of beef meat toward a healthier profile by including heat-treated oilseeds in the diet to influence the degree of lipid metabolism in the rumen.ID: S0377840111004007; M3: Article; Accession Number: S0377840111004007; Author: M.A. McNiven (a, ⁎); Author: J.L. Duynisveld (b); Author: T. Turner (a); Author: A.W. Mitchell (a); Affiliation: Department of Health Management, Atlantic Veterinary College, University of PEI, Charlottetown, PEI, Canada C1A 4P3; Affiliation: Agriculture and Agri-Food Canada, Nappan, NS, Canada B0L 1C0; Keyword: Oilseeds; Keyword: Roasted; Keyword: Extruded; Keyword: Fatty acids; Keyword: Healthy fat; Number of Pages: 11; Language: English
Dual Hierarchy for Gravitational n-body
No full textThe n-body problem is the simulation of pair-wise interactions between n objects. This problem appears in many forms, with the classic example being the modeling of gravitational forces between point masses, necessary for cosmological simulations. Many approximation approaches have been devised to reduce the complexity of this problem.t-SNE is a data visualization method that requires repeatedly solving a variant of the n-body problem. A recent paper (An Efficient Dual-Hierarchy t-SNE Minimization, van de Ruit et. al.) proposes a novel algorithm that outperforms other t-SNE minimization methods on medium-scale datasets. The report proves the viability of a dual-traversal method that uses an embedding tree to emit forces and an independent field tree to collect forces. Because the embedding tree is a Linear-BVH and the field tree is an orthtree built to a fixed depth, the overall algorithm has linear complexity.This thesis demonstrates how the dual-tree approach can be adapted for gravitational n-body simulations. Following this, it measures the performance against similar implementations of other algorithms and shows that while the adapted Dual Hierarchy approach is faster than Barnes-Hut, it is outperformed by the Fast Multipole Method on realistic large-scale cosmological datasets.https://github.com/JacksonCampolattaro/n-body Git repository containing an implementation of the adapted Dual Hierarchy algorithm for Gravitational n-body, as well as implementations of several other common algorithms compared against during benchmarking.Computer Engineerin
Stably stratified shear-produced turbulence and large-scalewaves in a lid driven cavity
No full textWe study experimentally stably stratified sheared turbulence and large-scale flows and waves in a lid driven cavity with a non-zero vertical mean temperature gradient. Geometrical properties of the large-scale vortex (e.g., its size and form) and the level of small-scale turbulence inside the vortex are controlled by the buoyancy (i.e., by the temperature stratification). The observed velocity fluctuations are produced by the shear of the large-scale vortex. At larger stratification obtained in our experiments, the strong turbulence region is located at the upper part of the cavity where the large scale vortex exists. In this region the Brunt-Väisälä frequency is small and increases in the direction outside the large-scale vortex. This is the reason of that the large-scale internal gravity waves are observed in the regions outside the large-scale vortex. We found these waves by analyzing the non instantaneous correlation functions of the temperature and velocity fields. The observed large-scale waves are nonlinear because the frequency of the waves determined from the temperature field measurements is two times smaller than that obtained from the velocity field measurements. The measured intensity of the waves is of the order of the level of the temperature turbulent fluctuations
Reprogramming CD8+ T-cell Branched N-Glycosylation Limits Exhaustion, Enhancing Cytotoxicity and Tumor Killin
No full textT-cell therapies have transformed cancer treatment. While surface glycans have been shown to play critical roles in regulating T-cell development and function, whether and how the glycome influences T cell–mediated tumor immunity remains an area of active investigation. In this study, we show that the intratumoral T-cell glycome is altered early in human colorectal cancer, with substantial changes in branched N-glycans. We demonstrated that CD8+ T cells expressing β1,6-GlcNAc branched N-glycans adopted an exhausted phenotype, marked by increased PD1 and Tim3 expression. CRISPR/Cas9 deletion of key branching glycosyltransferase genes revealed that Mgat5 played a prominent role in T-cell exhaustion. In culture-based assays and tumor studies, Mgat5 deletion in CD8+ T cells resulted in improved cancer cell killing. These findings prompted assessment of whether MGAT5 deletion in anti-CD19 chimeric-antigen receptor (CAR) T cells could enable this therapeutic modality in a solid tumor setting. We showed that MGAT5 KO anti-CD19-CAR T cells inhibited the growth of CD19-transduced tumors. Together, these findings show that MGAT5-mediated branched N-glycans regulate CD8+ T-cell function in cancer and provide a strategy to enhance antitumor activity of native and CAR T cells.S.S.P acknowledges Mizutani Foundation for Glycoscience (Grant 250007) for funding. SSP also acknowledges Liga Portuguesa Contra o Cancro LPCC/MULTICARE for funding (C 3035006C17); Portuguese Society of Digestive Endoscopy (SPED) and Porto Comprehensive Cancer Center Raquel Seruca (P.CCC Raquel Seruca) for the support. S.S.P acknowledges the Portuguese Foundation for Science and Technology (FCT - 2023.16654.ICDT) for funding. Co-funded by the European Union (ERC, GlycanSwitch, 101071386). Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council Executive Agency. Neither the European Union nor the granting authority can be held responsible for them. GMD acknowledges the National Institutes of Health (NIH) [R01AI171483, R01AI166598, R01CA277473], the Alliance for Cancer Gene Therapy, the Mark Foundation for Cancer Research’s Emerging Leader Award, a Cancer Research Institute’s Lloyd J. Old STAR Award, and the Sy Holzer Endowed Immunotherapy Fund. ÂF acknowledges the Portuguese Foundation for Science and Technology (FCT) (2022.01422. PTDC) and Sociedade Portuguesa de Neurologia (SPN – Grant Pereira Monteiro) for funding. CMA acknowledges FCT [BD/07357/2021], Fulbright and FLAD for PhD fellowship and funding. We also thank Professor Ronald A. DePinho, University of Texas MD Anderson Cancer Center for his critical scientific inputs in revising this manuscript
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