1,639 research outputs found
Influenza virus-infected dendritic cells stimulate strong proliferative and cytolytic responses from human CD8+ T cells
Antigen-specific, CD8+, cytolytic T lymphocytes (CTLs) could potentially provide resistance to several infectious and malignant diseases. However, the cellular requirements for the generation of specific CTLs in human lymphocyte cultures are not well defined, and repetitive stimulation with antigen is often required. We find that strong CD8+ CTL responses to influenza virus can be generated from freshly isolated blood T cells, as long as dendritic cells are used as antigen presenting cells (APCs). Small numbers of dendritic cells (APC:T cell ratio of 1:50-1:100) induce these CTL responses from most donors in 7 d of culture, but monocytes are weak or inactive. Whereas both dendritic cells and monocytes are infected with influenza virus, the former serve as effective APCs for the induction of CD8+ T cells while the latter act as targets for the CTLs that are induced. The strong CD8+ response to influenza virus-infected dendritic cells is accompanied by extensive proliferation of the CD8+ T cells, but the response can develop in the apparent absence of CD4+ helpers or exogenous lymphokines. CD4+ influenza virus-specific CTLs can also be induced by dendritic cells, but the cultures initially must be depleted of CD8+ cells. These findings should make it possible to use dendritic cells to generate human, antigen-specific, CD8+ CTLs to other targets. The results illustrate the principle that efficient T cell-mediated responses develop in two stages: an afferent limb in which dendritic cells are specialized APCs and an efferent limb in which the primed T cells carry out an immune response to many types of presenting cells
Influenza virus-infected dendritic cells stimulate strong proliferative and cytolytic responses from human CD8+ T cells
Bhardwaj, N., Bender, A., Gonzalez, N., Bui, L.K., Garrett, M.C., and Steinman, R.M. Influenza virus-infected dendritic cells stimulate strong proliferative and cytolytic responses from human CD8+ T cells. J. Clin. Invest. 94: 797-807,1994https://digitalcommons.rockefeller.edu/historical-scientific-reports/1038/thumbnail.jp
Air-cooled heat exchanger design using successive quadratic programming (SQP)
A nonlinear optimization algorithm is applied to the design of air-cooled heat exchangers. In such equipment, the cold fluid (air) is impelled across banks of finned tubes by means of fans in forced or induced draft. The hot stream flows inside the tubes in one or more passes, and the process that takes place may be cooling of either a gas or a liquid, or condensation of either a pure vapor or a mixture. The objective function is the minimum cost of the unit (investment and operation), subject to certain geometric and thermohydraulic constraints. The optimization algorithm used is that developed by Biegler and Cuthrell [1], and programmed by them in the OPT package. The problem posed in this case is made of 10 optimization variables, subject to five constraints related to geometric and operational parameters of the heat exchanger.Fil: Gonzalez, Maria Teresa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Planta Piloto de Ingeniería Química. Universidad Nacional del Sur. Planta Piloto de Ingeniería Química; ArgentinaFil: Petracci, Noemi Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Planta Piloto de Ingeniería Química. Universidad Nacional del Sur. Planta Piloto de Ingeniería Química; ArgentinaFil: Urbicain, Martin Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Planta Piloto de Ingeniería Química. Universidad Nacional del Sur. Planta Piloto de Ingeniería Química; Argentin
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SIRT3 Suppresses Rewiring of Glutamine Metabolism in Cancer
In the process of transformation, a cancer cell selects for a strategy to enhance its survival, growth, and proliferation. Metabolic rewiring is a hallmark of cancer cells and is at the heart of such a mechanism. Although oncogenes and tumor suppressors contribute to metabolic reprogramming in cancer, the exact mechanisms underlying deregulated nutrient metabolism continue to be elucidated. The mitochondrial sirtuin, SIRT3 has tumor suppressive function in various types of human cancer and represses the Warburg effect in breast cancer cells. Despite what is known about SIRT3 in the regulation of metabolism, the challenge in translating our findings into development of therapies for treatment of cancer remains. Thus, the goal of this dissertation was to develop a better understanding of the role of SIRT3 in tumorigenesis and to identify metabolic vulnerabilities associated with loss of SIRT3 in cancer.
In this dissertation, I identify deregulated glutamine metabolism as a vulnerability in tumor-like cells with SIRT3 deletion. First, I utilized immortalized WT and SIRT3 null (KO) cells and performed a small molecule screen to identify compounds that selectively decreased proliferation of cells lacking SIRT3. The top hit from the screen was a glutamine analog, azaserine. Like glucose, glutamine is crucial for synthesis of building blocks to support tumorigenesis. In combination with metabolomics analysis, RNA sequencing (RNA Seq), and bioinformatics analysis, I revealed that azaserine significantly represses a dependency on elevated de novo nucleotide metabolism, driven in part by increased mTORC1 signaling, to suppress growth of cells with decreased SIRT3 levels. Additionally, in human breast tumors, SIRT3 expression is lower in the more aggressive basal-like tumors compared to luminal breast tumors, and is associated with increased mTORC1 signaling. Moreover, I demonstrate that SIRT3 represses mTORC1 signaling to suppress tumorigenesis.
Given that azaserine is a glutamine analog and that SIRT3 loss results in enhanced glutamine consumption, I further examined the effect of SIRT3 loss on glutamine metabolism. Using a combination of glutamine tracing and RNA Seq, I uncover alterations in various nodes of glutamine metabolism in the absence of SIRT3. More specifically, I identify increased distribution of glutamine to glutathione and the tricarboxylic acid (TCA) cycle, which is coupled with production of nonessential amino acids (NEAAs) in SIRT3 KO cells. Lastly, I find that SIRT3 represses glutaminolysis in breast cancer cells.
Taken together, my findings reveal a pathway through which glutamine contributes to tumor growth and identifies previously undescribed nodes of tumor metabolism deregulated in the absence of SIRT3. My findings shed light on potential metabolic pathways that may be targeted in cancers with decreased SIRT3 expression to suppress tumorigenesis.Biology, Molecular and Cellula
Influence of ruminal degradable intake protein restriction on characteristics of digestion and growth performance of feedlot cattle during the late finishing phase.
Two trials were conducted to evaluate the influence of supplemental urea withdrawal on characteristics of digestion (Trial 1) and growth performance (Trial 2) of feedlot cattle during the last 40 days on feed. Treatments consisted of a steam-flaked corn-based finishing diet supplemented with urea to provide urea fermentation potential (UFP) of 0, 0.6, and 1.2%. In Trial 1, six Holstein steers (160 ± 10 kg) with cannulas in the rumen and proximal duodenum were used in a replicated 3 × 3 Latin square experiment. Decreasing supplemental urea decreased (linear effect, P ≤ 0.05) ruminal OM digestion. This effect was mediated by decreases (linear effect, P ≤ 0.05) in ruminal digestibility of NDF and N. Passage of non-ammonia and microbial N (MN) to the small intestine decreased (linear effect, P = 0.04) with decreasing dietary urea level. Total tract digestion of OM (linear effect, P = 0.06), NDF (linear effect, P = 0.07), N (linear effect, P = 0.04) and dietary DE (linear effect, P = 0.05) decreased with decreasing urea level. Treatment effects on total tract starch digestion, although numerically small, likewise tended (linear effect, P = 0.11) to decrease with decreasing urea level. Decreased fiber digestion accounted for 51% of the variation in OM digestion. Ruminal pH was not affected by treatments averaging 5.82. Decreasing urea level decreased (linear effect, P ≤ 0.05) ruminal N-NH and blood urea nitrogen. In Trial 2, 90 crossbred steers (468 kg ± 8), were used in a 40 d feeding trial (5 steers/pen, 6 pens/ treatment) to evaluate treatment effects on final-phase growth performance. Decreasing urea level did not affect DMI, but decreased (linear effect, P ≤ 0.03) ADG, gain efficiency, and dietary NE. It is concluded that in addition to effects on metabolizable amino acid flow to the small intestine, depriving cattle of otherwise ruminally degradable N (RDP) during the late finishing phase may negatively impact site and extent of digestion of OM, depressing ADG, gain efficiency, and dietary NE
Cultivo en maceta de Iris xiphium L. (Iris de Holanda) con diferentes concentraciones de humus de lombriz y sus lixiviados
Se evaluaron tres variedades de Iris xiphium L. cultivadas en maceta en cuatro proporciones de humus de lombriz y se aplicaron los lixiviados diluidos como bioabono foliar. El experimento se realizó en un diseño completamente al azar con arreglo trifactorial y se midieron ocho variables: longitud de tallo (LT), longitud de botón (LB), longitud de flor (LF), diámetro de botón (DB), diámetro de flor (DF), biomasa (B), área foliar (AF) y días de cosecha (DDC). Los resultados indicaron que la variedad Telstar resultó ser la más precoz. El mejor tratamiento en dicha variedad para las variables LT, LB, B, DF y DDC correspondió a la proporción 30/70 (% lombrihumus / % suelo) y la dilución 1:10 de lixiviado; el segundo mejor tratamiento fue en la variedad Discovery en la proporción 40/60 (%lombrihumus / %suelo) y dilución 1:10 de lixiviado para las variables LT, AF y B. El presente trabajo aporta nueva información en cuanto al uso de sustratos y abono foliar orgánicos para el manejo sustentable, con bajo impacto ambiental, en cultivos florícolas
Somatic Sex Determination in D. melanogaster: Insights in the Establishment to Maintenance Transition
In Drosophila melanogaster, sex is determined at the preblastoderm stage via an Xchromosome counting mechanism. During this process embryos that carry two X chromosomes begin to develop as females while embryos with one X start the male developmental program. The Xlinked genes involved in sex determination, also called Xsignal elements (XSEs), are: sisterlessA (sisA), sisterlessB (sisB), unpaired (upd), and runt. These genes are responsible for the transcriptional activation of the master regulatory gene Sexlethal (Sxl). Expression of Sxl is initially accomplished only in females through activation of the establishment promoter SxlPe. Later in development, Sxl is transcribed in both sexes through a maintenance promoter, SxlPm, but functional Sxl protein is only produced in female flies. Since Sxl is at the top of the sex determination cascade, understanding its regulation is key to comprehend the process of sex determination. The experiments in this dissertation were designed to better understand two aspects of the sex determination mechanism: How the protein encoded by XSE element sisA interacts with SxlPe, and how the transition from regulation by SxlPe to regulation by SxlPm occurs.
The sisA protein (SisA), as part of the bZIP protein family, is thought to bind to its target as a dimer, but a dimerization partner has not yet been found. This work uses knockouts and germline clones to examine interaction between sisA and three SisA partner candidates, atf4, CG16813, and CG16815. Although the evidence described here suggest that none of the three SisA partner candidates genetically interact with Sis, we cannot rule out the possibility of redundancy between the different candidate proteins.
This research unravels the timing and regulation of SxlPm expression. I have shown, contrary to previous thought, that expression of SxlPe and SxlPm overlaps for a brief period. Several of the same proteins that are involved in the regulation of SxlPe, including the XSE sisB, also regulate SxlPm. This sex specific regulation leads to a sexually dimorphic pattern of activation and early expression of SxlPm. A common enhancer region was found to regulate SxlPe as well as SxlPm. These results highlight the importance of the transition between SxlPe and SxlPm for the proper establishment of sex determination and have implications for how the sex determination mechanism evolved
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