47 research outputs found

    Individual motile CD4+ T cells can participate in efficient multikilling through conjugation to multiple tumor cells

    Get PDF
    T cells genetically modified to express a CD19-specific chimeric antigen receptor (CAR) for the investigational treatment of B-cell malignancies comprise a heterogeneous population, and their ability to persist and participate in serial killing of tumor cells is a predictor of therapeutic success. We implemented Timelapse Imaging Microscopy in Nanowell Grids (TIMING) to provide direct evidence that CD4+CAR+ T cells (CAR4 cells) can engage in multikilling via simultaneous conjugation to multiple tumor cells. Comparisons of the CAR4 cells and CD8+CAR+ T cells (CAR8 cells) demonstrate that, although CAR4 cells can participate in killing and multikilling, they do so at slower rates, likely due to the lower granzyme B content. Significantly, in both sets of T cells, a minor subpopulation of individual T cells identified by their high motility demonstrated efficient killing of single tumor cells. A comparison of the multikiller and single-killer CAR+ T cells revealed that the propensity and kinetics of T-cell apoptosis were modulated by the number of functional conjugations. T cells underwent rapid apoptosis, and at higher frequencies, when conjugated to single tumor cells in isolation, and this effect was more pronounced on CAR8 cells. Our results suggest that the ability of CAR+ T cells to participate in multikilling should be evaluated in the context of their ability to resist activation-induced cell death. We anticipate that TIMING may be used to rapidly determine the potency of T-cell populations and may facilitate the design and manufacture of next-generation CAR+ T cells with improved efficacy. Cancer Immunol Res; 3(5); 473–82. ©2015 AACR

    Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

    Get PDF
    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.peer-reviewe

    Progress and Challenges in Coupled Hydrodynamic-Ecological Estuarine Modeling

    Get PDF

    Shapewheel

    No full text

    Design for a sewerage system for Champaign: including a discussion of disposal by chemical precipitation, irrigation and direct discharge

    No full text
    Thesis (BS)--University of Illinois, 1891MsBound with 9 other University of Illinois theses IU-

    Modification of piglet behavior and welfare by dietary antibiotic alternatives

    No full text
    Society is demanding a decrease in prophylactic use of antibiotics in animal production. This could impact animal welfare unless alternatives can be found that confer similar benefits without risk of AMR. The objectives of these studies were to determine whether two alternatives – a probiotic and an amino acid supplement – would impact piglet behaviour and welfare post-weaning. In Experiment 1, 240 weaned piglets were assigned to 3 diets for a 2-wk period post-transport: A – an antibiotic diet including Chlortetracycline + Tiamulin, NA – a control diet, and GLN – a diet including L-glutamine. After the 2-week period, all piglets were fed the same control diet. At weaning, piglets were transported for 12 hours. Tear staining and skin lesions were recorded pre- and post-transport. Novel object tests were done in groups in the pigs’ home pen 4 times post-weaning. In Experiment 2, 36 female piglets were assigned to 2 supplement treatments from 24-h to 28 d of age: SYN – a synbioticcontaining Lactobacillus, fructo-oligosaccharide and ÎČ-glucan in chocolate milk, and CTL – chocolate milk only. Piglets were subject to episodic-like (Object Recognition), working (Barrier Solving) and long-term (T-maze) memory tests. In Expt 1, NA pigs had larger tear stains than A and GLN pigs. NA pigs had more skin lesions post-mixing than A and GLN pigs. In the first novel object test, A pigs avoided the object more than NA pigs. In later tests, NA pigs spent less time exploring the object and took longer to interact with the object than GLN and A pigs. In Expt 2, in the object recognition test, SYN piglets interacted more quickly with the novel object. In the barrier solving test, SYN piglets had shorter distances to finish the test. In the T-maze test, SYN piglets were quicker to learn the task. Overall, the results demonstrate that short-term feeding strategy can have both short- and long-term effects on behaviour and welfare. Supplementation with L-glutamine appears to confer similar benefits to dietary antibiotics and the synbiotic supplement improved piglet cognitive performance

    Effects of floor cooling on behavior and physiology of lactating sows during acute heat stress

    No full text
    Much U.S. swine production is in Köppen climate types classified as ‘hot-summer humid continental’ and ‘humid subtropical’. As a result, farrowing sows are often exposed to temperatures above their upper critical temperature. This heat stress (HS) can affect sow welfare and productivity and have a negative economic impact. The study objective was to evaluate the impact of a cooling pad on sows’ behavioral and heart rate responses to acute HS. Treatments were randomly allotted to 10 multiparous sows to receive a constant cool water flow of 0.00 (CONTROL, n=4), 0.25 (LOW, n=2), 0.55 (MEDIUM, n=2) or 0.85 (HIGH, n=2) L/min for 100 min and replicated eight times, switching treatments so that each sow was exposed to each treatment. The cooling was initiated 1 hour after the room reached 35°C for 100 min. Eating, drinking and nursing behaviors, postures and heart rate were recorded before heating (Period 1), prior to cooling (Period 2), and during cooling (Period 3). There were no differences between LOW, MEDIUM and HIGH flow rates for any periods on all behavioral and heart rate traits, so data were pooled (COOLED). There were no differences in any of the measures during Periods 1 and 2, except for the ratio of short term to long term heart rate variability (SD1:SD2) with higher values for CONTROL than COOLED sows in Period 2. During Period 3, CONTROL sows changed postures more frequently (11.5±1.6 vs 5.1±1.6 changes per hour), spent more time drinker-pressing/drinking (4.4±0.5 vs 1.4±0.4% of time), standing (6.6±1.7 vs 3.8±1.6% of time), sitting (10.0±1.2 vs 4.0±1.1), less time lying (83.0±1.8 vs 92.0±1.7% of time), especially lying laterally (62.0±5.6 vs 75.0±5.3% of time), than sows in all three cooling treatments (all P < 0.001). Heart rate during Period 3 was lower for COOLED sows compared to the CONTROL sows (100.2±3.4 vs 119.0±4.0 beat per min, P<0.001). Sows response to increased thermal load can be effectively reduced using water-cooled cooling pads, thereby improving sow comfort and welfare. The beneficial effects on behavior are noticeable from the lowest flow rate
    corecore