A quasi-three-dimensional method for calculating blade surface velocities for an axial flow turbine blade

Quasi-three-dimensional compressible flow analysis for calculating blade surface velocities for axial flow turbine blad

Aerodynamic design of a free power turbine for a 75 KW gas turbine automotive engine

A single stage axial-flow turbine having a tip diameter of 15.41 centimeters was designed. The design specifications are given and the aerodynamic design procedure is described. The design includes the transition duct and the turbine exit diffuser. The aerodynamic information includes typical results of a parametric study, velocity diagrams, blade surface and wall velocities, and blade profile and wall coordinates

Human lymphocytes mobilized with exercise have an anti-tumor transcriptomic profile and exert enhanced graft-versus-leukemia effects in xenogeneic mice

BackgroundEvery bout of exercise mobilizes and redistributes large numbers of effector lymphocytes with a cytotoxic and tissue migration phenotype. The frequent redistribution of these cells is purported to increase immune surveillance and play a mechanistic role in reducing cancer risk and slowing tumor progression in physically active cancer survivors. Our aim was to provide the first detailed single cell transcriptomic analysis of exercise-mobilized lymphocytes and test their effectiveness as a donor lymphocyte infusion (DLI) in xenogeneic mice engrafted with human leukemia.MethodsPeripheral blood mononuclear cells (PBMCs) were collected from healthy volunteers at rest and at the end of an acute bout of cycling exercise. Flow cytometry and single-cell RNA sequencing was performed to identify phenotypic and transcriptomic differences between resting and exercise-mobilized cells using a targeted gene expression panel curated for human immunology. PBMCs were injected into the tail vein of xenogeneic NSG-IL-15 mice and subsequently challenged with a luciferase tagged chronic myelogenous leukemia cell line (K562). Tumor growth (bioluminescence) and xenogeneic graft-versus-host disease (GvHD) were monitored bi-weekly for 40-days.ResultsExercise preferentially mobilized NK-cell, CD8+ T-cell and monocyte subtypes with a differentiated and effector phenotype, without significantly mobilizing CD4+ regulatory T-cells. Mobilized effector lymphocytes, particularly effector-memory CD8+ T-cells and NK-cells, displayed differentially expressed genes and enriched gene sets associated with anti-tumor activity, including cytotoxicity, migration/chemotaxis, antigen binding, cytokine responsiveness and alloreactivity (e.g. graft-versus-host/leukemia). Mice receiving exercise-mobilized PBMCs had lower tumor burden and higher overall survival (4.14E+08 photons/s and 47%, respectively) at day 40 compared to mice receiving resting PBMCs (12.1E+08 photons/s and 22%, respectively) from the same donors (p<0.05). Human immune cell engraftment was similar for resting and exercise-mobilized DLI. However, when compared to non-tumor bearing mice, K562 increased the expansion of NK-cell and CD3+/CD4-/CD8- T-cells in mice receiving exercise-mobilized but not resting lymphocytes, 1-2 weeks after DLI. No differences in GvHD or GvHD-free survival was observed between groups either with or without K562 challenge.ConclusionExercise in humans mobilizes effector lymphocytes with an anti-tumor transcriptomic profile and their use as DLI extends survival and enhances the graft-versus-leukemia (GvL) effect without exacerbating GvHD in human leukemia bearing xenogeneic mice. Exercise may serve as an effective and economical adjuvant to increase the GvL effects of allogeneic cell therapies without intensifying GvHD

Discovery and Functional Annotation of SIX6 Variants in Primary Open-Angle Glaucoma

Glaucoma is a leading cause of blindness worldwide. Primary open-angle glaucoma (POAG) is the most common subtype and is a complex trait with multigenic inheritance. Genome-wide association studies have previously identified a significant association between POAG and the SIX6 locus (rs10483727, odds ratio (OR) = 1.32, p = 3.87×10−11). SIX6 plays a role in ocular development and has been associated with the morphology of the optic nerve. We sequenced the SIX6 coding and regulatory regions in 262 POAG cases and 256 controls and identified six nonsynonymous coding variants, including five rare and one common variant, Asn141His (rs33912345), which was associated significantly with POAG (OR = 1.27, p = 4.2×10−10) in the NEIGHBOR/GLAUGEN datasets. These variants were tested in an in vivo Danio rerio (zebrafish) complementation assay to evaluate ocular metrics such as eye size and optic nerve structure. Five variants, found primarily in POAG cases, were hypomorphic or null, while the sixth variant, found only in controls, was benign. One variant in the SIX6 enhancer increased expression of SIX6 and disrupted its regulation. Finally, to our knowledge for the first time, we have identified a clinical feature in POAG patients that appears to be dependent upon SIX6 genotype: patients who are homozygous for the SIX6 risk allele (His141) have a statistically thinner retinal nerve fiber layer than patients homozygous for the SIX6 non-risk allele (Asn141). Our results, in combination with previous SIX6 work, lead us to hypothesize that SIX6 risk variants disrupt the development of the neural retina, leading to a reduced number of retinal ganglion cells, thereby increasing the risk of glaucoma-associated vision loss

The Hubble Deep Field: Observations, Data Reduction, and Galaxy Photometry

The Hubble Deep Field (HDF) is a Director's Discretionary program on HST in Cycle 5 to image an undistinguished field at high Galactic latitude in four passbands as deeply as reasonably possible. These images provide the most detailed view to date of distant field galaxies and are likely to be important for a wide range of studies in galaxy evolution and cosmology. In order to optimize observing in the time available, a field in the northern continuous viewing zone was selected and images were taken for ten consecutive days, or approximately 150 orbits. Shorter 1-2 orbit images were obtained of the fields immediately adjacent to the primary HDF in order to facilitate spectroscopic follow-up by ground-based telescopes. The observations were made from 18 to 30 December 1995, and both raw and reduced data have been put in the public domain as a community service. We present a summary of the criteria for selecting the field, the rationale behind the filter selection and observing times in each band, and the strategies for planning the observations to maximize the exposure time while avoiding earth-scattered light. Data reduction procedures are outlined, and images of the combined frames in each band are presented. Objects detected in these images are listed in a catalog with their basic photometric parameters.Comment: 37 pages, XX PostScript figures, uses aaspp4.sty astrobib.sty. (Astrobib is available from http://www.stsci.edu/software/TeX.html .) To appear the Astronomical Journal. More info on the Hubble deep field can be found at http://www.stsci.edu/../ftp/observer/hdf/hdf.html . More figures (images) can be found at http://www.stsci.edu/../ftp/observer/hdf/references/williams/ and the full source catalog is available at http://www.stsci.edu/../ftp/observer/hdf/archive/v2catalog

Mutations in LRRC50 Predispose Zebrafish and Humans to Seminomas

Seminoma is a subclass of human testicular germ cell tumors (TGCT), the most frequently observed cancer in young men with a rising incidence. Here we describe the identification of a novel gene predisposing specifically to seminoma formation in a vertebrate model organism. Zebrafish carrying a heterozygous nonsense mutation in Leucine-Rich Repeat Containing protein 50 (lrrc50 also called dnaaf1), associated previously with ciliary function, are found to be highly susceptible to the formation of seminomas. Genotyping of these zebrafish tumors shows loss of heterozygosity (LOH) of the wild-type lrrc50 allele in 44.4% of tumor samples, correlating with tumor progression. In humans we identified heterozygous germline LRRC50 mutations in two different pedigrees with a family history of seminomas, resulting in a nonsense Arg488* change and a missense Thr590Met change, which show reduced expression of the wild-type allele in seminomas. Zebrafish in vivo complementation studies indicate the Thr590Met to be a loss-of-function mutation. Moreover, we show that a pathogenic Gln307Glu change is significantly enriched in individuals with seminoma tumors (13% of our cohort). Together, our study introduces an animal model for seminoma and suggests LRRC50 to be a novel tumor suppressor implicated in human seminoma pathogenesis

Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights

Genome-wide association studies (GWAS) have identified over 100 risk loci for schizophrenia, but the causal mechanisms remain largely unknown. We performed a transcriptome-wide association study (TWAS) integrating a schizophrenia GWAS of 79,845 individuals from the Psychiatric Genomics Consortium with expression data from brain, blood, and adipose tissues across 3,693 primarily control individuals. We identified 157 TWAS-significant genes, of which 35 did not overlap a known GWAS locus. Of these 157 genes, 42 were associated with specific chromatin features measured in independent samples, thus highlighting potential regulatory targets for follow-up. Suppression of one identified susceptibility gene, mapk3, in zebrafish showed a significant effect on neurodevelopmental phenotypes. Expression and splicing from the brain captured most of the TWAS effect across all genes. This large-scale connection of associations to target genes, tissues, and regulatory features is an essential step in moving toward a mechanistic understanding of GWAS

Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency

Inactivating mutations in chromodomain helicase DNA binding protein 7 (CHD7) cause CHARGE syndrome, a severe multiorgan system disorder of which Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a minor feature. Recent reports have described predominantly missense CHD7 alleles in IGD patients, but it is unclear if these alleles are relevant to causality or overall genetic burden of Kallmann syndrome (KS) and normosmic form of IGD. To address this question, we sequenced CHD7 in 783 well-phenotyped IGD patients lacking full CHARGE features; we identified nonsynonymous rare sequence variants in 5.2% of the IGD cohort (73% missense and 27% splice variants). Functional analyses in zebrafish using a surrogate otolith assay of a representative set of these CHD7 alleles showed that rare sequence variants observed in controls showed no altered function. In contrast, 75% of the IGD-associated alleles were deleterious and resulted in both KS and normosmic IGD. In two families, pathogenic mutations in CHD7 coexisted with mutations in other known IGD genes. Taken together, our data suggest that rare deleterious CHD7 alleles contribute to the mutational burden of patients with both KS and normosmic forms of IGD in the absence of full CHARGE syndrome. These findings (i) implicate a unique role or preferential sensitivity for CHD7 in the ontogeny of GnRH neurons, (ii) reiterate the emerging genetic complexity of this family of IGD disorders, and (iii) demonstrate how the coordinated use of well-phenotyped cohorts, families, and functional studies can inform genetic architecture and provide insights into the developmental biology of cellular systems

COVID-19 vaccination produces exercise-responsive SARS-CoV-2-specific T-cells regardless of infection history

Purpose: The mobilization and redistribution of severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) specific T-cells and neutralizing antibodies during exercise is purported to increase immune surveillance and protect against severe coronavirus disease 2019 (COVID-19). We sought to determine if COVID-19 vaccination would elicit exercise-responsive SARS-CoV-2 T-cells and transiently alter neutralizing antibody titers. Methods: 18 healthy participants completed a 20 min bout of graded cycling exercise before and/or after receiving a COVID-19 vaccine. All major leukocyte subtypes were enumerated before, during, and after exercise by flow cytometry, and immune responses to SARS CoV-2 were determined using whole blood peptide stimulation assays, T-cell receptor (TCR) sequencing, and SARS-CoV-2 neutralizing antibody serology. Results: COVID-19 vaccination had no effect on the mobilization or egress of major leukocyte subsets in response to intensity-controlled graded exercise. However, noninfected participants had a significantly reduced mobilization of CD4+ and CD8+ naive T-cells, as well as CD4+ central memory T-cells, after vaccination (synthetic immunity group); this was not seen after vaccination in those with prior SARS CoV-2 infection (hybrid immunity group). Acute exercise after vaccination robustly mobilized SARSCoV-2 specific T-cells to blood in an intensity-dependent manner. Both groups mobilized T-cells that reacted to spike protein; however, only the hybrid immunity group mobilized T-cells that reacted to membrane and nucleocapsid antigens. Neutralizing antibodies increased significantly during exercise only in the hybrid immunity group. Conclusion: These data indicate that acute exercise mobilizes SARS CoV-2-specific Tcells that recognize spike protein and increases the redistribution of neutralizing antibodies in individuals with hybrid immunity

Assessing the ecological risk posed by a recently established invasive alien predator: Harmonia axyridis as a case study

Invasive alien predators are a serious threat to biodiversity worldwide. However, there is no generic method for assessing which local species are most at risk following the invasion of a new predator. The harlequin ladybird, Harmonia axyridis (Pallas) (Coleoptera: Coccinellidae), is an alien in Europe and many other parts of the world where it affects other species of ladybirds through competition for food and intra-guild predation (IGP). Here, we describe a method developed to assess which European ladybird species are most at risk following the invasion of H. axyridis. The three components of the risk assessment are: the likelihood that the assessed native species encounters H. axyridis in the field, the hazard of competition for food, and the IGP hazard. Thirty native European ladybird species were assessed through data obtained from field observations, laboratory experiments and literature reviews. The species that are considered most at risk are found on deciduous trees, have immature stages which are highly vulnerable to IGP by H. axyridis, and are primarily aphidophagous. These species should be the focus of specific studies and possibly conservation actions. The risk assessment method proposed here could be applied to other alien predators which are considered a threat to native species through competition and predation