Genetic Determinants of Circulating Sphingolipid Concentrations in European Populations

Sphingolipids have essential roles as structural components of cell membranes and in cell signalling, and disruption of their metabolism causes several diseases, with diverse neurological, psychiatric, and metabolic consequences. Increasingly, variants within a few of the genes that encode enzymes involved in sphingolipid metabolism are being associated with complex disease phenotypes. Direct experimental evidence supports a role of specific sphingolipid species in several common complex chronic disease processes including atherosclerotic plaque formation, myocardial infarction (MI), cardiomyopathy, pancreatic beta-cell failure, insulin resistance, and type 2 diabetes mellitus. Therefore, sphingolipids represent novel and important intermediate phenotypes for genetic analysis, yet little is known about the major genetic variants that influence their circulating levels in the general population. We performed a genome-wide association study (GWAS) between 318,237 single-nucleotide polymorphisms (SNPs) and levels of circulating sphingomyelin (SM), dihydrosphingomyelin (Dih-SM), ceramide (Cer), and glucosylceramide (GluCer) single lipid species (33 traits); and 43 matched metabolite ratios measured in 4,400 subjects from five diverse European populations. Associated variants (32) in five genomic regions were identified with genome-wide significant corrected p-values ranging down to 9.08 x 10(-66). The strongest associations were observed in or near 7 genes functionally involved in ceramide biosynthesis and trafficking: SPTLC3, LASS4, SGPP1, ATP10D, and FADS1-3. Variants in 3 loci (ATP10D, FADS3, and SPTLC3) associate with MI in a series of three German MI studies. An additional 70 variants across 23 candidate genes involved in sphingolipid-metabolizing pathways also demonstrate association (p = 10(-4) or less). Circulating concentrations of several key components in sphingolipid metabolism are thus under strong genetic control, and variants in these loci can be tested for a role in the development of common cardiovascular, metabolic, neurological, and psychiatric diseases

Transport and Performance in DIII-D Discharges With Weak or Negative Central Magnetic Shear

Discharges exhibiting the highest plasma energy and fusion reactivity yet realized in the DIII-D tokamak have been produced by combining the benefits of a hollow or weakly sheared central current profile with a high confinement (H-mode) edge. In these discharges, low power neutral beam injection heats the electrons during the initial current ramp, and {open_quotes}freezes in{close_quotes} a hollow or flat central current profile. When the neutral beam power is increased, formation of a region of reduced transport and highly peaked profiles in the core often results. Shortly before these plasmas would otherwise disrupt, a transition is triggered from the low (L-mode) to high (H-mode) confinement regimes, thereby broadening the pressure profile and avoiding the disruption. These plasmas continue to evolve until the high performance phase is terminated nondisruptively at much higher {beta}{sub T} (ratio of plasma pressure to toroidal magnetic field pressure) than would be attainable with peaked profiles and an L-mode edge. Transport analysis indicates that in this phase, the ion diffusivity is equivalent to that predicted by Chang-Hinton neoclassical theory over the entire plasma volume. This result is consistent with suppression of turbulence by locally enhanced E x B flow shear, and is supported by observations of reduced fluctuations in the plasma. Calculations of performance in these discharges extrapolated to a deuterium-tritium fuel mixture indicates that such plasmas could produce a DT fusion gain Q{sub DT} = 0.32

Minority youth, crime, conflict, and belonging in Australia

In recent decades, the size and diversity of the minority population of contemporary western societies has increased significantly. To the critics of immigration, minority youth have been increasingly linked to crime, criminal gangs, anti-social behaviour, and riots. In this article, we draw on fieldwork conducted in Sydney, Australia's largest and most ethnically diverse city, to probe aspects of the criminality, anti-social behaviour, national identity, and belonging of ethnic minority youth in Australia. We conclude that the evidence on minority youth criminality is weak and that the panic about immigrant youth crime and immigrant youth gangs is disproportionate to the reality, drawing on and in turn creating racist stereotypes, particularly with youth of 'Middle Eastern appearance'. A review of the events leading up to the Sydney Cronulla Beach riots of December 2005 suggests that the underlying cause of the riots were many years of international, national, and local anti-Arab, anti-Muslim media discourse, and political opportunism, embedded in changing but persistent racist attitudes and practises. Our argument is that such inter-ethnic conflict between minority and majority youth in Sydney is the exception, not the rule. Finally, we draw on a hitherto unpublished survey of youth in Sydney to explore issues of national identity and belonging among young people of diverse ethnic and religious background. We conclude that minority youth in Sydney do not live 'parallel lives' but contradictory, inter-connected cosmopolitan lives. They are connected to family and local place, have inter-ethnic friendships but are often disconnected to the nation and the flag. © 2009 Springer Science+Business Media B.V

The Relative Risk of COVID-19 in Solid Organ Transplant Recipients Over Waves of the Pandemic

Solid organ transplant recipients (SOTR) are at increased risk from COVID-19. Over time, the absolute risk of adverse outcomes after COVID-19 has decreased in both the non-immunosuppressed/immunocompromised (non-ISC) general population, and amongst SOTR. Using the N3C, we examined the absolute risk of mortality, major adverse renal or cardiac events, and hospitalization after COVID-19 diagnosis amongst non-ISC and SOTR populations over five waves of the pandemic (Wave 1: Ancestral COVID; Wave 2: Alpha; Wave 3: Delta; Wave 4: Omicron; Wave 5: Omicron). Within each wave, we determined the relative risk of each outcome for SOTR versus the non-ISC population based on crude event rates, and then used multivariable cox proportional hazards models and logistic regression to determine the adjusted risk of each outcome based on SOT status. Throughout the pandemic, including during the Omicron wave (Wave 5), SOTR were at greater absolute risk for each outcome than non-ISC patients (p-values all <0.001). The adjusted risk of SOT status for each outcome was relatively stable over time (aHR 1.28–1.61 for mortality; aHR 1.31–1.47 for MACE; aHR 1.72–1.90 for MARCE; aHR 1.75–2.07 for AKI; and aOR 1.53–1.81 for hospitalization). Despite a reduction in the absolute risk of COVID-19 complications, the relative risk for SOTR versus the non-ISC population has not improved

Detection of epithelial to mesenchymal transition in airways of a bleomycin induced pulmonary fibrosis model derived from an α-smooth muscle actin-Cre transgenic mouse

BACKGROUND: Epithelial to mesenchymal transition (EMT) in alveolar epithelial cells (AECs) has been widely observed in patients suffering interstitial pulmonary fibrosis. In vitro studies have also demonstrated that AECs could convert into myofibroblasts following exposure to TGF-β1. In this study, we examined whether EMT occurs in bleomycin (BLM) induced pulmonary fibrosis, and the involvement of bronchial epithelial cells (BECs) in the EMT. Using an α-smooth muscle actin-Cre transgenic mouse (α-SMA-Cre/R26R) strain, we labelled myofibroblasts in vivo. We also performed a phenotypic analysis of human BEC lines during TGF-β1 stimulation in vitro. METHODS: We generated the α-SMA-Cre mouse strain by pronuclear microinjection with a Cre recombinase cDNA driven by the mouse α-smooth muscle actin (α-SMA) promoter. α-SMA-Cre mice were crossed with the Cre-dependent LacZ expressing strain R26R to produce the double transgenic strain α-SMA-Cre/R26R. β-galactosidase (βgal) staining, α-SMA and smooth muscle myosin heavy chains immunostaining were carried out simultaneously to confirm the specificity of expression of the transgenic reporter within smooth muscle cells (SMCs) under physiological conditions. BLM-induced peribronchial fibrosis in α-SMA-Cre/R26R mice was examined by pulmonary βgal staining and α-SMA immunofluorescence staining. To confirm in vivo observations of BECs undergoing EMT, we stimulated human BEC line 16HBE with TGF-β1 and examined the localization of the myofibroblast markers α-SMA and F-actin, and the epithelial marker E-cadherin by immunofluorescence. RESULTS: βgal staining in organs of healthy α-SMA-Cre/R26R mice corresponded with the distribution of SMCs, as confirmed by α-SMA and SM-MHC immunostaining. BLM-treated mice showed significantly enhanced βgal staining in subepithelial areas in bronchi, terminal bronchioles and walls of pulmonary vessels. Some AECs in certain peribronchial areas or even a small subset of BECs were also positively stained, as confirmed by α-SMA immunostaining. In vitro, addition of TGF-β1 to 16HBE cells could also stimulate the expression of α-SMA and F-actin, while E-cadherin was decreased, consistent with an EMT. CONCLUSION: We observed airway EMT in BLM-induced peribronchial fibrosis mice. BECs, like AECs, have the capacity to undergo EMT and to contribute to mesenchymal expansion in pulmonary fibrosis

Associations between COVID-19 therapies and outcomes in rural and urban America: A multisite, temporal analysis from the Alpha to Omicron SARS-CoV-2 variants

Purpose: To investigate the enduring disparities in adverse COVID-19 events between urban and rural communities in the United States, focusing on the effects of SARS-CoV-2 vaccination and therapeutic advances on patient outcomes. Methods: Using National COVID Cohort Collaborative (N3C) data from 2021 to 2023, this retrospective cohort study examined COVID-19 hospitalization, inpatient death, and other adverse events. Populations were categorized into urban, urban-adjacent rural (UAR), and nonurban-adjacent rural (NAR). Adjustments included demographics, variant-dominant waves, comorbidities, region, and SARS-CoV-2 treatment and vaccination. Statistical methods included Kaplan-Meier survival estimates, multivariable logistic, and Cox regression. Findings: The study included 3,018,646 patients, with rural residents constituting 506,204. These rural dwellers were older, had more comorbidities, and were less vaccinated than their urban counterparts. Adjusted analyses revealed higher hospitalization odds in UAR and NAR (aOR 1.07 [1.05–1.08] and 1.06 [1.03–1.08]), greater inpatient death hazard (aHR 1.30 [1.26–1.35] UAR and 1.37 [1.30–1.45] NAR), and greater risk of other adverse events compared to urban dwellers. Delta increased, while Omicron decreased, inpatient adverse events relative to pre-Delta, with rural disparities persisting throughout. Treatment effectiveness and vaccination were similarly protective across all cohorts, but dexamethasone post-ventilation was effective only in urban areas. Nirmatrelvir/ritonavir and molnupiravir better protected rural residents against hospitalization. Conclusions: Despite advancements in treatment and vaccinations, disparities in adverse COVID-19 outcomes persist between urban and rural communities. The effectiveness of some therapeutic agents appears to vary based on rurality, suggesting a nuanced relationship between treatment and geographic location while highlighting the need for targeted rural health care strategies

2022 Review of Data-Driven Plasma Science

Data-driven science and technology offer transformative tools and methods to science. This review article highlights the latest development and progress in the interdisciplinary field of data-driven plasma science (DDPS), i.e., plasma science whose progress is driven strongly by data and data analyses. Plasma is considered to be the most ubiquitous form of observable matter in the universe. Data associated with plasmas can, therefore, cover extremely large spatial and temporal scales, and often provide essential information for other scientific disciplines. Thanks to the latest technological developments, plasma experiments, observations, and computation now produce a large amount of data that can no longer be analyzed or interpreted manually. This trend now necessitates a highly sophisticated use of high-performance computers for data analyses, making artificial intelligence and machine learning vital components of DDPS. This article contains seven primary sections, in addition to the introduction and summary. Following an overview of fundamental data-driven science, five other sections cover widely studied topics of plasma science and technologies, i.e., basic plasma physics and laboratory experiments, magnetic confinement fusion, inertial confinement fusion and high-energy-density physics, space and astronomical plasmas, and plasma technologies for industrial and other applications. The final section before the summary discusses plasma-related databases that could significantly contribute to DDPS. Each primary section starts with a brief introduction to the topic, discusses the state-of-the-art developments in the use of data and/or data-scientific approaches, and presents the summary and outlook. Despite the recent impressive signs of progress, the DDPS is still in its infancy. This article attempts to offer a broad perspective on the development of this field and identify where further innovations are required

Functional Implications of Novel Human Acid Sphingomyelinase Splice Variants

BACKGROUND: Acid sphingomyelinase (ASM) hydrolyses sphingomyelin and generates the lipid messenger ceramide, which mediates a variety of stress-related cellular processes. The pathological effects of dysregulated ASM activity are evident in several human diseases and indicate an important functional role for ASM regulation. We investigated alternative splicing as a possible mechanism for regulating cellular ASM activity. METHODOLOGY/PRINCIPAL FINDINGS: We identified three novel ASM splice variants in human cells, termed ASM-5, -6 and -7, which lack portions of the catalytic- and/or carboxy-terminal domains in comparison to full-length ASM-1. Differential expression patterns in primary blood cells indicated that ASM splicing might be subject to regulatory processes. The newly identified ASM splice variants were catalytically inactive in biochemical in vitro assays, but they decreased the relative cellular ceramide content in overexpression studies and exerted a dominant-negative effect on ASM activity in physiological cell models. CONCLUSIONS/SIGNIFICANCE: These findings indicate that alternative splicing of ASM is of functional significance for the cellular stress response, possibly representing a mechanism for maintaining constant levels of cellular ASM enzyme activity