Postural Changes in Blood Pressure Associated with Interactions between Candidate Genes for Chronic Respiratory Diseases and Exposure to Particulate Matter

BACKGROUND. Fine particulate matter [aerodynamic diameter ≤ 2.5 μm (PM2.5)] has been associated with autonomic dysregulation. OBJECTIVE. We hypothesized that PM2.5 influences postural changes in systolic blood pressure (ΔSBP) and in diastolic blood pressure (ΔDBP) and that this effect is modified by genes thought to be related to chronic lung disease. METHODS. We measured blood pressure in participants every 3-5 years. ΔSBP and ΔDBP were calculated as sitting minus standing SBP and DBP. We averaged PM2.5 over 48 hr before study visits and analyzed 202 single nucleotide polymorphisms (SNPs) in 25 genes. To address multiple comparisons, data were stratified into a split sample. In the discovery cohort, the effects of SNP x PM2.5 interactions on ΔSBP and ΔDBP were analyzed using mixed models with subject-specific random intercepts. We defined positive outcomes as p < 0.1 for the interaction; we analyzed only these SNPs in the replicate cohort and confirmed them if p < 0.025 with the same sign. Confirmed associations were analyzed within the full cohort in models adjusted for anthropometric and lifestyle factors. RESULTS. Nine hundred forty-five participants were included in our analysis. One interaction with rs9568232 in PHD finger protein 11 (PHF11) was associated with greater ΔDBP. Interactions with rs1144393 in matrix metalloprotease 1 (MMP1) and rs16930692, rs7955200, and rs10771283 in inositol 1,4,5-triphosphate receptor, type 2 (ITPR2) were associated with significantly greater ΔSBP. Because SNPs associated with ΔSBP in our analysis are in genes along the renin-angiotensin pathway, we then examined medications affecting that pathway and observed significant interactions for angiotensin receptor blockers but not angiotensin-converting enzyme inhibitors with PM2.5. CONCLUSIONS. PM2.5 influences blood pressure and autonomic function. This effect is modified by genes and drugs that also act along this pathway.National Institute of Environmental Health Sciences (T32 ES07069, ES0002, ES015172-01, ES014663, P01 ES09825); United States Environmental Protection Agency (R827353, R832416); National Institutes of Health/National Institute of Aging (AG027014); United States Department of Veterans Affairs; Massachusetts Veterans Epidemiology Research and Information Cente

Expulsion of Trichuris muris is associated with increased expression of angiogenin 4 in the gut and increased acidity of mucins within the goblet cell

<p>Abstract</p> <p>Background</p> <p><it>Trichuris muris </it>in the mouse is an invaluable model for infection of man with the gastrointestinal nematode <it>Trichuris trichiura</it>. Three <it>T. muris </it>isolates have been studied, the Edinburgh (E), the Japan (J) and the Sobreda (S) isolates. The S isolate survives to chronicity within the C57BL/6 host whereas E and J are expelled prior to reaching fecundity. How the S isolate survives so successfully in its host is unclear.</p> <p>Results</p> <p>Microarray analysis was used as a tool to identify genes whose expression could determine the differences in expulsion kinetics between the E and S <it>T. muris </it>isolates. Clear differences in gene expression profiles were evident as early as day 7 post-infection (p.i.). 43 probe sets associated with immune and defence responses were up-regulated in gut tissue from an E isolate-infected C57BL/6 mouse compared to tissue from an S isolate infection, including the message for the anti-microbial protein, angiogenin 4 (Ang4). This led to the identification of distinct differences in the goblet cell phenotype post-infection with the two isolates.</p> <p>Conclusion</p> <p>Differences in gene expression levels identified between the S and E-infected mice early during infection have furthered our knowledge of how the S isolate persists for longer than the E isolate in the C57BL/6 mouse. Potential new targets for manipulation in order to aid expulsion have been identified. Further we provide evidence for a potential new marker involving the acidity of the mucins within the goblet cell which may predict outcome of infection within days of parasite exposure.</p

Do consanguineous parents of a child affected by an autosomal recessive disease have more DNA identical-by-descent than similarly-related parents with healthy offspring? Design of a case-control study

<p>Abstract</p> <p>Background</p> <p>The offspring of consanguineous relations have an increased risk of congenital/genetic disorders and early mortality. Consanguineous couples and their offspring account for approximately 10% of the global population. The increased risk for congenital/genetic disorders is most marked for autosomal recessive disorders and depends on the degree of relatedness of the parents. For children of first cousins the increased risk is 2-4%. For individual couples, however, the extra risk can vary from zero to 25% or higher, with only a minority of these couples having an increased risk of at least 25%. It is currently not possible to differentiate between high-and low-risk couples. The quantity of DNA identical-by-descent between couples with the same degree of relatedness shows a remarkable variation. Here we hypothesize that consanguineous partners with children affected by an autosomal recessive disease have more DNA identical-by-descent than similarly-related partners who have only healthy children. The aim of the study is thus to establish whether the amount of DNA identical-by-descent in consanguineous parents of children with an autosomal recessive disease is indeed different from its proportion in consanguineous parents who have healthy children only.</p> <p>Methods/Design</p> <p>This project is designed as a case-control study. Cases are defined as consanguineous couples with one or more children with an autosomal recessive disorder and controls as consanguineous couples with at least three healthy children and no affected child. We aim to include 100 case couples and 100 control couples. Control couples are matched by restricting the search to the same family, clan or ethnic origin as the case couple. Genome-wide SNP arrays will be used to test our hypothesis.</p> <p>Discussion</p> <p>This study contains a new approach to risk assessment in consanguineous couples. There is no previous study on the amount of DNA identical-by-descent in consanguineous parents of affected children compared to the consanguineous parents of healthy children. If our hypothesis proves to be correct, further studies are needed to obtain different risk figure estimates for the different proportions of DNA identical-by-descent. With more precise information about their risk status, empowerment of couples can be improved when making reproductive decisions.</p

Effectiveness of enhanced diabetes care to patients of South Asian ethnicity : the United Kingdom Asian Diabetes Study (UKADS) : a cluster randomised controlled trial

Background: Delivering high quality and evidence based healthcare to deprived sectors of the community is a major goal for society. We investigated the effectiveness of a culturally sensitive enhanced care package in UK general practice in improving cardiovascular risk factors in South Asian patients with type 2 diabetes. Methods: 21 inner city practices were randomised to intervention (enhanced practice nurse time, link worker and diabetes specialist nurse support) (n=868) or control (standard care) (n=618) groups. Prescribing algorithms with clearly defined targets were provided for all practices. Main outcome measures comprised changes in blood pressure, total cholesterol and glycaemic control (HbA1c) after 2 years. Findings: At baseline, groups were similar with respect to age, sex and cardiovascular risk factors. Comparing treatment groups, after adjustment for confounders, and clustering, differences in diastolic blood pressure (1.91mmHg, P=0.0001) and mean arterial pressure (1.36mmHg, P=0.0180) were significant. There were no significant differences between groups for total cholesterol or HbA1c. Economic analysis indicates the nurse-led intervention was not cost-effective. Across the whole study population systolic blood pressure, diastolic blood pressure and cholesterol decreased significantly by 4.9mmHg, 3.8mmHg and 0.45mmol/L respectively, but there was no change in HbA1c. Interpretation: Additional, although limited, benefits were observed from our culturally enhanced care package over and above the secular changes achieved in the UK in recent years. Stricter targets in general practice and further measures to motivate patients are needed to maximise healthcare outcomes in South Asian patients with diabetes

Testing KiDS cross-correlation redshifts with simulations

Measuring cosmic shear in wide-field imaging surveys requires accurate knowledge of the redshift distribution of all sources. The clustering-redshift technique exploits the angular cross-correlation of a target galaxy sample with unknown redshifts and a reference sample with known redshifts. It represents an attractive alternative to colour-based methods of redshift calibration. Here we test the performance of such clustering redshift measurements using mock catalogues that resemble the Kilo-Degree Survey (KiDS). These mocks are created from the MICE simulation and closely mimic the properties of the KiDS source sample and the overlapping spectroscopic reference samples. We quantify the performance of the clustering redshifts by comparing the cross-correlation results with the true redshift distributions in each of the five KiDS photometric redshift bins. Such a comparison to an informative model is necessary due to the incompleteness of the reference samples at high redshifts. Clustering mean redshifts are unbiased at |Δz|< 0.006 under these conditions. The redshift evolution of the galaxy bias of the reference and target samples represents one of the most important systematic errors when estimating clustering redshifts. It can be reliably mitigated at this level of precision using auto-correlation measurements and self-consistency relations, and will not become a dominant source of systematic error until the arrival of Stage-IV cosmic shear surveys. Using redshift distributions from a direct colour-based estimate instead of the true redshift distributions as a model for comparison with the clustering redshifts increases the biases in the mean to up to |Δz|∼0.04. This indicates that the interpretation of clustering redshifts in real-world applications will require more sophisticated (parameterised) models of the redshift distribution in the future. If such better models are available, the clustering-redshift technique promises to be a highly complementary alternative to other methods of redshift calibration

Galaxy and Mass Assembly (GAMA): Panchromatic data release (far-UV–far-IR) and the low-z energy budget

We present the Galaxy And Mass Assembly (GAMA) Panchromatic Data Release (PDR) constituting over 230 deg2 of imaging with photometry in 21 bands extending from the farUV to the far-IR. These data complement our spectroscopic campaign of over 300k galaxies, and are compiled from observations with a variety of facilities including: GALaxy Evolution eXplorer, Sloan Digital Sky Survey, Visible and Infrared Telescope for Astronomy (VISTA), Wide-field Infrared Survey Explorer, and Herschel, with the GAMA regions currently being surveyedbyVLTSurveyTelescope(VST)andscheduledforobservationsbyAustralianSquare Kilometer Array Pathfinder (ASKAP). These data are processed to a common astrometric solution, from which photometry is derived for ∼221373 galaxies with r < 19.8 mag. Online tools are provided to access and download data cutouts, or the full mosaics of the GAMA regions in each band. We focus, in particular, on the reduction and analysis of the VISTA VIsta Kilo-degree INfrared Galaxy data, and compare to earlier data sets (i.e. 2MASS and UKIDSS) before combining the data and examining its integrity. Having derived the 21-band photometric catalogue, we proceed to fit the data using the energy balance code MAGPHYS. These measurements are then used to obtain the first fully empirical measurement of the 0.1–500 μm energy output of the Universe. Exploring the cosmic spectral energy distribution across three time-intervals (0.3–1.1, 1.1–1.8, and 1.8–2.4 Gyr), we find that the Universe is currently generating (1.5 ± 0.3) × 1035 h70 W Mpc−3, down from (2.5 ± 0.2) × 1035 h70 W Mpc−3 2.3 Gyr ago. More importantly, we identify significant and smooth evolution in the integrated photon escape fraction at all wavelengths, with the UV escape fraction increasing from 27(18) per cent at z= 0.18 in NUV(FUV) to 34(23) per cent at z= 0.06. The GAMA PDR can be found at: http://gama-psi.icrar.org/

Evaluating the Potential of Disaggregated Memory Systems for HPC applications

Disaggregated memory is a promising approach that addresses the limitations of traditional memory architectures by enabling memory to be decoupled from compute nodes and shared across a data center. Cloud platforms have deployed such systems to improve overall system memory utilization, but performance can vary across workloads. High-performance computing (HPC) is crucial in scientific and engineering applications, where HPC machines also face the issue of underutilized memory. As a result, improving system memory utilization while understanding workload performance is essential for HPC operators. Therefore, learning the potential of a disaggregated memory system before deployment is a critical step. This paper proposes a methodology for exploring the design space of a disaggregated memory system. It incorporates key metrics that affect performance on disaggregated memory systems: memory capacity, local and remote memory access ratio, injection bandwidth, and bisection bandwidth, providing an intuitive approach to guide machine configurations based on technology trends and workload characteristics. We apply our methodology to analyze thirteen diverse workloads, including AI training, data analysis, genomics, protein, fusion, atomic nuclei, and traditional HPC bookends. Our methodology demonstrates the ability to comprehend the potential and pitfalls of a disaggregated memory system and provides motivation for machine configurations. Our results show that eleven of our thirteen applications can leverage injection bandwidth disaggregated memory without affecting performance, while one pays a rack bisection bandwidth penalty and two pay the system-wide bisection bandwidth penalty. In addition, we also show that intra-rack memory disaggregation would meet the application's memory requirement and provide enough remote memory bandwidth.Comment: The submission builds on the following conference paper: N. Ding, S. Williams, H.A. Nam, et al. Methodology for Evaluating the Potential of Disaggregated Memory Systems,2nd International Workshop on RESource DISaggregation in High-Performance Computing (RESDIS), November 18, 2022. It is now submitted to the CCPE journal for revie

Starting School: a large-scale start of school assessment within the ‘Born in Bradford’ longitudinal cohort [version 1; peer review: 1 approved with reservations]

The Born in Bradford (BiB) cohort of 13,776 children born between 2007-2011 and their parents provides a rich data resource for researchers exploring protective and risk factors influencing long-term developmental and health outcomes. Educational attainment is a critical factor related to later health. Literacy and communication, fine motor skills and social and emotional health are key ‘early’ predictors of educational attainment and can be used to identify children in need of additional support. We describe our BiB ‘Starting School’ data collection protocol which assessed literacy and communication, fine motor skills and social and emotional health on 3,444 BiB children aged 4-5 years old. These measures supplement the existing dataset, and complement the routine educational, health and social care data available for the cohort

Pneumocystis cell wall β-glucan stimulates calcium-dependent signaling of IL-8 secretion by human airway epithelial cells

<p>Abstract</p> <p>Background</p> <p>Respiratory failure secondary to alveolar inflammation during <it>Pneumocystis </it>pneumonia is a major cause of death in immunocompromised patients. Neutrophil infiltration in the lung of patients with <it>Pneumocystis </it>infection predicts severity of the infection and death. Several previous studies indicate that airway epithelial cells release the neutrophil chemoattractant proteins, MIP-2 (rodents) and IL-8 (humans), in response to <it>Pneumocystis </it>and purified <it>Pneumocystis </it>cell wall β-glucans (PCBG) through the NF-κB-dependent pathway. However, little is known about the molecular mechanisms that are involved in the activation of airway epithelium cells by PCBG resulting in the secretion of IL-8.</p> <p>Method</p> <p>To address this, we have studied the activation of different calcium-dependent mitogen-activated protein kinases (MAPKs) in 1HAEo^-cells, a human airway epithelial cell line.</p> <p>Results</p> <p>Our data provide evidence that PCBG induces phosphorylation of the MAPKs, ERK, and p38, the activation of NF-κB and the subsequently secretion of IL-8 in a calcium-dependent manner. Further, we evaluated the role of glycosphingolipids as possible receptors for β-glucans in human airway epithelial cells. Preincubation of the cells with D-<it>threo</it>-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) a potent inhibitor of the glycosphingolipids synthesis, prior to PCBG stimulation, significantly decreased IL-8 production.</p> <p>Conclusion</p> <p>These data indicate that PCBG activates calcium dependent MAPK signaling resulting in the release of IL-8 in a process that requires glycosphingolipid for optimal signaling.</p