Association of extreme blood lipid profile phenotypic variation with 11 reverse cholesterol transport genes and 10 non-genetic cardiovascular disease risk factors

This study explored the genetic basis of the combination of extreme blood levels of HDL-C and LDL-C, a well-studied endophenotype for CVD, which has several attractive features as a target for genetic analysis: (1) the trait is moderately heritable; (2) non-genetic risk factors account for a significant but still limited portion of the phenotypic variance; (3) it is known to be moderated by a number of gene products. We exhaustively surveyed 11 candidate genes for allelic variation in a random population-based sample characterized for known CVD risk factors and blood lipid profiles. With the goal of generating specific etiological hypotheses, we compared two groups of subjects with extreme lipid phenotypes, from the same source population, using a case-control design. Cases (n=186) were subjects, within the total sample of 1708 people, who scored in the upper tertile of LDL-C and the lowest tertile of HDL-C, while controls (n=185) scored in the lowest tertile of LDL-C and the upper tertile of HDL-C. We used logistic regression and a four-tiered, systematic model building strategy with internal cross-validation and bootstrapping to investigate the relationships between the trait and 275 genetic variants in the presence of 10 non-genetic risk factors. Our results implicate a subset of nine genetic variants, spanning seven candidate genes, together with five environmental risk factors, in the etiology of extreme lipoprotein phenotypes. We propose a model involving these 14 genetic and non-genetic risk factors for evaluation in future independent studie

WRF-CMAQ two-way coupled system with aerosol feedback: software development and preliminary results

Air quality models such as the EPA Community Multiscale Air Quality (CMAQ) require meteorological data as part of the input to drive the chemistry and transport simulation. The Meteorology-Chemistry Interface Processor (MCIP) is used to convert meteorological data into CMAQ-ready input. Key shortcoming of such one-way coupling include: excessive temporal interpolation of coarsely saved meteorological input and lack of feedback of atmospheric pollutant loading on simulated dynamics. We have developed a two-way coupled system to address these issues. A single source code principle was used to construct this two-way coupling system so that CMAQ can be consistently executed as a stand-alone model or part of the coupled system without any code changes; this approach eliminates maintenance of separate code versions for the coupled and uncoupled systems. The design also provides the flexibility to permit users: (1) to adjust the call frequency of WRF and CMAQ to balance the accuracy of the simulation versus computational intensity of the system, and (2) to execute the two-way coupling system with feedbacks to study the effect of gases and aerosols on short wave radiation and subsequent simulated dynamics. Details on the development and implementation of this two-way coupled system are provided. When the coupled system is executed without radiative feedback, computational time is virtually identical when using the Community Atmospheric Model (CAM) radiation option and a slightly increased (~8.5 %) when using the Rapid Radiative Transfer Model for GCMs (RRTMG) radiation option in the coupled system compared to the offline WRF-CMAQ system. Once the feedback mechanism is turned on, the execution time increases only slightly with CAM but increases about 60 % with RRTMG due to the use of a more detailed Mie calculation in this implementation of feedback mechanism. This two-way model with radiative feedback shows noticeably reduced bias in simulated surface shortwave radiation and 2 m temperatures as well improved correlation of simulated ambient ozone and PM<sub>2.5</sub> relative to observed values for a test case with significant tropospheric aerosol loading from California wildfires

Ornamental plants, 1979: a summary of research

An analysis of production costs for containerized nursery products / David E. Hahn, Jerry L. Robertson, and Elton M. Smith -- Monoterpene investigations with creeping juniper cultivars (Juniperus horizontalis Moench.) / Thomas A. Fretz -- Woody flora in Hokkaido adaptable to the north central United States / Makoto Kawase -- An evaluation of microfoam on plant quality following overwintering of container-grown woody ornamentals / Christopher F. Rizzo, Elton M. Smith, and Thomas A. Fretz -- Evaluation of winter barrels as a heat source in woody ornamental winter storage structures / Christopher F. Rizzo, Elton M. Smith, and Thomas A. Fretz_ -- Effective utilization of applied fertilizer in relation to multiple flushes of growth on 'Helleri' holly / C. H. Gilliam and R. D. Wright -- Tissue nitrogen changes during a growth flush on 'Helleri' holly / C. H. Gilliam and R. D. Wright -- Controlling winter annual and perennial weeds in field-grown Cotoneaster divaricata / Elton M. Smith and Sharon A. Treaster -- Evaluation of oxadiazon for weed control in container-grown nursery stock / Thomas A. Fretz and Wendy J. Sheppard -- A 10-year evaluation of flowering crabapple susceptibility to apple scab in Ohio / Elton M. Smith -- Fungicides for the control of diseases of ornamental plants: results of 1977 trials / C. C. Powell and James A. Chatfield -- An evaluation of fungicides on container-grown woody ornamentals during winter storage under microfoam / Christopher F. Rizzo, Elton M. Smith, and Thomas A. Fretz -- Resistance of maple cultivars and species to verticillium wilt: a preliminary report / H. A. J. Hoitink, T. D. Sydnor, and C. L. Wilso

Incremental testing of the Community Multiscale Air Quality (CMAQ) modeling system version 4.7

This paper describes the scientific and structural updates to the latest release of the Community Multiscale Air Quality (CMAQ) modeling system version 4.7 (v4.7) and points the reader to additional resources for further details. The model updates were evaluated relative to observations and results from previous model versions in a series of simulations conducted to incrementally assess the effect of each change. The focus of this paper is on five major scientific upgrades: (a) updates to the heterogeneous N<sub>2</sub>O<sub>5</sub> parameterization, (b) improvement in the treatment of secondary organic aerosol (SOA), (c) inclusion of dynamic mass transfer for coarse-mode aerosol, (d) revisions to the cloud model, and (e) new options for the calculation of photolysis rates. Incremental test simulations over the eastern United States during January and August 2006 are evaluated to assess the model response to each scientific improvement, providing explanations of differences in results between v4.7 and previously released CMAQ model versions. Particulate sulfate predictions are improved across all monitoring networks during both seasons due to cloud module updates. Numerous updates to the SOA module improve the simulation of seasonal variability and decrease the bias in organic carbon predictions at urban sites in the winter. Bias in the total mass of fine particulate matter (PM<sub>2.5</sub>) is dominated by overpredictions of unspeciated PM<sub>2.5</sub> (PM<sub>other</sub>) in the winter and by underpredictions of carbon in the summer. The CMAQv4.7 model results show slightly worse performance for ozone predictions. However, changes to the meteorological inputs are found to have a much greater impact on ozone predictions compared to changes to the CMAQ modules described here. Model updates had little effect on existing biases in wet deposition predictions

DNA methylation in Friedreich ataxia silences expression of frataxin isoform E

Supplementary Information: https://static-content.springer.com/esm/art%3A10.1038%2Fs41598-022-09002-5/MediaObjects/41598_2022_9002_MOESM1_ESM.pdfCopyright © The Author(s) 2022. Epigenetic silencing in Friedreich ataxia (FRDA), induced by an expanded GAA triplet-repeat in intron 1 of the FXN gene, results in deficiency of the mitochondrial protein, frataxin. A lesser known extramitochondrial isoform of frataxin detected in erythrocytes, frataxin-E, is encoded via an alternate transcript (FXN-E) originating in intron 1 that lacks a mitochondrial targeting sequence. We show that FXN-E is deficient in FRDA, including in patient-derived cell lines, iPS-derived proprioceptive neurons, and tissues from a humanized mouse model. In a series of FRDA patients, deficiency of frataxin-E protein correlated with the length of the expanded GAA triplet-repeat, and with repeat-induced DNA hypermethylation that occurs in close proximity to the intronic origin of FXN-E. CRISPR-induced epimodification to mimic DNA hypermethylation seen in FRDA reproduced FXN-E transcriptional deficiency. Deficiency of frataxin E is a consequence of FRDA-specific epigenetic silencing, and therapeutic strategies may need to address this deficiency.National Institutes of Health [R01 NS072418; P30 ES013508; U01 NS114143; Muscular Dystrophy Association [MDA604011; Friedreich Ataxia Research Alliance; CureFA Foundation

Prospects for progress on health inequalities in England in the post-primary care trust era : professional views on challenges, risks and opportunities

Background - Addressing health inequalities remains a prominent policy objective of the current UK government, but current NHS reforms involve a significant shift in roles and responsibilities. Clinicians are now placed at the heart of healthcare commissioning through which significant inequalities in access, uptake and impact of healthcare services must be addressed. Questions arise as to whether these new arrangements will help or hinder progress on health inequalities. This paper explores the perspectives of experienced healthcare professionals working within the commissioning arena; many of whom are likely to remain key actors in this unfolding scenario. Methods - Semi-structured interviews were conducted with 42 professionals involved with health and social care commissioning at national and local levels. These included representatives from the Department of Health, Primary Care Trusts, Strategic Health Authorities, Local Authorities, and third sector organisations. Results - In general, respondents lamented the lack of progress on health inequalities during the PCT commissioning era, where strong policy had not resulted in measurable improvements. However, there was concern that GP-led commissioning will fare little better, particularly in a time of reduced spending. Specific concerns centred on: reduced commitment to a health inequalities agenda; inadequate skills and loss of expertise; and weakened partnership working and engagement. There were more mixed opinions as to whether GP commissioners would be better able than their predecessors to challenge large provider trusts and shift spend towards prevention and early intervention, and whether GPs’ clinical experience would support commissioning action on inequalities. Though largely pessimistic, respondents highlighted some opportunities, including the potential for greater accountability of healthcare commissioners to the public and more influential needs assessments via emergent Health & Wellbeing Boards. Conclusions - There is doubt about the ability of GP commissioners to take clearer action on health inequalities than PCTs have historically achieved. Key actors expect the contribution from commissioning to address health inequalities to become even more piecemeal in the new arrangements, as it will be dependent upon the interest and agency of particular individuals within the new commissioning groups to engage and influence a wider range of stakeholders.</p

Strong Association of De Novo Copy Number Mutations with Autism

We tested the hypothesis that de novo copy number variation (CNV) is associated with autism spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regions were validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping. Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (3%) of patients with an affected first-degree relative, and in 2 out of 196 (1%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized