Signal enhancement of the in-plane and out-of-plane Rayleigh wave components

Several groups have reported an enhancement of the ultrasonic Rayleigh wave when scanning close to a surface-breaking defect in a metal sample. This enhancement may be explained as an interference effect where the waves passing directly between source and receiver interfere with those waves reflected back from the defect. We present finite element models of the predicted enhancement when approaching a defect, along with experiments performed using electromagnetic acoustic transducers sensitive to either in-plane or out-of-plane motion. A larger enhancement of the in-plane motion than the out-of-plane motion is observed and can be explained by considering ultrasonic reflections and mode conversion at the defect

Non-linear enhancement of laser generated ultrasonic Rayleigh waves by cracks

Laser generated ultrasound has been widely used for detecting cracks, surface and sub-surface defects in many different materials. It provides a non-contact wideband excitation source which can be focused into different geometries. Previous workers have reported enhancement of the laser generated Rayleigh wave when a crack is illuminated by pulsed laser beam irradiation. We demonstrate that the enhancement observed is due to a combination of source truncation, the free boundary condition at the edge of the crack and interference effects. Generating a Rayleigh wave over a crack can lead to enhancement of the amplitude of the Rayleigh wave signal, a shift in the dominant frequency of the wideband Rayleigh wave and strong enhancement of the high frequency components of the Rayleigh wave

Performance-based fi nancing at the Global Fund to Fight AIDS, Tuberculosis and Malaria: an analysis of grant ratings and funding, 2003–12

Background Performance-based fi nancing can be used by global health funding agencies to improve programme performance and thus value for money. The Global Fund to Fight AIDS, Tuberculosis and Malaria was one of the fi rst global-health funders to deploy a performance-based fi nancing system. However, its complex, multistep system for calculating and paying on grant ratings has several components that are subjective and discretionary. We aimed to test the association between grant ratings and disbursements, an indication of the extent to which incentives for performance are transmitted to grant recipients. Methods We obtained publicly available data for 508 Global Fund grants from 2003 to 2012 with performance ratings and corresponding disbursements, merged with other datasets that contained data for relevant country characteristics. We used regression analysis to identify predictors of grant disbursements in phase 2 (typically the latter 3 of 5 years of a grant), using two dependent variables: whether a grant had any phase-2 disbursements, and the phase-2 disbursement amount. In a separate analysis, we also investigated the predictors of grant performance ratings. Findings Grant performance rating in phase 1 was positively associated with having any disbursements in phase 2, but no association was seen between phase-1 ratings and phase-2 disbursement amounts. Further more, performance ratings are not replicable by external observers, both because subjective and discretionary decisions are made in the generation of performance measures and because the underlying data are not available. Interpretation The Global Fund’s present performance-based funding system does not adequately convey incentives for performance to recipients, and the organisation should redesign this system to explicitly link a portion of the funds to a simple performance measure in health coverage or outcomes, measured independently and robustly

GeV Gamma-Ray Attenuation and the High-Redshift UV Background

We present new calculations of the evolving UV background out to the epoch of cosmological reionization and make predictions for the amount of GeV gamma-ray attenuation by electron-positron pair production. Our results are based on recent semi-analytic models of galaxy formation, which provide predictions of the dust-extinguished UV radiation field due to starlight, and empirical estimates of the contribution due to quasars. We account for the reprocessing of ionizing photons by the intergalactic medium. We test whether our models can reproduce estimates of the ionizing background at high redshift from flux decrement analysis and proximity effect measurements from quasar spectra, and identify a range of models that can satisfy these constraints. Pair-production against soft diffuse photons leads to a spectral cutoff feature for gamma rays observed between 10 and 100 GeV. This cutoff varies with redshift and the assumed star formation and quasar evolution models. We find only negligible amounts of absorption for gamma rays observed below 10 GeV for any emission redshift. With observations of high-redshift sources in sufficient numbers by the Fermi Gamma-ray Space Telescope and new ground-based instruments it should be possible to constrain the extragalactic background light in the UV and optical portion of the spectrum.Comment: 19 pages, 12 figures, Accepted for publication in MNRAS, this version includes minor correction

Pan-viral serology implicates enteroviruses in acute flaccid myelitis.

Since 2012, the United States of America has experienced a biennial spike in pediatric acute flaccid myelitis (AFM)1-6. Epidemiologic evidence suggests non-polio enteroviruses (EVs) are a potential etiology, yet EV RNA is rarely detected in cerebrospinal fluid (CSF)2. CSF from children with AFM (n = 42) and other pediatric neurologic disease controls (n = 58) were investigated for intrathecal antiviral antibodies, using a phage display library expressing 481,966 overlapping peptides derived from all known vertebrate and arboviruses (VirScan). Metagenomic next-generation sequencing (mNGS) of AFM CSF RNA (n = 20 cases) was also performed, both unbiased sequencing and with targeted enrichment for EVs. Using VirScan, the viral family significantly enriched by the CSF of AFM cases relative to controls was Picornaviridae, with the most enriched Picornaviridae peptides belonging to the genus Enterovirus (n = 29/42 cases versus 4/58 controls). EV VP1 ELISA confirmed this finding (n = 22/26 cases versus 7/50 controls). mNGS did not detect additional EV RNA. Despite rare detection of EV RNA, pan-viral serology frequently identified high levels of CSF EV-specific antibodies in AFM compared with controls, providing further evidence for a causal role of non-polio EVs in AFM

Detailed Clinical and Psychological Phenotype of the X-linked HNRNPH2-Related Neurodevelopmental Disorder

Objective: To expand the clinical phenotype of the X-linked HNRNPH2-related neurodevelopmental disorder in 33 individuals. Methods: Participants were diagnosed with pathogenic or likely pathogenic variants in HNRNPH2 using American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria, largely identified via clinical exome sequencing. Genetic reports were reviewed. Clinical data were collected by retrospective chart review and caregiver report including standardized parent report measures. Results: We expand our clinical characterization of HNRNPH2-related disorders to include 33 individuals, aged 2-38 years, both females and males, with 11 different de novo missense variants, most within the nuclear localization signal. The major features of the phenotype include developmental delay/intellectual disability, severe language impairment, motor problems, growth, and musculoskeletal disturbances. Minor features include dysmorphic features, epilepsy, neuropsychiatric diagnoses such as autism spectrum disorder, and cortical visual impairment. Although rare, we report early stroke and premature death with this condition. Conclusions: The spectrum of X-linked HNRNPH2-related disorders continues to expand as the allelic spectrum and identification of affected males increases.Grant support for L. Boyle provided by TL1TR001875.info:eu-repo/semantics/publishedVersio

Genetic determinants of co-accessible chromatin regions in activated T cells across humans.

Over 90% of genetic variants associated with complex human traits map to non-coding regions, but little is understood about how they modulate gene regulation in health and disease. One possible mechanism is that genetic variants affect the activity of one or more cis-regulatory elements leading to gene expression variation in specific cell types. To identify such cases, we analyzed ATAC-seq and RNA-seq profiles from stimulated primary CD4+ T cells in up to 105 healthy donors. We found that regions of accessible chromatin (ATAC-peaks) are co-accessible at kilobase and megabase resolution, consistent with the three-dimensional chromatin organization measured by in situ Hi-C in T cells. Fifteen percent of genetic variants located within ATAC-peaks affected the accessibility of the corresponding peak (local-ATAC-QTLs). Local-ATAC-QTLs have the largest effects on co-accessible peaks, are associated with gene expression and are enriched for autoimmune disease variants. Our results provide insights into how natural genetic variants modulate cis-regulatory elements, in isolation or in concert, to influence gene expression

Seasonal climatic effects and feedbacks of anthropogenic heat release due to global energy consumption with CAM5

Anthropogenic heat release (AHR) is the heat generated in global energy consumption, which has not been considered in global climate models generally. The global high-resolution AHR from 1992 to 2013, which is estimated by using the Defense Meteorological Satellite Program (DMSP)/Operational Linescan System (OLS) satellite data, is implemented into the Community Atmosphere Model version 5 (CAM5). The seasonal climatic effects and possible feedbacks of AHR are examined in this study. The modeling results show that AHR increases the global annual mean surface temperature and land surface temperature by 0.02 ± 0.01 K (1σ uncertainty) and 0.05 ± 0.02 K (1σ uncertainty), respectively. The global climatic effect of AHR varies with season: with a stronger climatic effect in the boreal winter leading to global mean land surface temperature increases by 0.10 ± 0.01 K (1σ uncertainty). In the selected regions (40°N–60°N, 0°E–45°E) of Central and Western Europe the average surface temperature increases by 0.46 K in the boreal summer, and in the selected regions (45°N–75°N, 30°E–140°E) of northern Eurasia the average surface temperature increases by 0.83 K in the boreal winter. AHR changes the height and thermodynamic structure of the global planetary boundary layer, as well as the stability of the lower troposphere, which affects the global atmospheric circulation and low cloud fraction. In addition, at the surface both the shortwave radiation flux in the boreal summer and the down-welling longwave flux in the boreal winter change signifi- cantly, as a result of the change in low clouds caused by the effect of AHR. This study suggests a possible new mechanism of AHR effect on global climate through changing the global low-cloud fraction, which is crucial for global energy balance, by modifying the thermodynamic structure and stability of the lower troposphere. Thus this study improves our understanding of the global climate change caused by human activities

HCV+ Hepatocytes Induce Human Regulatory CD4+ T Cells through the Production of TGF-β

Background: Hepatitis C Virus (HCV) is remarkably efficient at establishing persistent infection and is associated with the development of chronic liver disease. Impaired T cell responses facilitate and maintain persistent HCV infection. Importantly, CD4 + regulatory T cells (Tregs) act by dampening antiviral T cell responses in HCV infection. The mechanism for induction and/or expansion of Tregs in HCV is unknown. Methodology/Principal Findings: HCV-expressing hepatocytes were used to determine if hepatocytes are able to induce Tregs. The infected liver environment was modeled by establishing the co-culture of the human hepatoma cell line, Huh7.5, containing the full-length genome of HCV genotype 1a (Huh7.5-FL) with activated CD4 + T cells. The production of IFN-c was diminished following co-culture with Huh7.5-FL as compared to controls. Notably, CD4 + T cells in contact with Huh7.5-FL expressed an increased level of the Treg markers, CD25, Foxp3, CTLA-4 and LAP, and were able to suppress the proliferation of effector T cells. Importantly, HCV + hepatocytes upregulated the production of TGF-b and blockade of TGF-b abrogated Treg phenotype and function. Conclusions/Significance: These results demonstrate that HCV infected hepatocytes are capable of directly inducing Tregs development and may contribute to impaired host T cell responses

LRP1 Functions as an Atheroprotective Integrator of TGFβ and PDGF Signals in the Vascular Wall: Implications for Marfan Syndrome

BACKGROUND: The multifunctional receptor LRP1 controls expression, activity and trafficking of the PDGF receptor-β in vascular smooth muscle cells (VSMC). LRP1 is also a receptor for TGFβ1 and is required for TGFβ mediated inhibition of cell proliferation. METHODS AND PRINCIPAL FINDINGS: We show that loss of LRP1 in VSMC (smLRP(−)) in vivo results in a Marfan-like syndrome with nuclear accumulation of phosphorylated Smad2/3, disruption of elastic layers, tortuous aorta, and increased expression of the TGFβ target genes thrombospondin-1 (TSP1) and PDGFRβ in the vascular wall. Treatment of smLRP1(−) animals with the PPARγ agonist rosiglitazone abolished nuclear pSmad accumulation, reversed the Marfan-like phenotype, and markedly reduced smooth muscle proliferation, fibrosis and atherosclerosis independent of plasma cholesterol levels. CONCLUSIONS AND SIGNIFICANCE: Our findings are consistent with an activation of TGFβ signals in the LRP1-deficient vascular wall. LRP1 may function as an integrator of proliferative and anti-proliferative signals that control physiological mechanisms common to the pathogenesis of Marfan syndrome and atherosclerosis, and this is essential for maintaining vascular wall integrity