Forbush decreases and turbulence levels at CME fronts

We seek to estimate the average level of MHD turbulence near coronal mass ejection (CME) fronts as they propagate from the Sun to the Earth. We examine the cosmic ray data from the GRAPES-3 tracking muon telescope at Ooty, together with the data from other sources for three well observed Forbush decrease events. Each of these events are associated with frontside halo Coronal Mass Ejections (CMEs) and near-Earth magnetic clouds. In each case, we estimate the magnitude of the Forbush decrease using a simple model for the diffusion of high energy protons through the largely closed field lines enclosing the CME as it expands and propagates from the Sun to the Earth. We use estimates of the cross-field diffusion coefficient $D_{\perp}$ derived from published results of extensive Monte Carlo simulations of cosmic rays propagating through turbulent magnetic fields. Our method helps constrain the ratio of energy density in the turbulent magnetic fields to that in the mean magnetic fields near the CME fronts. This ratio is found to be $\sim$ 2% for the 11 April 2001 Forbush decrease event, $\sim$ 6% for the 20 November 2003 Forbush decrease event and $\sim$ 249% for the much more energetic event of 29 October 2003.Comment: Accepted for publication in Astronomy and Astrophysics. (Abstract abridged) Typos correcte

Changes in the expression of the type 2 diabetes-associated gene VPS13C in the β cell are associated with glucose intolerance in humans and mice

Single nucleotide polymorphisms (SNPs) close to the VPS13C, C2CD4A and C2CD4B genes on chromosome 15q are associated with impaired fasting glucose and increased risk of type 2 diabetes. eQTL analysis revealed an association between possession of risk (C) alleles at a previously implicated causal SNP, rs7163757, and lowered VPS13C and C2CD4A levels in islets from female (n = 40, P < 0.041) but not from male subjects. Explored using promoter-reporter assays in β-cells and other cell lines, the risk variant at rs7163757 lowered enhancer activity. Mice deleted for Vps13c selectively in the β-cell were generated by crossing animals bearing a floxed allele at exon 1 to mice expressing Cre recombinase under Ins1 promoter control (Ins1Cre). Whereas Vps13cfl/fl:Ins1Cre (βVps13cKO) mice displayed normal weight gain compared with control littermates, deletion of Vps13c had little effect on glucose tolerance. Pancreatic histology revealed no significant change in β-cell mass in KO mice vs. controls, and glucose-stimulated insulin secretion from isolated islets was not altered in vitro between control and βVps13cKO mice. However, a tendency was observed in female null mice for lower insulin levels and β-cell function (HOMA-B) in vivo. Furthermore, glucose-stimulated increases in intracellular free Ca2+ were significantly increased in islets from female KO mice, suggesting impaired Ca2+ sensitivity of the secretory machinery. The present data thus provide evidence for a limited role for changes in VPS13C expression in conferring altered disease risk at this locus, particularly in females, and suggest that C2CD4A may also be involved

The level and duration of RSV-specific maternal IgG in infants in Kilifi Kenya

Background Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infection in infants. The rate of decay of RSV-specific maternal antibodies (RSV-matAb), the factors affecting cord blood levels, and the relationship between these levels and protection from infection are poorly defined. Methods A birth cohort (n = 635) in rural Kenya, was studied intensively to monitor infections and describe age-related serological characteristics. RSV specific IgG antibody (Ab) in serum was measured by the enzyme linked immunosorbent assay (ELISA) in cord blood, consecutive samples taken 3 monthly, and in paired acute and convalescent samples. A linear regression model was used to calculate the rate of RSV-matAb decline. The effect of risk factors on cord blood titres was investigated. Results The half-life of matAb in the Kenyan cohort was calculated to be 79 days (95% confidence limits (CL): 76–81 days). Ninety seven percent of infants were born with RSV-matAb. Infants who subsequently experienced an infection in early life had significantly lower cord titres of anti-RSV Ab in comparison to infants who did not have any incident infection in the first 6 months (P = 0.011). RSV infections were shown to have no effect on the rate of decay of RSV-matAb. Conclusion Maternal-specific RSV Ab decline rapidly following birth. However, we provide evidence of protection against severe disease by RSV-matAb during the first 6–7 months. This suggests that boosting maternal-specific Ab by RSV vaccination may be a useful strategy to consider

PD-L1 testing for lung cancer in the UK: recognizing the challenges for implementation.

A new approach to the management of non-small-cell lung cancer (NSCLC) has recently emerged that works by manipulating the immune checkpoint controlled by programmed death receptor 1 (PD-1) and its ligand programmed death ligand 1 (PD-L1). Several drugs targeting PD-1 (pembrolizumab and nivolumab) or PD-L1 (atezolizumab, durvalumab, and avelumab) have been approved or are in the late stages of development. Inevitably, the introduction of these drugs will put pressure on healthcare systems, and there is a need to stratify patients to identify those who are most likely to benefit from such treatment. There is evidence that responsiveness to PD-1 inhibitors may be predicted by expression of PD-L1 on neoplastic cells. Hence, there is considerable interest in using PD-L1 immunohistochemical staining to guide the use of PD-1-targeted treatments in patients with NSCLC. This article reviews the current knowledge about PD-L1 testing, and identifies current research requirements. Key factors to consider include the source and timing of sample collection, pre-analytical steps (sample tracking, fixation, tissue processing, sectioning, and tissue prioritization), analytical decisions (choice of biomarker assay/kit and automated staining platform, with verification of standardized assays or validation of laboratory-devised techniques, internal and external quality assurance, and audit), and reporting and interpretation of the results. This review addresses the need for integration of PD-L1 immunohistochemistry with other tests as part of locally agreed pathways and protocols. There remain areas of uncertainty, and guidance should be updated regularly as new information becomes available

Expansion of magnetic clouds in the outer heliosphere

A large amount of magnetized plasma is frequently ejected from the Sun as coronal mass ejections (CMEs). Some of these ejections are detected in the solar wind as magnetic clouds (MCs) that have flux rope signatures. Magnetic clouds are structures that typically expand in the inner heliosphere. We derive the expansion properties of MCs in the outer heliosphere from one to five astronomical units to compare them with those in the inner heliosphere. We analyze MCs observed by the Ulysses spacecraft using insitu magnetic field and plasma measurements. The MC boundaries are defined in the MC frame after defining the MC axis with a minimum variance method applied only to the flux rope structure. As in the inner heliosphere, a large fraction of the velocity profile within MCs is close to a linear function of time. This is indicative of} a self-similar expansion and a MC size that locally follows a power-law of the solar distance with an exponent called zeta. We derive the value of zeta from the insitu velocity data. We analyze separately the non-perturbed MCs (cases showing a linear velocity profile almost for the full event), and perturbed MCs (cases showing a strongly distorted velocity profile). We find that non-perturbed MCs expand with a similar non-dimensional expansion rate (zeta=1.05+-0.34), i.e. slightly faster than at the solar distance and in the inner heliosphere (zeta=0.91+-0.23). The subset of perturbed MCs expands, as in the inner heliosphere, at a significantly lower rate and with a larger dispersion (zeta=0.28+-0.52) as expected from the temporal evolution found in numerical simulations. This local measure of the expansion also agrees with the distribution with distance of MC size,mean magnetic field, and plasma parameters. The MCs interacting with a strong field region, e.g. another MC, have the most variable expansion rate (ranging from compression to over-expansion)

On the Brightness and Waiting-time Distributions of a Type III Radio Storm observed by STEREO/WAVES

Type III solar radio storms, observed at frequencies below approximately 16 MHz by space borne radio experiments, correspond to the quasi-continuous, bursty emission of electron beams onto open field lines above active regions. The mechanisms by which a storm can persist in some cases for more than a solar rotation whilst exhibiting considerable radio activity are poorly understood. To address this issue, the statistical properties of a type III storm observed by the STEREO/WAVES radio experiment are presented, examining both the brightness distribution and (for the first time) the waiting-time distribution. Single power law behavior is observed in the number distribution as a function of brightness; the power law index is approximately 2.1 and is largely independent of frequency. The waiting-time distribution is found to be consistent with a piecewise-constant Poisson process. This indicates that during the storm individual type III bursts occur independently and suggests that the storm dynamics are consistent with avalanche type behavior in the underlying active region.Comment: 14 pages, 4 figures, 1 table. Accepted for publication in Astrophysical Journal Letter

Decreased STARD10 expression is associated with defective insulin secretion in humans and mice

Genetic variants near ARAP1 (CENTD2) and STARD10 influence type 2 diabetes (T2D) risk. The risk alleles impair glucose-induced insulin secretion and, paradoxically but characteristically, are associated with decreased proinsulin:insulin ratios, indicating improved proinsulin conversion. Neither the identity of the causal variants nor the gene(s) through which risk is conferred have been firmly established. Whereas ARAP1 encodes a GTPase activating protein, STARD10 is a member of the steroidogenic acute regulatory protein (StAR)-related lipid transfer protein family. By integrating genetic fine-mapping and epigenomic annotation data and performing promoter-reporter and chromatin conformational capture (3C) studies in β cell lines, we localize the causal variant(s) at this locus to a 5 kb region that overlaps a stretch-enhancer active in islets. This region contains several highly correlated T2D-risk variants, including the rs140130268 indel. Expression QTL analysis of islet transcriptomes from three independent subject groups demonstrated that T2D-risk allele carriers displayed reduced levels of STARD10 mRNA, with no concomitant change in ARAP1 mRNA levels. Correspondingly, β-cell-selective deletion of StarD10 in mice led to impaired glucose-stimulated Ca2+ dynamics and insulin secretion and recapitulated the pattern of improved proinsulin processing observed at the human GWAS signal. Conversely, overexpression of StarD10 in the adult β cell improved glucose tolerance in high fat-fed animals. In contrast, manipulation of Arap1 in β cells had no impact on insulin secretion or proinsulin conversion in mice. This convergence of human and murine data provides compelling evidence that the T2D risk associated with variation at this locus is mediated through reduction in STARD10 expression in the β cell