BackgroundA double-blind, placebo-controlled trial that involved 38,546 subjects ⩾60 years old demonstrated efficacy of a high-potency live-attenuated Oka/Merck varicella-zoster virus (VZV) vaccine. ...The trial included an immunology substudy to determine the relationship of VZV-specific immune responses to vaccination and clinical outcome MethodsThe immunology substudy enrolled 1395 subjects at 2 sites where blood samples obtained prior to vaccination, at 6 weeks after vaccination, and at 1, 2, and 3 years thereafter were tested for VZV-specific cell-mediated immunity (VZV-CMI) by γ-interferon ELISPOT and responder cell frequency assays and for VZV antibody by glycoprotein ELISA ResultsVZV-CMI and VZV antibodies were significantly increased in vaccine recipients at 6 weeks after vaccination. The vaccine-induced increases in VZV-CMI persisted during the 3 years of follow-up, although their magnitude decreased over time. The magnitude of these VZV-specific immune responses was greater in subjects 60–69 years old than in subjects ⩾70 years old ConclusionsThe zoster vaccine induced a significant increase in VZV-CMI and VZV antibody. The magnitude and duration of the boost in VZV-CMI in vaccine recipients and the relationship of this boost to age paralleled the clinical effects of the vaccine observed during the efficacy trial. These findings support the hypothesis that boosting VZV-CMI protects older adults against herpes zoster and postherpetic neuralgia
We investigate numerically the transient linear growth of three-dimensional (3D) perturbations in a homogeneous time-evolving mixing layer in order to identify which perturbations are optimal in ...terms of their kinetic energy gain over a finite, predetermined time interval. We model the mixing layer with an initial parallel velocity distribution
$\mathbi{U}(y)= {U}_{0} \tanh (y/ d)\mathbi{e}_{x}$
with Reynolds number
$Re= {U}_{0} d/ \nu = 1000$
, where
$\nu $
is the kinematic viscosity of the fluid. We consider a range of time intervals on both a constant ‘frozen’ base flow and a time-dependent two-dimensional (2D) flow associated with the growth and nonlinear saturation of two wavelengths of the most-unstable eigenmode of linear theory of the initial parallel velocity distribution, which rolls up into two classical Rayleigh instabilities commonly referred to as Kelvin–Helmholtz (KH) billows, which eventually pair to form a larger vortex. For short times, the most-amplified perturbations on the frozen
$\tanh $
profile are inherently 3D, and are most appropriately described as oblique wave ‘OL’ perturbations which grow through a combination of the Orr and lift-up mechanisms, while for longer times, the optimal perturbations are 2D and similar to the KH normal mode, with a slight enhancement of gain. For the time-evolving KH base flow, OL perturbations continue to dominate over sufficiently short time intervals. However, for longer time intervals which involve substantial evolution of the primary KH billows, two broad classes of inherently 3D linear optimal perturbation arise, associated at low wavenumbers with the well-known core-centred elliptical translative instability, and at higher wavenumbers with the braid-centred hyperbolic instability. The hyperbolic perturbation is relatively inefficient in exploiting the gain of the OL perturbations, and so only dominates the smaller wavenumber (ultimately) core-centred perturbations when the time evolution of the base flow or the start time of the optimization interval does not allow the OL perturbations much opportunity to grow. When the OL perturbations can grow, they initially grow in the braid, and then trigger an elliptical core-centred perturbation by a strong coupling with the primary KH billow. If the optimization time interval includes pairing of the primary billows, the secondary elliptical perturbations are strongly suppressed during the pairing event, due to the significant disruption of the primary billow cores during pairing.
Several strands of evidence question the dogma that human mitochondrial DNA (mtDNA) is inherited exclusively down the maternal line, most recently in three families where several individuals harbored ...a 'heteroplasmic haplotype' consistent with biparental transmission. Here we report a similar genetic signature in 7 of 11,035 trios, with allelic fractions of 5-25%, implying biparental inheritance of mtDNA in 0.06% of offspring. However, analysing the nuclear whole genome sequence, we observe likely large rare or unique nuclear-mitochondrial DNA segments (mega-NUMTs) transmitted from the father in all 7 families. Independently detecting mega-NUMTs in 0.13% of fathers, we see autosomal transmission of the haplotype. Finally, we show the haplotype allele fraction can be explained by complex concatenated mtDNA-derived sequences rearranged within the nuclear genome. We conclude that rare cryptic mega-NUMTs can resemble paternally mtDNA heteroplasmy, but find no evidence of paternal transmission of mtDNA in humans.
The safety and immunogenecity of a booster dose of live attenuated varicella-zoster virus (VZV) vaccine was evaluated in 196 healthy subjects, ⩾60 years old, who had already received a VZV vaccine >5 ...years before. This repeat booster dose was well tolerated. Cell-mediated immunity (CMI) to VZV was measured by an interferon-γ (IFN-γ) enzyme-linked immunosorbent spot-forming cell (ELISPOT) assay and a limiting dilution responder cell frequency (RCF) assay. Prevaccination responses decreased as a function of increasing age but were detectable in all subjects by use of the IFN-γ ELISPOT assay. In most subjects, VZV-specific CMI was increased at 6 weeks postvaccination. The magnitude of the vaccine-induced IFN-γ ELISPOT response was inversely related to prevaccination values. Although there was a significant correlation between the IFN-γ ELISPOT and RCF assays, the ELISPOT assay had greater sensitivity and a wider dynamic range. A live attenuated VZV vaccine is safe and immunogenic in an elderly population, and the vaccine-induced immunity may be monitored by the IFN-γ ELISPOT assay
Whole-genome sequencing (WGS) permits comprehensive cancer genome analyses, revealing mutational signatures, imprints of DNA damage and repair processes that have arisen in each patient's cancer. We ...performed mutational signature analyses on 12,222 WGS tumor-normal matched pairs, from patients recruited via the UK National Health Service. We contrasted our results to two independent cancer WGS datasets, the International Cancer Genome Consortium (ICGC) and Hartwig Foundation, involving 18,640 WGS cancers in total. Our analyses add 40 single and 18 double substitution signatures to the current mutational signature tally. Critically, we show for each organ, that cancers have a limited number of 'common' signatures and a long tail of 'rare' signatures. We provide a practical solution for utilizing this concept of common versus rare signatures in future analyses.
Abstract Alpha-tubulin 4A encoding gene (TUBA4A) has been associated with familial amyotrophic lateral sclerosis (fALS) and fronto-temporal dementia (FTD), based on identification of likely ...pathogenic variants in patients from distinct ALS and FTD cohorts. By screening a multicentric French cohort of 448 unrelated probands presenting with cerebellar ataxia, we identified ultra-rare TUBA4A missense variants, all being absent from public databases and predicted pathogenic by multiple in-silico tools. In addition, gene burden analyses in the 100,000 genomes project (100KGP) showed enrichment of TUBA4A rare variants in the inherited ataxia group compared to controls (OR: 57.0847 10.2- 576.7; p = 4.02 x10-07). Altogether, we report 12 patients presenting with spasticity and/or cerebellar ataxia and harboring a predicted pathogenic TUBA4A missense mutation, including 5 confirmed de novo cases and a mutation previously reported in a large family presenting with spastic ataxia. Cultured fibroblasts from 3 patients harboring distinct TUBA4A missense showed significant alterations in microtubule organisation and dynamics, providing insight of TUBA4A variants pathogenicity. Our data confirm the identification of a hereditary spastic ataxia disease gene with variable age of onset, expanding the clinical spectrum of TUBA4A associated phenotypes.
Abstract
Systematic variations in the crystal cargo and whole-rock isotopic compositions of mantle-derived basalts in the intraplate Dunedin Volcano (New Zealand) indicate the influence of a complex ...mantle-to-crust polybaric plumbing system. Basaltic rocks define a compositional spectrum from low-alkali basalts through mid-alkali basalts to high-alkali basalts. High-alkali basalts display clinopyroxene crystals with sector (hourglass) and oscillatory zoning (Mg#61–82) as well as Fe-rich green cores (Mg#43–69), whereas low-alkali basalts are characterized by clinopyroxenes with unzoned overgrowths (Mg#69–83) on resorbed mafic cores (Mg#78–88), coexisting with reversely zoned plagioclase crystals (An43–68 to An60–84 from core to rim). Complex magma dynamics are indicated by distinctive compositional variations in clinopyroxene phenocrysts, with Cr-rich zones (Mg#74–87) indicating continuous recharge by more mafic magmas. Crystallization of olivine, clinopyroxene and titanomagnetite occurred within a polybaric plumbing system extending from upper mantle to mid-crustal depths (485–1059 MPa and 1147–1286°C), whereas crystallization of plagioclase with subordinate clinopyroxene and titanomagnetite proceeded towards shallower crustal levels. The compositions of high-alkali basalts and mid-alkali basalts resemble those of ocean island basalts and are characterized by FOZO-HIMU isotopic signatures (87Sr/86Sri = 0.70277–0.70315, 143Nd/144Ndi = 0.51286–0.51294 and 206Pb/204Pb = 19.348–20.265), whereas low-alkali basalts have lower incompatible element abundances and isotopic compositions trending towards EMII (87Sr/86Sri = 0.70327–70397, 143Nd/144Ndi = 0.51282–0.51286 and 206Pb/204Pb = 19.278–19.793). High- and mid-alkali basalt magmas mostly crystallized in the lower crust, whereas low-alkali basalt magma recorded deeper upper mantle clinopyroxene crystallization before eruption. The variable alkaline character and isotope composition may result from interaction of low-alkaline melts derived from the asthenosphere with melts derived from lithospheric mantle, possibly initiated by asthenospheric melt percolation. The transition to more alkaline compositions was induced by variable degrees of melting of metasomatic lithologies in the lithospheric mantle, leading to eruption of predominantly small-volume, high-alkali magmas at the periphery of the volcano. Moreover, the lithosphere imposed a filtering effect on the alkalinity of these intraplate magmas. As a consequence, the eruption of low-alkali basalts with greater asthenospheric input was concentrated at the centre of the volcano, where the plumbing system was more developed.
Background. The Depression Substudy of the Shingles Prevention Study (SPS) was designed to evaluate the association between major depression and immune responses to a high-titer live attenuated ...varicella zoster virus (VZV) vaccine (zoster vaccine), which boosts cell-mediated immunity (CMI) to VZV and decreases the incidence and severity of herpes zoster (HZ). The Depression Substudy was a 2-year longitudinal cohort study in 92 community-dwelling adults ≥60 years of age who were enrolled in the SPS, a large, double-blind, placebo-controlled Veterans Affairs Cooperative zoster vaccine efficacy study. Methods. Forty subjects with major depressive disorder, stratified by use of antidepressant medications, and 52 age- and sex-matched controls with no history of depression or other mental illness had their VZV-CMI measured prior to vaccination with zoster vaccine or placebo and at 6 weeks, 1 year, and 2 years postvaccination. Results. Depressed subjects who were not treated with antidepressant medications had lower levels of VZV-CMI following administration of zoster vaccine than nondepressed controls or depressed subjects receiving antidepressants even when antidepressant medications failed to alter depressive symptom severity (P < .005). Similar results were obtained taking into account the time-varying status of depression and use of antidepressant medications, as well as changes in depressive symptoms, during the postvaccination period. Conclusions. Depressed patients have diminished VZV-CMI responses to zoster vaccine, and treatment with antidepressant medication is associated with normalization of these responses. Because higher levels of VZV-CMI correlate with lower risk and severity of HZ, untreated depression may increase the risk and severity of HZ and reduce the efficacy of zoster vaccine.
Cilia are highly specialized cellular organelles that serve multiple functions in human development and health. Their central importance in the body is demonstrated by the occurrence of a diverse ...range of developmental disorders that arise from defects of cilia structure and function, caused by a range of different inherited mutations found in more than 150 different genes. Genetic analysis has rapidly advanced our understanding of the cell biological basis of ciliopathies over the past two decades, with more recent technological advances in genomics rapidly accelerating this progress. The 100,000 Genomes Project was launched in 2012 in the UK to improve diagnosis and future care for individuals affected by rare diseases like ciliopathies, through whole genome sequencing (WGS). In this review we discuss the potential promise and medical impact of WGS for ciliopathies and report on current progress of the 100,000 Genomes Project, reviewing the medical, technical and ethical challenges and opportunities that new, large scale initiatives such as this can offer.
Uric acid (UA) is the final catabolic product of purine metabolism and elevated levels are associated with diabetes and cardiovascular disease. A recent meta-analysis of genome-wide association ...studies totalling 28 141 participants identified five novel loci associated with serum UA levels. In our population-based cohort of 7795 subjects, we replicated four of these five loci; PDZK1 (rs12129861, P = 1.07 × 10−3), glucokinase regulator protein (GCKR) (rs780094, P = 4.83 × 10−4), SLC16A9 (rs742132, P = 0.047) and SLC22A11 (rs17300741, P = 6.13 × 10−3), but not LRRC16A (rs742132, P = 0.645). Serum UA concentration is a complex trait, closely associated to renal UA handling (fractional UA excretion, P < 1 × 10−300), renal function (serum creatinine, P < 1 × 10−300) and the metabolic syndrome (including fasting insulin, P = 2.48 × 10−232; insulin resistance, P = 2.51 × 10−258; waist circumference, P < 1 × 10−300) and systolic blood pressure (P = 1.93 × 10−219). Together these factors explain 67% of the variance in UA levels. Therefore, we sought to determine the potential contribution of these factors to the association of these novel loci with UA levels, by including them as additional explanatory variables in our analyses, and by considering them as alternative response variables. The association with the GCKR locus is attenuated by serum triglycerides and fractional UA excretion. We also observed the GCKR locus to be associated with total cholesterol (P = 7.52 × 10−6), triglycerides (P = 2.65 × 10−9), fasting glucose (P = 0.011), fractional UA excretion (P = 3.36 × 10−5) and high-sensitive CRP (P = 1.18 × 10−3) also after adjusting for serum UA levels. We argue that GCKR locus affects serum UA levels through a factor that also affects triglycerides.
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