We aimed to increase our understanding of the genetic determinants of vitamin D levels by undertaking a large-scale genome-wide association study (GWAS) of serum 25 hydroxyvitamin D (25OHD). To do ...so, we used imputed genotypes from 401,460 white British UK Biobank participants with available 25OHD levels, retaining single-nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) > 0.1% and imputation quality score > 0.3. We performed a linear mixed model GWAS on standardized log-transformed 25OHD, adjusting for age, sex, season of measurement, and vitamin D supplementation. These results were combined with those from a previous GWAS including 42,274 Europeans. In silico functional follow-up of the GWAS results was undertaken to identify enrichment in gene sets, pathways, and expression in tissues, and to investigate the partitioned heritability of 25OHD and its shared heritability with other traits. Using this approach, the SNP heritability of 25OHD was estimated to 16.1%. 138 conditionally independent SNPs were detected (p value < 6.6 × 10−9) among which 53 had MAF < 5%. Single variant association signals mapped to 69 distinct loci, among which 63 were previously unreported. We identified enrichment in hepatic and lipid metabolism gene pathways and enriched expression of the 25OHD genes in liver, skin, and gastrointestinal tissues. We observed partially shared heritability between 25OHD and socio-economic traits, a feature which may be mediated through time spent outdoors. Therefore, through a large 25OHD GWAS, we identified 63 loci that underline the contribution of genes outside the vitamin D canonical metabolic pathway to the genetic architecture of 25OHD.
For generations the study of vocal development and its role in language has been conducted laboriously, with human transcribers and analysts coding and taking measurements from small recorded ...samples. Our research illustrates a method to obtain measures of early speech development through automated analysis of massive quantities of day-long audio recordings collected naturalistically in children's homes. A primary goal is to provide insights into the development of infant control over infrastructural characteristics of speech through large-scale statistical analysis of strategically selected acoustic parameters. In pursuit of this goal we have discovered that the first automated approach we implemented is not only able to track children's development on acoustic parameters known to play key roles in speech, but also is able to differentiate vocalizations from typically developing children and children with autism or language delay. The method is totally automated, with no human intervention, allowing efficient sampling and analysis at unprecedented scales. The work shows the potential to fundamentally enhance research in vocal development and to add a fully objective measure to the battery used to detect speech-related disorders in early childhood. Thus, automated analysis should soon be able to contribute to screening and diagnosis procedures for early disorders, and more generally, the findings suggest fundamental methods for the study of language in natural environments.
This report will review the history of antibiotic growth promoter (AGP) use in the animal industry, concerns about development of antimicrobial resistance, and response in the European Union and ...United States to these concerns. A brief description of the history of legislation regarding feed use of antimicrobials in Denmark and the experience of animal producers following the 1998 ban will serve to illustrate the consequences on animal performance and health of withdrawing the approval for this use. The biological basis for antibiotic effects on animal growth efficiency will consider effects on intestinal microbiota and effects on the host animal and will use the germ-free animal to illustrate effects of the conventional microflora. The probability that no single compound will replace all of the functions of antimicrobial growth promoters will be considered, and methods to consolidate and analyze the enlarging database will be discussed.
ABSTRACT We present 1625 new 15 GHz (2 cm) VLBA images of 295 jets associated with active galactic nuclei (AGNs) from the MOJAVE and 2 cm VLBA surveys, spanning observations between 1994 August 31 ...and 2013 August 20. For 274 AGNs with at least 5 VLBA epochs, we have analyzed the kinematics of 961 individual bright features in their parsec-scale jets. A total of 122 of these jets have not been previously analyzed by the MOJAVE program. In the case of 451 jet features that had at least 10 epochs, we also examined their kinematics for possible accelerations. At least half of the well-sampled features have non-radial and/or accelerating trajectories, indicating that non-ballistic motion is common in AGN jets. Since it is impossible to extrapolate any accelerations that occurred before our monitoring period, we could only determine reliable ejection dates for of those features that had significant proper motions. The distribution of maximum apparent jet speeds in all 295 AGNs measured by our program to date is peaked below , with very few jets with apparent speeds above . The fastest speed in our survey is , measured in the jet of the quasar PKS 0805−07, and is indicative of a maximum jet Lorentz factor of ∼50 in the parent population. An envelope in the maximum jet speed versus redshift distribution of our sample provides additional evidence of this upper limit to the speeds of radio-emitting regions in parsec-scale AGN jets. The Fermi-LAT-detected gamma-ray AGNs in our sample have, on average, higher jet speeds than non-LAT-detected AGNs, indicating a strong correlation between parsec-scale jet speed and the gamma-ray Doppler boosting factor. We have identified 11 moderate-redshift ( ) AGNs with fast apparent speeds ( ) that are strong candidates for future TeV gamma-ray detection. Of the five gamma-ray loud narrow-lined Seyfert I AGNs in our sample, three show highly superluminal jet motions, while the others have sub-luminal speeds. This indicates that some narrow-lined Seyfert I AGNs possess powerful jets with Lorentz factors in excess of 10, and viewing angles less than , consistent with those of typical BL Lac objects and flat-spectrum radio quasars.
Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus capable of causing a severe hemorrhagic fever disease in humans. There are currently no licensed vaccines to prevent ...CCHFV-associated disease. We developed a DNA vaccine expressing the M-segment glycoprotein precursor gene of CCHFV and assessed its immunogenicity and protective efficacy in two lethal mouse models of disease: type I interferon receptor knockout (IFNAR-/-) mice; and a novel transiently immune suppressed (IS) mouse model. Vaccination of mice by muscle electroporation of the M-segment DNA vaccine elicited strong antigen-specific humoral immune responses with neutralizing titers after three vaccinations in both IFNAR-/- and IS mouse models. To compare the protective efficacy of the vaccine in the two models, groups of vaccinated mice (7-10 per group) were intraperitoneally (IP) challenged with a lethal dose of CCHFV strain IbAr 10200. Weight loss was markedly reduced in CCHFV DNA-vaccinated mice as compared to controls. Furthermore, whereas all vector-control vaccinated mice succumbed to disease by day 5, the DNA vaccine protected >60% of the animals from lethal disease. Mice from both models developed comparable levels of antibodies, but the IS mice had a more balanced Th1/Th2 response to vaccination. There were no statistical differences in the protective efficacies of the vaccine in the two models. Our results provide the first comparison of these two mouse models for assessing a vaccine against CCHFV and offer supportive data indicating that a DNA vaccine expressing the glycoprotein genes of CCHFV elicits protective immunity against CCHFV.
Cell Biology of the Plant Nucleus Meier, Iris; Richards, Eric J; Evans, David E
Annual review of plant biology,
04/2017, Letnik:
68, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The eukaryotic nucleus is enclosed by the nuclear envelope, which is perforated by the nuclear pores, the gateways of macromolecular exchange between the nucleoplasm and cytoplasm. The nucleoplasm is ...organized in a complex three-dimensional fashion that changes over time and in response to stimuli. Within the cell, the nucleus must be viewed as an organelle (albeit a gigantic one) that is a recipient of cytoplasmic forces and capable of morphological and positional dynamics. The most dramatic reorganization of this organelle occurs during mitosis and meiosis. Although many of these aspects are less well understood for the nuclei of plants than for those of animals or fungi, several recent discoveries have begun to place our understanding of plant nuclei firmly into this broader cell-biological context.
The etiology of multiple sclerosis (MS) involves a complex interplay of genetic and environmental factors. Epidemiologic studies have furthered our understanding of these risk factors but remain ...limited by residual confounding and potential for reverse causation, particularly in MS where time of disease onset is not known. Mendelian randomization (MR) uses genetic variants to study the causal effect of modifiable exposures on an outcome. This method avoids some of the limitations of classical epidemiology and can strengthen causal inference. Here, we introduce the basic concepts of MR and review its contributions to the field of MS. Indeed, several studies using MR have now provided support for a causal role for low vitamin D level and obesity in the development of MS.
Fermi has provided the largest sample of gamma -ray-selected blazars to date. In this work we use a complete sample of flat spectrum radio quasars (FSRQs) detected during the first year of operation ...to determine the luminosity function (LF) and its evolution with cosmic time. The number density of FSRQs grows dramatically up to redshift ~0.5-2.0 and declines thereafter. The redshift of the peak in the density is luminosity dependent, with more luminous sources peaking at earlier times; thus the LF of gamma -ray FSRQs follows a luminosity-dependent density evolution similar to that of radio-quiet active galactic nuclei. Also, using data from the Swift Burst Alert Telescope we derive the average spectral energy distribution (SED) of FSRQs in the 10 keV-300 GeV band and show that there is no correlation between the luminosity at the peak of the gamma -ray emission component and its peak frequency. Using this luminosity-independent SED with the derived LF allows us to predict that the contribution of FSRQs to the Fermi isotropic gamma -ray background is 9.3 super(+1.6) sub(-1.0)% (+ or -3% systematic uncertainty) in the 0.1-100 GeV band. Finally we determine the LF of unbeamed FSRQs, finding that FSRQs have an average Lorentz factor of gamma = 11.7 super(+3.3) sub(-2.2), that most are seen within 5degrees of the jet axis, and that they represent only ~0.1 % of the parent population.
Sympatric speciation illustrates how natural and sexual selection may create new species in isolation without geographic barriers. However, recent genomic reanalyses of classic examples of sympatric ...speciation reveal complex histories of secondary gene flow from outgroups into the radiation. In contrast, the rich theoretical literature on this process distinguishes among a diverse range of models based on simple genetic histories and different types of reproductive isolating barriers. Thus, there is a need to revisit how to connect theoretical models of sympatric speciation and their predictions to empirical case studies in the face of widespread gene flow. Here, theoretical differences among different types of sympatric speciation and speciation‐with‐gene‐flow models are reviewed and summarized, and genomic analyses are proposed for distinguishing which models apply to case studies based on the timing and function of adaptive introgression. Investigating whether secondary gene flow contributed to reproductive isolation is necessary to test whether predictions of theory are ultimately borne out in nature.
Sympatric speciation means two different things to empirical and theoretical biologists. Recent genomic analyses of classic sympatric speciation examples reveal complex histories of secondary gene flow from outgroups. It is argued that reconciling diverse theoretical models with existing empirical examples requires investigating the role that gene flow played in the process.
Most replicated genetic determinants for type 1 diabetes are common (minor allele frequency MAF >5%). We aimed to identify novel rare or low-frequency (MAF <5%) single nucleotide polymorphisms with ...large effects on risk of type 1 diabetes. We undertook deep imputation of genotyped data followed by genome-wide association testing and meta-analysis of 9,358 type 1 diabetes case and 15,705 control subjects from 12 European cohorts. Candidate variants were replicated in a separate cohort of 4,329 case and 9,543 control subjects. Our meta-analysis identified 27 independent variants outside the MHC, among which 3 were novel and had MAF <5%. Three of these variants replicated with
< 0.05 and
<
In silico analysis prioritized a rare variant at 2q24.3 (rs60587303 C, MAF 0.5%) within the first intron of
with an effect size comparable with those of common variants in the
and
loci (combined from the discovery and replication cohorts estimate of odds ratio OR
1.97, 95% CI 1.58-2.47,
= 2.9 × 10
). Pharmacological inhibition of
activity in primary murine T cells augmented effector responses through enhancement of interleukin 2 signaling. These findings provide insight into the genetic architecture of type 1 diabetes and have identified rare variants having a large effect on disease risk.
PDF
