Induced hyperlipaemia and immune challenge in locusts

Injections of immunogens, such as β-1,3-glucan or lipopolysaccharide (LPS), bring about a marked hyperlipaemia with associated changes in lipophorins and apolipophorin-III in the haemolymph of Locusta migratoria. These changes are similar to those observed after injection of adipokinetic hormone (AKH). The possibility that endogenous AKH is released as part of the response to these immunogens is investigated using passive immunisation against AKH-I, and measurement of AKH-I titre in the haemolymph after injection of immunogens. The data presented show that, despite the similarity of the changes brought about by the presence of immunogens in the haemolymph to those brought about by AKH, there is no release of endogenous AKH after injection of laminarin or LPS. A direct effect of the immunogens on release of neutral lipids by the fat body cannot be demonstrated in vitro, and the mechanism by which hyperlipaemia is induced during immune challenge remains uncertain

Effects of Scavenging, Entrainment, and Aqueous Chemistry on Peroxides and Formaldehyde in Deep Convective Outflow over the Central and Southeast U.S.

Deep convective transport of gaseous precursors to ozone (O3) and aerosols to the upper troposphere is affected by liquid- and mixed-phase scavenging, entrainment of free tropospheric air, and aqueous chemistry. The contributions of these processes are examined using aircraft measurements obtained in storm inflow and outflow during the 2012 Deep Convective Clouds and Chemistry (DC3) experiment combined with high resolution (dx <= 3 km) WRF-Chem simulations of a severe storm, an airmass storm, and a mesoscale convective system (MCS). The simulation results for the MCS suggest that formaldehyde (CH2O) is not retained in ice when cloud water freezes, in agreement with previous studies of the severe storm. By analyzing WRF-Chem trajectories, the effects of scavenging, entrainment, and aqueous chemistry on outflow mixing ratios of CH2O, methyl hydroperoxide (CH3OOH), and hydrogen peroxide (H2O2) are quantified. Liquid-phase microphysical scavenging was the dominant process reducing CH2O and H2O2 outflow mixing ratios in all three storms. Aqueous chemistry did not significantly affect outflow mixing ratios of all three species. In the severe storm and MCS, the higher than expected reductions in CH3OOH mixing ratios in the storm cores were primarily due to entrainment of low background CH3OOH. In the airmass storm, lower CH3OOH and H2O2 scavenging efficiencies (SEs) than in the MCS were partly due to entrainment of higher background CH3OOH and H2O2. Overestimated rain and hail production in WRF-Chem reduces the confidence in ice retention fraction values determined for the peroxides and CH2O

The pathogenesis of low pathogenicity H7 avian influenza viruses in chickens, ducks and turkeys

<p>Abstract</p> <p>Background</p> <p>Avian influenza (AI) viruses infect numerous avian species, and low pathogenicity (LP) AI viruses of the H7 subtype are typically reported to produce mild or subclinical infections in both wild aquatic birds and domestic poultry. However relatively little work has been done to compare LPAI viruses from different avian species for their ability to cause disease in domestic poultry under the same conditions. In this study twelve H7 LPAI virus isolates from North America were each evaluated for their comparative pathogenesis in chickens, ducks, and turkeys.</p> <p>Results</p> <p>All 12 isolates were able to infect all three species at a dose of 10⁶50% egg infectious doses based on seroconversion, although not all animals seroconverted with each isolate-species combination. The severity of disease varied among isolate and species combinations, but there was a consistent trend for clinical disease to be most severe in turkeys where all 12 isolates induced disease, and mortality was observed in turkeys exposed to 9 of the 12 viruses. Turkeys also shed virus by the oral and cloacal routes at significantly higher titers than either ducks or chickens at numerous time points. Only 3 isolates induced observable clinical disease in ducks and only 6 isolates induced disease in chickens, which was generally very mild and did not result in mortality. Full genome sequence was completed for all 12 isolates and some isolates did have features consistent with adaptation to poultry (e.g. NA stalk deletions), however none of these features correlated with disease severity.</p> <p>Conclusions</p> <p>The data suggests that turkeys may be more susceptible to clinical disease from the H7 LPAI viruses included in this study than either chickens or ducks. However the severity of disease and degree of virus shed was not clearly correlated with any isolate or group of isolates, but relied on specific species and isolate combinations.</p

Lupus risk variants in the PXK locus alter B-cell receptor internalization

Genome wide association studies have identified variants in PXK that confer risk for humoral autoimmune diseases, including systemic lupus erythematosus (SLE or lupus), rheumatoid arthritis and more recently systemic sclerosis. While PXK is involved in trafficking of epidermal growth factor Receptor (EGFR) in COS-7 cells, mechanisms linking PXK to lupus pathophysiology have remained undefined. In an effort to uncover the mechanism at this locus that increases lupus-risk, we undertook a fine-mapping analysis in a large multi-ancestral study of lupus patients and controls. We define a large (257kb) common haplotype marking a single causal variant that confers lupus risk detected only in European ancestral populations and spans the promoter through the 3' UTR of PXK. The strongest association was found at rs6445972 with P &lt; 4.62 × 10-10, OR 0.81 (0.75 - 0.86). Using stepwise logistic regression analysis, we demonstrate that one signal drives the genetic association in the region. Bayesian analysis confirms our results, identifying a 95% credible set consisting of 172 variants spanning 202 kb. Functionally, we found that PXK operates on the B-cell antigen receptor (BCR); we confirmed that PXK influenced the rate of BCR internalization. Furthermore, we demonstrate that individuals carrying the risk haplotype exhibited a decreased rate of BCR internalization, a process known to impact B cell survival and cell fate. Taken together, these data define a new candidate mechanism for the genetic association of variants around PXK with lupus risk and highlight the regulation of intracellular trafficking as a genetically regulated pathway mediating human autoimmunity

Characteristics and Impact of Drug Detailing for Gabapentin

BACKGROUND: Sales visits by pharmaceutical representatives (“drug detailing”) are common, but little is known about the content of these visits or about the impact of visit characteristics on prescribing behavior. In this study, we evaluated the content and impact of detail visits for gabapentin by analyzing market research forms completed by physicians after receiving a detail visit for this drug. METHODS AND FINDINGS: Market research forms that describe detail visits for gabapentin became available through litigation that alleged that gabapentin was promoted for “off-label” uses. Forms were available for 97 physicians reporting on 116 detail visits between 1995 and 1999. Three-quarters of recorded visits (91/116) occurred in 1996. Two-thirds of visits (72/107) were 5 minutes or less in duration, 65% (73/113) were rated of high informational value, and 39% (42/107) were accompanied by the delivery or promise of samples. During the period of this study, gabapentin was approved by the US Food and Drug Administration only for the adjunctive treatment of partial seizures, but in 38% of visits (44/115) the “main message” of the visit involved at least one off-label use. After receiving the detail visit, 46% (50/108) of physicians reported the intention to increase their prescribing or recommending of gabapentin in the future. In multivariable analysis, intent to increase future use or recommendation of gabapentin was associated with receiving the detail in a small group (versus one-on-one) setting and with low or absent baseline use of the drug, but not with other factors such as visit duration, discussion of “on-label” versus “off-label” content, and the perceived informational value of the presentation. CONCLUSIONS: Detail visits for gabapentin were of high perceived informational value and often involved messages about unapproved uses. Despite their short duration, detail visits were frequently followed by physician intentions to increase their future recommending or prescribing of the drug

A Pleistocene legacy structures variation in modern seagrass ecosystems

Distribution of Earth’s biomes is structured by the match between climate and plant traits, which in turn shape associated communities and ecosystem processes and services. However, that climate–trait match can be disrupted by historical events, with lasting ecosystem impacts. As Earth’s environment changes faster than at any time in human history, critical questions are whether and how organismal traits and ecosystems can adjust to altered conditions. We quantified the relative importance of current environmental forcing versus evolutionary history in shaping the growth form (stature and biomass) and associated community of eelgrass ( Zostera marina ), a widespread foundation plant of marine ecosystems along Northern Hemisphere coastlines, which experienced major shifts in distribution and genetic composition during the Pleistocene. We found that eelgrass stature and biomass retain a legacy of the Pleistocene colonization of the Atlantic from the ancestral Pacific range and of more recent within-basin bottlenecks and genetic differentiation. This evolutionary legacy in turn influences the biomass of associated algae and invertebrates that fuel coastal food webs, with effects comparable to or stronger than effects of current environmental forcing. Such historical lags in phenotypic acclimatization may constrain ecosystem adjustments to rapid anthropogenic climate change, thus altering predictions about the future functioning of ecosystems

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

A Pleistocene legacy structures variation in modern seagrass ecosystems

Distribution of Earth's biomes is structured by the match between climate and plant traits, which in turn shape associated communities and ecosystem processes and services. However, that climate-trait match can be disrupted by historical events, with lasting ecosystem impacts. As Earth's environment changes faster than at any time in human history, critical questions are whether and how organismal traits and ecosystems can adjust to altered conditions. We quantified the relative importance of current environmental forcing versus evolutionary history in shaping the growth form (stature and biomass) and associated community of eelgrass (Zostera marina), a widespread foundation plant of marine ecosystems along Northern Hemisphere coastlines, which experienced major shifts in distribution and genetic composition during the Pleistocene. We found that eelgrass stature and biomass retain a legacy of the Pleistocene colonization of the Atlantic from the ancestral Pacific range and of more recent within-basin bottlenecks and genetic differentiation. This evolutionary legacy in turn influences the biomass of associated algae and invertebrates that fuel coastal food webs, with effects comparable to or stronger than effects of current environmental forcing. Such historical lags in phenotypic acclimatization may constrain ecosystem adjustments to rapid anthropogenic climate change, thus altering predictions about the future functioning of ecosystems.This work was supported by the US NSF (OCE-1031061, OCE-1336206, OCE0-1336741, OCE-1336905) and the Smithsonian Institution. F.T. was supported by José Castillejo Award CAS14/00177. A.H.E. was supported by the FCT (Foundation for Science and Technology) through Project UIDB/04326/2020 and Contract CEECINST/00114/2018. This is Contribution 106 from the Smithsonian’s MarineGEO and Tennenbaum Marine Observatories Network and Contribution 4105 of the Virginia Institute of Marine Science, College of William & Mary