Exposure to illicit cocaine and its frequent adulterant, levamisole, is associated with ANCAs targeting neutrophil elastase (NE), neutropenia and vasculitic/thrombotic skin purpura. The mechanisms of ...cocaine/levamisole-associated autoimmunity (CLAA) are unknown. The aim of this study was to assess the ability of cocaine and levamisole to induce the release of neutrophil extracellular traps (NETs), a potential source of autoantigen and tissue injury.
We performed quantitative and qualitative assessment of NET formation in neutrophils from healthy donors exposed to either drug in vitro . In addition, IgG from sera of individuals with CLAA (CLAA-IgG) was assessed for its ability to enhance formation of, and to bind to, drug-induced NETs.
Both cocaine and levamisole could induce formation of NETs enriched in NE and, potentially, inflammatory mitochondrial DNA. Both drugs could also augment simultaneous release of B cell-activating factor belonging to the TNF family (BAFF). CLAA-IgG, but not IgG from healthy individuals, could potentiate drug-induced NETosis. Furthermore, CLAA-IgG, but not ANCA + control IgG, bound to drug-induced NETs in a pattern consistent with NE targeting.
Both cocaine and levamisole may contribute to the development of ANCAs by inducing release of potentially inflammatory NETs in association with NE autoantigen and BAFF. Enhancement of drug-induced NET release by CLAA-IgG provides a potential mechanism linking vasculitis/pupuric skin disease to acute drug exposure in patients with CLAA. Further study of this under-recognized form of autoimmunity will be likely to provide mechanistic insight into ANCA-associated vasculitis and other diseases associated with NETosis.
Sexual dimorphism is evident in the risk and expression of several human autoimmune diseases. Differences in disease manifestations observed between sexes are likely to involve immunomodulation by ...sex steroids, nonhormonal factors encoded by genes on the X and Y chromosomes, and immunological phenomena unique to pregnancy. In systemic lupus erythematosus (SLE), and perhaps other autoantibody-mediated diseases, oestrogen seems to increase the risk of disease in genetically predisposed women by targeting key immune pathways, including the type 1 interferon (IFN) response, differentiation of CD4(+) T helper cells and survival of autoreactive B cells. By contrast, progesterone seems to reduce the risk of SLE by counteracting the effects of oestrogen on some of these same pathways, which suggests that the balance between oestrogen and progesterone can determine disease expression. In this Review we focus on the roles of the sex steroid hormones oestrogen and progesterone in modulating the risk and expression of SLE and rheumatoid arthritis. Intensive research in this area promises to identify novel therapeutic strategies and improve understanding of the immunological requirements and complications of pregnancy, and is expected to define the mechanisms behind sexual dimorphism in autoimmunity, immunity and other aspects of human health--a newly announced directive of the NIH.
Declining oxygen in the global ocean and coastal waters Breitburg, Denise; Levin, Lisa A; Oschlies, Andreas ...
Science (American Association for the Advancement of Science),
01/2018, Volume:
359, Issue:
6371
Journal Article, Web Resource
Peer reviewed
Open access
Oxygen is fundamental to life. Not only is it essential for the survival of individual animals, but it regulates global cycles of major nutrients and carbon. The oxygen content of the open ocean and ...coastal waters has been declining for at least the past half-century, largely because of human activities that have increased global temperatures and nutrients discharged to coastal waters. These changes have accelerated consumption of oxygen by microbial respiration, reduced solubility of oxygen in water, and reduced the rate of oxygen resupply from the atmosphere to the ocean interior, with a wide range of biological and ecological consequences. Further research is needed to understand and predict long-term, global- and regional-scale oxygen changes and their effects on marine and estuarine fisheries and ecosystems.
Natural variation occurs in the uptake and distribution of essential and nonessential trace elements among crop species and among cultivars within species. Such variation can be responsible for trace ...element deficiencies and toxicities, which in turn can affect the quality of food. Plant breeding can be an important tool to both increase the concentration of desirable trace elements and reduce that of potentially harmful trace elements such as cadmium (Cd). Selection programs for a low-Cd content of various crops, including durum wheat, sunflower, rice and soybean have been established and low-Cd durum wheat cultivars and sunflower hybrids have been developed. In durum wheat (
Triticum turgidum L. var
durum), low-Cd concentration is controlled by a single dominant gene. The trait is highly heritable, and incorporation of the low-Cd allele can help to reduce the average grain Cd to levels below proposed international limits. The allele for low-Cd concentration does not appear to affect major economic traits and should not cause problems when incorporated into durum cultivars. The cost of Cd selection in a breeding program is initially large both in terms of Cd determination and reduced progress towards development of other economic traits, but declines as more breeding lines in the program carry the low-Cd trait and are utilized in new crosses. Production of low-Cd crop cultivars can be used as a tool to reduce the risk of movement of Cd into the human diet.
The neuromodulator melatonin synchronizes circadian rhythms and related physiological functions through the actions of two G-protein-coupled receptors: MT
and MT
. Circadian release of melatonin at ...night from the pineal gland activates melatonin receptors in the suprachiasmatic nucleus of the hypothalamus, synchronizing the physiology and behaviour of animals to the light-dark cycle
. The two receptors are established drug targets for aligning circadian phase to this cycle in disorders of sleep
and depression
. Despite their importance, few in vivo active MT
-selective ligands have been reported
, hampering both the understanding of circadian biology and the development of targeted therapeutics. Here we docked more than 150 million virtual molecules to an MT
crystal structure, prioritizing structural fit and chemical novelty. Of these compounds, 38 high-ranking molecules were synthesized and tested, revealing ligands with potencies ranging from 470 picomolar to 6 micromolar. Structure-based optimization led to two selective MT
inverse agonists-which were topologically unrelated to previously explored chemotypes-that acted as inverse agonists in a mouse model of circadian re-entrainment. Notably, we found that these MT
-selective inverse agonists advanced the phase of the mouse circadian clock by 1.3-1.5 h when given at subjective dusk, an agonist-like effect that was eliminated in MT
- but not in MT
-knockout mice. This study illustrates the opportunities for modulating melatonin receptor biology through MT
-selective ligands and for the discovery of previously undescribed, in vivo active chemotypes from structure-based screens of diverse, ultralarge libraries.
Each B-cell receptor consists of a pair of heavy and light chains. High-throughput sequencing can identify large numbers of heavy- and light-chain variable regions (V(H) and V(L)) in a given B-cell ...repertoire, but information about endogenous pairing of heavy and light chains is lost after bulk lysis of B-cell populations. Here we describe a way to retain this pairing information. In our approach, single B cells (>5 × 10(4) capacity per experiment) are deposited in a high-density microwell plate (125 pl/well) and lysed in situ. mRNA is then captured on magnetic beads, reverse transcribed and amplified by emulsion V(H):V(L) linkage PCR. The linked transcripts are analyzed by Illumina high-throughput sequencing. We validated the fidelity of V(H):V(L) pairs identified by this approach and used the method to sequence the repertoire of three human cell subsets-peripheral blood IgG(+) B cells, peripheral plasmablasts isolated after tetanus toxoid immunization and memory B cells isolated after seasonal influenza vaccination.
Freshwater ecosystems are affected by various stressors, such as contamination and exotic species, making them amongst the most imperilled biological systems on the planet. In Australia and ...elsewhere, copper is one of the most common metal contaminants in freshwater systems and the European carp (Cyprinus carpio L.) is one of the most pervasive and widespread invasive fish species. Copper (Cu) and carp can both directly affect primary production and decomposition, which are critical and interrelated nutrient cycling processes and ecosystem services. The aim of this study was to explore the direct and indirect effects of Cu and carp individually, and together on periphyton cover, chlorophyll a concentration, growth of the macrophyte Vallisneria spiralis L., and the decomposition of leaf litter and cotton strips in a controlled, factorial experiment in outdoor experimental ponds. In isolation, Cu reduced macrophyte growth and organic matter decomposition, while chlorophyll a concentrations and periphyton cover remained unchanged, possibly due to the Low-Cu concentrations in the overlying water. Carp addition alone had a direct negative effect on the biomass of aquatic plants outside protective cages, but also increased plant biomass inside the cages, periphyton cover and chlorophyll a concentrations. Leaf litter was more decomposed in the carp only ponds compared to controls, while there was no significant effect on cotton strip decomposition. Aquatic plants were absent in the Cu + carp ponds caused by the combined effects of Cu toxicity, carp disturbance and the increase in turbidity due to carp bioturbation. Increases in periphyton cover in Low-Cu + carp, while absence in the High-Cu + carp ponds, and differences in the decomposition of surface and buried cotton strips were not as predicted, which highlights the need for such studies to understand the complex interactions among stressors for environmental risk assessment.
Display omitted
•Cu reduced Vallisneria growth and slowed decomposition of cotton strips and leaves.•Cyprinus carpio uprooted macrophytes and increased turbidity and nutrients.•Nutrients increased chlorophyll a and periphyton which stabilized Low Cu sediments.•High-Cu reduced algal cover, carp increased turbidity, and reduced primary production.
Sexual selection is a key evolutionary force but varies widely between populations. Two key factors that influence sexual selection are the extent to which females copulate with multiple males ...(polyandry) and variation in the social environment. Increasing research demonstrates populations are structured by complex socio‐sexual networks, and the structure of these networks can influence sexual selection by shaping the relationship between male precopulatory mating success and the intensity of postcopulatory competition. However, comparatively less attention has been dedicated to the influence of group structure on sexual selection and how differences in the size of groups may impact on the relative force of pre‐ and postcopulatory sexual selection in polyandrous populations. The presence of groups (i.e., group structure) and the size of groups varies widely in nature and forms an implicit part of much experimental sexual selection research under laboratory conditions. Here I use simulations of mating competition within populations that vary in the size of groups they contain, to show that variation in group size, and in particular small groups, can influence sexual selection. Specifically, I show that null expectations for the operation of pre‐ and postcopulatory sexual selection is governed by the size of groups within populations because smaller group sizes constrain the structure of sexual networks leading to reinforcing episodes of pre‐ and postcopulatory sexual selection. Given broad variation in group structure in nature and the tendency for experimental sexual selection research to study replicate small groups, these effects have implications for our understanding of the operation of sexual selection in polyandrous populations.
A key goal in sexual selection research is to understand the role that polyandry plays in shaping the strength of sexual selection and the relationship between pre‐ and postcopulatory sexual selection. Here, I use simulations of mating competition within populations that vary in the size of groups they contain, to show that variation in group size, and in particular small groups, influences sexual selection. I show that the operation of pre‐ and postcopulatory sexual selection is governed by the size of groups within populations because smaller group sizes constrain the structure of sexual networks leading to reinforcing episodes of pre‐ and postcopulatory sexual selection. Given the tendency for experimental sexual selection research to study replicate small groups, these effects have implications for our understanding of the operation of sexual selection in polyandrous populations.
Introduction
Mucosal melanoma (MM) is a rare condition with a poor prognosis. Surgery is the corner stone of treatment, however, radiotherapy has been commonly employed as a treatment strategy and ...recent studies suggesting that survival outcomes may be improving are emerging.
Methods
A systematic review and meta‐analysis comparing risk ratios of radiotherapy and surgery and radiotherapy (SRT) with surgery for 5‐year overall survival, local recurrence and distant metastasis in head and neck mucosal melanoma (HNMM).
Results
SRT has a lower risk of death compared to surgery RR 0.93 95% CI = 0.87, 0.98 (P = .01) and a reduced risk of local recurrence RR 0.63 95% CI = 0.48, 0.82 (P = .005). SRT has no effect on distant metastasis. Radiotherapy has worse survival when compared to surgery RR 1.2 95% CI = 1.03, 1.33 (P = .0006).
Conclusions
SRT confers a moderate survival advantage in HNMM compared to surgery. This is most likely secondary to reduced local recurrence.
It has become widely accepted that sample cellular composition is a significant determinant of the gene expression patterns observed in any transcriptomic experiment performed with bulk tissue. ...Despite this, many investigations currently performed with whole blood do not experimentally account for possible inter-specimen differences in cellularity, and often assume that any observed gene expression differences are a result of true differences in nuclear transcription. In order to determine how confounding of an assumption this may be, in this study, we recruited a large cohort of human donors (n = 138) and used a combination of next generation sequencing and flow cytometry to quantify and compare the underlying contributions of variance in leukocyte counts versus variance in other biological factors to overall variance in whole blood transcript levels. Our results suggest that the combination of donor neutrophil and lymphocyte counts alone are the primary determinants of whole blood transcript levels for up to 75% of the protein-coding genes expressed in peripheral circulation, whereas the other factors such as age, sex, race, ethnicity, and common disease states have comparatively minimal influence. Broadly, this infers that a majority of gene expression differences observed in experiments performed with whole blood are driven by latent differences in leukocyte counts, and that cell count heterogeneity must be accounted for to meaningfully biologically interpret the results.
•The influence of leukocyte counts versus other biological factors on whole blood gene expression patterns was compared.•Leukocyte counts are the primary determinants of whole blood transcript levels for a majority of genes.•Most gene expression differences observed in experiments performed with whole blood are likely driven by differences in leukocyte counts.
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