Autoantibodies target the RNA binding protein Ro60 in systemic lupus erythematosus (SLE) and Sjögren's syndrome. However, it is unclear whether Ro60 and its associated RNAs contribute to disease ...pathogenesis. We catalogued the Ro60-associated RNAs in human cell lines and found that among other RNAs, Ro60 bound an RNA motif derived from endogenous Alu retroelements. Alu transcripts were induced by type I interferon and stimulated proinflammatory cytokine secretion by human peripheral blood cells. Ro60 deletion resulted in enhanced expression of Alu RNAs and interferon-regulated genes. Anti-Ro60–positive SLE immune complexes contained Alu RNAs, and Alu transcripts were up-regulated in SLE whole blood samples relative to controls. These findings establish a link among the lupus autoantigen Ro60, Alu retroelements, and type I interferon.
Shifts in rainfall patterns and increasing temperatures associated with climate change are likely to cause widespread forest decline in regions where droughts are predicted to increase in duration ...and severity. One primary cause of productivity loss and plant mortality during drought is hydraulic failure. Drought stress creates trapped gas emboli in the water transport system, which reduces the ability of plants to supply water to leaves for photosynthetic gas exchange and can ultimately result in desiccation and mortality. At present we lack a clear picture of how thresholds to hydraulic failure vary across a broad range of species and environments, despite many individual experiments. Here we draw together published and unpublished data on the vulnerability of the transport system to drought-induced embolism for a large number of woody species, with a view to examining the likely consequences of climate change for forest biomes. We show that 70% of 226 forest species from 81 sites worldwide operate with narrow (,1 megapascal) hydraulic safety margins against injurious levels of drought stress and therefore potentially face long-term reductions in productivity and survival if temperature and aridity increase as predicted for many regions across the globe. Safety margins are largely independent of mean annual precipitation, showing that there is global convergence in the vulnerability of forests to drought, with all forest biomes equally vulnerable to hydraulic failure regardless of their current rainfall environment. These findings provide insight into why drought-induced forest decline is occurring not only in arid regions but also in wet forests not normally considered at drought risk.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Heterogeneous seascapes and strong environmental gradients in coastal waters are expected to influence adaptive divergence, particularly in species with large population sizes where selection is ...expected to be highly efficient. However, these influences might also extend to species characterized by strong social structure, natal philopatry and small home ranges. We implemented a seascape genomic study to test this hypothesis in Indo‐Pacific bottlenose dolphins (Tursiops aduncus) distributed along the environmentally heterogeneous coast of southern Australia. The data sets included oceanographic and environmental variables thought to be good predictors of local adaptation in dolphins and 8081 filtered single nucleotide polymorphisms (SNPs) genotyped for individuals sampled from seven different bioregions. From a neutral perspective, population structure and connectivity of the dolphins were generally influenced by habitat type and social structuring. Genotype‐environment association analysis identified 241 candidate adaptive loci and revealed that sea surface temperature and salinity gradients influenced adaptive divergence in these animals at both large‐ (1000 km) and fine‐scales (<100 km). Enrichment analysis and annotation of candidate genes revealed functions related to sodium‐activated ion transport, kidney development, adipogenesis and thermogenesis. The findings of spatial adaptive divergence and inferences of putative physiological adaptations challenge previous suggestions that marine megafauna is most likely to be affected by environmental and climatic changes via indirect, trophic effects. Our work contributes to conservation management of coastal bottlenose dolphins subjected to anthropogenic disturbance and to efforts of clarifying how seascape heterogeneity influences adaptive diversity and evolution in small cetaceans.
Dominant mutations in ubiquitously expressed transfer RNA (tRNA) synthetase genes cause axonal peripheral neuropathy, accounting for at least six forms of Charcot-Marie-Tooth (CMT) disease. Genetic ...evidence in mouse and
models suggests a gain-of-function mechanism. In this study, we used in vivo, cell type–specific transcriptional and translational profiling to show that mutant tRNA synthetases activate the integrated stress response (ISR) through the sensor kinase GCN2 (general control nonderepressible 2). The chronic activation of the ISR contributed to the pathophysiology, and genetic deletion or pharmacological inhibition of
alleviated the peripheral neuropathy. The activation of GCN2 suggests that the aberrant activity of the mutant tRNA synthetases is still related to translation and that inhibiting GCN2 or the ISR may represent a therapeutic strategy in CMT.
• Here, hypotheses about stem and root xylem structure and function were assessed by analyzing xylem in nine chaparral Rhamnaceae species. • Traits characterizing xylem transport efficiency and ...safety, mechanical strength and storage were analyzed using linear regression, principal components analysis and phylogenetic independent contrasts (PICs). • Stems showed a strong, positive correlation between xylem mechanical strength (xylem density and modulus of rupture) and xylem transport safety (resistance to cavitation and estimated vessel implosion resistance), and this was supported by PICs. Like stems, greater root cavitation resistance was correlated with greater vessel implosion resistance; however, unlike stems, root cavitation resistance was not correlated with xylem density and modulus of rupture. Also different from stems, roots displayed a trade-off between xylem transport safety from cavitation and xylem transport efficiency. Both stems and roots showed a trade-off between xylem transport safety and xylem storage of water and nutrients, respectively. • Stems and roots differ in xylem structural and functional relationships, associated with differences in their local environment (air vs soil) and their primary functions.
Following establishment of the IGNITE Network in 2013, the Pharmacogenetics Working Group was formed in January 2015 with the goals of broadly engaging institutions (funded IGNITE sites and affiliate ...members) implementing pharmacogenetics into practice to: i) share and collectively disseminate data on implementation strategies, metrics, and patient‐related outcomes following the utilization of genotype‐guided therapy; and ii) examine healthcare costs with pharmacogenetic implementation at multiple institutions. Gene–drug pairs implemented into clinical practice at institutions participating in the IGNITE Pharmacogenetics Working Group Institution Gene–drug pairs implemented University of Florida CYP2C19‐clopidogrel; CYP2D6‐codeine, tramadol; TPMT‐thiopurines; CYP2D6/CYP2C19‐SSRIs; CYP2C19‐PPIs; CYP2C19‐voriconazole (in development) Vanderbilt University CYP2C19‐clopidogrel; SLCO1B1‐simvastatin; CYP2C9/VKORC1‐warfarin; CYP3A5‐tacrolimus; TPMT‐thiopurines Indiana University CYP2C19‐clopidogrel, voriconazole, PPIs, citalopram; CYP2D6‐opioids, SSRIs, aripiprazole, atomoxetine; SLCO1B1‐simvastatin; CYP2C9/VKORC1/CYP4F2‐warfarin; CYP3A5‐tacrolimus; TPMT‐thiopurines; CYP2D6/CYP2C19‐TCAs; DPYD‐5‐fluorouracil, capecitabine, tegafur; G6PD‐rasburicase; ITPA‐thioguanine; CYP2B6‐efavirenz Sanford Health CYP2C19‐clopidogrel; CYP2C9/VKORC1‐warfarin; CYP2D6/CYP2C19‐SSRIs, TCAs; CYP2D6‐opioids; CYP3A5‐tacrolimus; SLCO1B1‐simvastatin; TPMT‐thiopurines; DPYD‐capecitabine, fluorouracil, tegafur University of Maryland CYP2C19‐clopidogrel Mount Sinai CYP2C19‐clopidogrel; CYP2C9/VKORC1‐warfarin; SLCO1B1‐simvastatin; CYP2D6‐codeine, tramadol; CYP2D6/CYP2C19‐TCAs (in development); CYP2D6/SSRIs (in development) Duke University SLCO1B1‐statins University of North Carolina at Chapel Hill CYP2C19‐clopidogrel Nemours Children's Health System CYP2C19‐PPIs University of Illinois at Chicago CYP2C19‐clopidogrel; CYP2C9/VKORC1‐warfarin Mission Health System HLA‐B*1502‐carbamazepine St. Luke's Mountain States Tumor Institute DPYD‐fluorouracil, capecitabine; TPMT‐thiopurines University of Pittsburgh CYP2C19‐clopidogrel University of Pennsylvania CYP2C19‐clopidogrel H. Lee Moffitt Cancer Center & Research Institute CYP2C19‐voriconazole; CYP2D6‐opioids; TPMT‐thiopurines University of Alabama, Birmingham CYP2C19‐clopidogrel PPI, proton pump inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant. Additional sensitivity analysis can be used to explore the impact of apparent unexplained variation in costs and outcomes, and to identify priorities for future research, while complementary decision analytic models can be used to explore heterogeneity of costs and effects across time, patient groups, and clinical settings. ...the coordination of analyses across sites provides an opportunity not only to provide statistically more precise estimates for use in economic modeling, but also to better understand how results generalize across different implementation strategies for dissemination of pharmacogenetics test results in real‐world settings. Additional support provided by NIH U01 GM074492 and U01 HL105198 (both part of the NIH Pharmacogenomics Research Network), and by substantial institutional support from the University of Florida and its Clinical Translational Science Institute (UL1 TR000064 and UL1 TR001427) for LHC, EA, KWW, and JAJ; NIH U01 HL105198, and support from the University of Maryland Medical Center and University of Maryland School of Medicine Program for Personalized and Genomic Medicine for ALB and LJBJ; NIH K23 GM112014 and the University of Illinois at Chicago Offices of the Vice President for Health Affairs and Vice Chancellor for Research for JDD; American Society of Health System Pharmacists, NIH UL1TR0000005, and by an Anonymous Donor for PEE; Penn Center for Precision Medicine at the Perelman School of Medicine at the University of Pennsylvania for ST; NIH R01HL092173, 1K24HL133373, University of Alabama, Birmingham Health Service Foundations' General Endowment Fund, and NIH UL1TR000165 for NAL; R01 GM088076 for TCS; Indiana University Health – Indiana University School of Medicine Strategic Research Initiative for VMP.
No effective pharmacological or non-pharmacological interventions exist for patients with long COVID. We aimed to describe recovery 1 year after hospital discharge for COVID-19, identify factors ...associated with patient-perceived recovery, and identify potential therapeutic targets by describing the underlying inflammatory profiles of the previously described recovery clusters at 5 months after hospital discharge.
The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a prospective, longitudinal cohort study recruiting adults (aged ≥18 years) discharged from hospital with COVID-19 across the UK. Recovery was assessed using patient-reported outcome measures, physical performance, and organ function at 5 months and 1 year after hospital discharge, and stratified by both patient-perceived recovery and recovery cluster. Hierarchical logistic regression modelling was performed for patient-perceived recovery at 1 year. Cluster analysis was done using the clustering large applications k-medoids approach using clinical outcomes at 5 months. Inflammatory protein profiling was analysed from plasma at the 5-month visit. This study is registered on the ISRCTN Registry, ISRCTN10980107, and recruitment is ongoing.
2320 participants discharged from hospital between March 7, 2020, and April 18, 2021, were assessed at 5 months after discharge and 807 (32·7%) participants completed both the 5-month and 1-year visits. 279 (35·6%) of these 807 patients were women and 505 (64·4%) were men, with a mean age of 58·7 (SD 12·5) years, and 224 (27·8%) had received invasive mechanical ventilation (WHO class 7–9). The proportion of patients reporting full recovery was unchanged between 5 months (501 25·5% of 1965) and 1 year (232 28·9% of 804). Factors associated with being less likely to report full recovery at 1 year were female sex (odds ratio 0·68 95% CI 0·46–0·99), obesity (0·50 0·34–0·74) and invasive mechanical ventilation (0·42 0·23–0·76). Cluster analysis (n=1636) corroborated the previously reported four clusters: very severe, severe, moderate with cognitive impairment, and mild, relating to the severity of physical health, mental health, and cognitive impairment at 5 months. We found increased inflammatory mediators of tissue damage and repair in both the very severe and the moderate with cognitive impairment clusters compared with the mild cluster, including IL-6 concentration, which was increased in both comparisons (n=626 participants). We found a substantial deficit in median EQ-5D-5L utility index from before COVID-19 (retrospective assessment; 0·88 IQR 0·74–1·00), at 5 months (0·74 0·64–0·88) to 1 year (0·75 0·62–0·88), with minimal improvements across all outcome measures at 1 year after discharge in the whole cohort and within each of the four clusters.
The sequelae of a hospital admission with COVID-19 were substantial 1 year after discharge across a range of health domains, with the minority in our cohort feeling fully recovered. Patient-perceived health-related quality of life was reduced at 1 year compared with before hospital admission. Systematic inflammation and obesity are potential treatable traits that warrant further investigation in clinical trials.
UK Research and Innovation and National Institute for Health Research.
Biogenic volatile organic compounds (BVOCs) can react in the atmosphere to form organic nitrates, which serve as NOx (NO + NO2) reservoirs, impacting ozone and secondary organic aerosol production, ...the oxidative capacity of the atmosphere, and nitrogen availability to ecosystems. To examine the contributions of biogenic emissions and the formation and fate of organic nitrates in a forest environment, we simulated the oxidation of 57 individual BVOCs emitted from a rural mixed forest in northern Michigan. Key BVOC-oxidant reactions were identified for future laboratory and field investigations into reaction rate constants, yields, and speciation of oxidation products. Of the total simulated organic nitrates, monoterpenes contributed ~70% in the early morning at ~12 m above the forest canopy when isoprene emissions were low. In the afternoon, when vertical mixing and isoprene nitrate production were highest, the simulated contribution of isoprene-derived organic nitrates was greater than 90% at all altitudes, with the concentration of secondary isoprene nitrates increasing with altitude. Notably, reaction of isoprene with NO3 leading to isoprene nitrate formation was found to be significant (~8% of primary organic nitrate production) during the daytime, and monoterpene reactions with NO3 were simulated to comprise up to ~83% of primary organic nitrate production at night. Lastly, forest succession, wherein aspen trees are being replaced by pine and maple trees, was predicted to lead to increased afternoon concentrations of monoterpene-derived organic nitrates. This further underscores the need to understand the formation and fate of these species, which have different chemical pathways and oxidation products compared to isoprene-derived organic nitrates and can lead to secondary organic aerosol formation.
This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence ...variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.
We have used Escherichia coli as a model system to investigate the initiation of biofilm formation. Here, we demonstrate that E. coli forms biofilms on multiple abiotic surfaces in a ...nutrient‐dependent fashion. In addition, we have isolated insertion mutations that render this organism defective in biofilm formation. One‐half of these mutations was found to perturb normal flagellar function. Using defined fli, flh, mot and che alleles, we show that motility, but not chemotaxis, is critical for normal biofilm formation. Microscopic analyses of these mutants suggest that motility is important for both initial interaction with the surface and for movement along the surface. In addition, we present evidence that type I pili (harbouring the mannose‐specific adhesin, FimH) are required for initial surface attachment and that mannose inhibits normal attachment. In light of the observations presented here, a working model is discussed that describes the roles of both motility and type I pili in biofilm development.
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