Antibiotic resistance is ancient D'COSTA, Vanessa M; KING, Christine E; GOLDING, G. Brian ...
Nature (London),
09/2011, Letnik:
477, Številka:
7365
Journal Article
Recenzirano
The discovery of antibiotics more than 70 years ago initiated a period of drug innovation and implementation in human and animal health and agriculture. These discoveries were tempered in all cases ...by the emergence of resistant microbes. This history has been interpreted to mean that antibiotic resistance in pathogenic bacteria is a modern phenomenon; this view is reinforced by the fact that collections of microbes that predate the antibiotic era are highly susceptible to antibiotics. Here we report targeted metagenomic analyses of rigorously authenticated ancient DNA from 30,000-year-old Beringian permafrost sediments and the identification of a highly diverse collection of genes encoding resistance to β-lactam, tetracycline and glycopeptide antibiotics. Structure and function studies on the complete vancomycin resistance element VanA confirmed its similarity to modern variants. These results show conclusively that antibiotic resistance is a natural phenomenon that predates the modern selective pressure of clinical antibiotic use.
Bromodomains are protein modules that bind to acetylated lysine residues. Their interaction with histone proteins suggests that they function as “readers” of histone lysine acetylation, a component ...of the proposed “histone code”. Bromodomain-containing proteins are often found as components of larger protein complexes with roles in fundamental cellular process including transcription. The publication of two potent ligands for the BET bromodomains in 2010 demonstrated that small molecules can inhibit the bromodomain–acetyl-lysine protein–protein interaction. These molecules display strong phenotypic effects in a number of cell lines and affect a range of cancers in vivo. This work stimulated intense interest in developing further ligands for the BET bromodomains and the design of ligands for non-BET bromodomains. Here we review the recent progress in the field with particular attention paid to ligand design, the assays employed in early ligand discovery, and the use of computational approaches to inform ligand design.
Parallel evolution can occur through selection on novel mutations, standing genetic variation or adaptive introgression. Uncovering parallelism and introgressed populations can complicate management ...of threatened species as parallelism may have influenced conservation unit designations and admixed populations are not generally considered under legislations. We examined high coverage whole‐genome sequences of 30 caribou (Rangifer tarandus) from across North America and Greenland, representing divergent intraspecific lineages, to investigate parallelism and levels of introgression contributing to the formation of ecotypes. Caribou are split into four subspecies and 11 extant conservation units, known as designatable units (DUs), in Canada. Using genomes from all four subspecies and six DUs, we undertake demographic reconstruction and confirm two previously inferred instances of parallel evolution in the woodland subspecies and uncover an additional instance of parallelism of the eastern migratory ecotype. Detailed investigations reveal introgression in the woodland subspecies, with introgressed regions found spread throughout the genomes encompassing both neutral and functional sites. Our investigations using whole genomes highlight the difficulties in unequivocally demonstrating parallelism through adaptive introgression in nonmodel species with complex demographic histories, with standing variation and introgression both potentially involved. Additionally, the impact of parallelism and introgression on conservation policy for management units needs to be considered in general, and the caribou designations will need amending in light of our results. Uncovering and decoupling parallelism and differential patterns of introgression will become prevalent with the availability of comprehensive genomic data from nonmodel species, and we highlight the need to incorporate this into conservation unit designations.
Prolonged, isocaloric, time-restricted feeding (TRF) protocols can promote weight loss, improve metabolic dysregulation, and mitigate non-alcoholic fatty liver disease (NAFLD). In addition, 3-day, ...severe caloric restriction can improve liver metabolism and glucose homeostasis prior to significant weight loss. Thus, we hypothesized that short-term, isocaloric TRF would improve NAFLD and characteristics of metabolic syndrome in diet-induced obese male mice. After 26 weeks of ad libitum access to western diet, mice either continued feeding ad libitum or were provided with access to the same quantity of western diet for 8 h daily, over the course of two weeks. Remarkably, this short-term TRF protocol modestly decreased liver tissue inflammation in the absence of changes in body weight or epidydimal fat mass. There were no changes in hepatic lipid accumulation or other characteristics of NAFLD. We observed no changes in liver lipid metabolism-related gene expression, despite increased plasma free fatty acids and decreased plasma triglycerides in the TRF group. However, liver
and
expression were decreased with TRF suggesting hepatic endoplasmic reticulum (ER) stress and activation of inflammatory pathways may have been diminished. We conclude that two-week, isocaloric TRF can potentially decrease liver inflammation, without significant weight loss or reductions in hepatic steatosis, in obese mice with NAFLD.
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•Elongation factor 1A1 inhibitor didemnin B improves fatty liver, glucose tolerance, and blood lipids in obesity.•Didemnin B moderately upregulates pathways involved in cell stress ...response and energy balance in the liver.•Didemnin B targets cells involved in liver inflammation and fibrosis.
Inhibition of eukaryotic elongation factor 1A1 (EEF1A1) with the marine compound didemnin B decreases lipotoxic HepG2 cell death in vitro and improves early stage non-alcoholic fatty liver disease (NAFLD) in young genetically obese mice. However, the effects of didemnin B on NAFLD in a model of long-term diet-induced obesity are not known. We investigated the effects of didemnin B on NAFLD severity and metabolic parameters in western diet-induced obese mice, and on the cell types that contribute to liver inflammation and fibrosis in vitro. Male 129S6 mice were fed either standard chow or western diet for 26 weeks, followed by intervention with didemnin B (50 μg/kg) or vehicle by intraperitoneal (i.p.) injection once every 3 days for 14 days. Didemnin B decreased liver and plasma triglycerides, improved oral glucose tolerance, and decreased NAFLD severity. Moreover, didemnin B moderately increased hepatic expression of genes involved in ER stress response (Perk, Chop), and fatty acid oxidation (Fgf21, Cpt1a). In vitro, didemnin B decreased THP-1 monocyte proliferation, disrupted THP-1 monocyte-macrophage differentiation, decreased THP-1 macrophage IL-1β secretion, and decreased hepatic stellate cell (HSteC) proliferation and collagen secretion under both basal and lipotoxic (high fatty acid) conditions. Thus, didemnin B improves hepatic steatosis, glucose tolerance, and blood lipids in obesity, in association with moderate, possibly hormetic, upregulation of pathways involved in cell stress response and energy balance in the liver. Furthermore, it decreases the activity of the cell types implicated in liver inflammation and fibrosis in vitro. These findings highlight the therapeutic potential of partial protein synthesis inhibition in the treatment of NAFLD.
The severity and frequency of drought has increased around the globe, creating challenges in ensuring food security for a growing world population. As a consequence, improving water use efficiency by ...crops has become an important objective for crop improvement. Some wild crop relatives have adapted to extreme osmotic stresses and can provide valuable insights into traits and genetic signatures that can guide efforts to improve crop tolerance to water deficits. Eutrema salsugineum, a close relative of many cruciferous crops, is a halophytic plant and extremophyte model for abiotic stress research.
Using comparative transcriptomics, we show that two E. salsugineum ecotypes display significantly different transcriptional responses towards a two-stage drought treatment. Even before visibly wilting, water deficit led to the differential expression of almost 1,100 genes for an ecotype from the semi-arid, sub-arctic Yukon, Canada, but only 63 genes for an ecotype from the semi-tropical, monsoonal, Shandong, China. After recovery and a second drought treatment, about 5,000 differentially expressed genes were detected in Shandong plants versus 1,900 genes in Yukon plants. Only 13 genes displayed similar drought-responsive patterns for both ecotypes. We detected 1,007 long non-protein coding RNAs (lncRNAs), 8% were only expressed in stress-treated plants, a surprising outcome given the documented association between lncRNA expression and stress. Co-expression network analysis of the transcriptomes identified eight gene clusters where at least half of the genes in each cluster were differentially expressed. While many gene clusters were correlated to drought treatments, only a single cluster significantly correlated to drought exposure in both ecotypes.
Extensive, ecotype-specific transcriptional reprogramming with drought was unexpected given that both ecotypes are adapted to saline habitats providing persistent exposure to osmotic stress. This ecotype-specific response would have escaped notice had we used a single exposure to water deficit. Finally, the apparent capacity to improve tolerance and growth after a drought episode represents an important adaptive trait for a plant that thrives under semi-arid Yukon conditions, and may be similarly advantageous for crop species experiencing stresses attributed to climate change.
Summary
Background
Intestinal ultrasound (IUS) is a valuable tool for assessment of Crohn’s disease (CD). However, there is no widely accepted luminal disease activity index.
Aims
To identify ...appropriate IUS protocols, indices, items, and scoring methods for measurement of luminal CD activity and integration of IUS in CD clinical trials.
Methods
An expert international panel of adult and paediatric gastroenterologists (n = 15) and radiologists (n = 3) rated the appropriateness of 120 statements derived from literature review and expert opinion (scale of 1‐9) using modified RAND/UCLA methodology. Median panel scores of 1 to ≤3.5, >3.5 to <6.5 and ≥6.5 to 9 were considered inappropriate, uncertain and appropriate ratings respectively. The statement list and survey results were discussed prior to voting.
Results
A total of 91 statements were rated appropriate with agreement after two rounds of voting. Items considered appropriate measures of disease activity were bowel wall thickness (BWT), vascularity, stratification and mesenteric inflammatory fat. There was uncertainty if any of the existing IUS disease activity indices were appropriate for use in CD clinical trials. Appropriate trial applications for IUS included patient recruitment qualification when diseased segments cannot be adequately assessed by ileocolonoscopy and screening for exclusionary complications. At outcome assessment, remission endpoints including BWT and vascularity, with or without mesenteric inflammatory fat, were considered appropriate. Components of an ideal IUS disease activity index were identified based upon panel discussions.
Conclusions
The panel identified appropriate component items and applications of IUS for CD clinical trials. Empiric evidence, and development and validation of an IUS disease activity index are needed.
This study employed a modified RAND/UCLA appropriateness methodology to define an evidence‐based approach to standardise IUS assessment of luminal CD activity and determine areas of uncertainty and inconsistency of practice. These results will be used to inform future studies whose ultimate goals include the development and validation of an IUS‐based CD activity score for implementation in clinical trials and clinical practice.
Brain swelling is a major predictor of mortality in pediatric cerebral malaria (CM). However, the mechanisms leading to swelling remain poorly defined. Here, we combined neuroimaging, parasite ...transcript profiling, and laboratory blood profiles to develop machine-learning models of malarial retinopathy and brain swelling. We found that parasite var transcripts encoding endothelial protein C receptor (EPCR)-binding domains, in combination with high parasite biomass and low platelet levels, are strong indicators of CM cases with malarial retinopathy. Swelling cases presented low platelet levels and increased transcript abundance of parasite PfEMP1 DC8 and group A EPCR-binding domains. Remarkably, the dominant transcript in 50% of swelling cases encoded PfEMP1 group A CIDRα1.7 domains. Furthermore, a recombinant CIDRα1.7 domain from a pediatric CM brain autopsy inhibited the barrier-protective properties of EPCR in human brain endothelial cells in vitro. Together, these findings suggest a detrimental role for EPCR-binding CIDRα1 domains in brain swelling.
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•Stringently defined cerebral malaria cases profiled for PfEMP1/var expression•Low platelet count linked to malarial retinopathy and brain swelling•EPCR-binding PfEMP1 enriched in malarial retinopathy and brain swelling•Parasite PfEMP1 CIDRα1.7 domain from brain autopsies counteracts EPCR protection
Brain swelling is associated with cerebral malaria mortality, but the parasite and host factors responsible for development of brain swelling are unknown. Kessler et al. demonstrate an association of low platelet count and EPCR-binding PfEMP1 with brain swelling in children with cerebral malaria.
The aim of this study was to evaluate the association of annual trauma patient volume on outcomes for emergency medical services (EMS) agencies.
Regionalization of trauma care saves lives. The ...underlying concept driving this is a volume-outcome relationship. EMS are the entry point to the trauma system, yet it is unknown if a volume-outcome relationship exists for EMS.
A retrospective analysis of prospective cohort including 8 trauma centers and 20 EMS air medical and metropolitan ground transport agencies. Patients 18 to 90 years old with injury severity scores ≥9 transported from the scene were included. Patient and agency-level risk-adjusted regression determined the association between EMS agency trauma patient volume and early mortality.
A total of 33,511 were included with a median EMS agency volume of 374 patients annually (interquartile range: 90-580). Each 50-patient increase in EMS agency volume was associated with 5% decreased odds of 6-hour mortality (adjusted odds ratio=0.95; 95% CI: 0.92-0.99, P =0.03) and 3% decreased odds of 24-hour mortality (adjusted odds ratio=0.97; 95% CI: 0.95-0.99, P =0.04). Prespecified subgroup analysis showed EMS agency volume was associated with reduced odds of mortality for patients with prehospital shock, requiring prehospital airway placement, undergoing air medical transport, and those with traumatic brain injury. Agency-level analysis demonstrated that high-volume (>374 patients/year) EMS agencies had a significantly lower risk-standardized 6-hour mortality rate than low-volume (<374 patients/year) EMS agencies (1.9% vs 4.8%, P <0.01).
A higher volume of trauma patients transported at the EMS agency level is associated with improved early mortality. Further investigation of this volume-outcome relationship is necessary to leverage quality improvement, benchmarking, and educational initiatives.
Abstract Background People with serious mental illness (SMI) and people with intellectual disabilities/developmental disabilities (ID/DD) are at higher risk for COVID-19 and more severe outcomes. We ...compare a tailored versus general best practice COVID-19 prevention program in group homes (GHs) for people with SMI or ID/DD in Massachusetts (MA). Methods A hybrid effectiveness-implementation cluster randomized control trial compared a four-component implementation strategy ( Tailored Best Practices : TBP) to dissemination of standard prevention guidelines ( General Best-Practices : GBP) in GHs across six MA behavioral health agencies. GBP consisted of standard best practices for preventing COVID-19. TBP included GBP plus four components including: (1) trusted-messenger peer testimonials on benefits of vaccination; (2) motivational interviewing; (3) interactive education on preventive practices; and (4) fidelity feedback dashboards for GHs. Primary implementation outcomes were full COVID-19 vaccination rates (baseline: 1/1/2021–3/31/2021) and fidelity scores (baseline: 5/1/21–7/30/21), at 3-month intervals to 15-month follow-up until October 2022. The primary effectiveness outcome was COVID-19 infection (baseline: 1/1/2021–3/31/2021), measured every 3 months to 15-month follow-up. Cumulative incidence of vaccinations were estimated using Kaplan-Meier curves. Cox frailty models evaluate differences in vaccination uptake and secondary outcomes. Linear mixed models (LMMs) and Poisson generalized linear mixed models (GLMMs) were used to evaluate differences in fidelity scores and incidence of COVID-19 infections. Results GHs ( n =415) were randomized to TBP ( n =208) and GBP ( n =207) including 3,836 residents (1,041 ID/DD; 2,795 SMI) and 5,538 staff. No differences were found in fidelity scores or COVID-19 incidence rates between TBP and GBP, however TBP had greater acceptability, appropriateness, and feasibility. No overall differences in vaccination rates were found between TBP and GBP. However, among unvaccinated group home residents with mental disabilities, non-White residents achieved full vaccination status at double the rate for TBP (28.6%) compared to GBP (14.4%) at 15 months. Additionally, the impact of TBP on vaccine uptake was over two-times greater for non-White residents compared to non-Hispanic White residents (ratio of HR for TBP between non-White and non-Hispanic White: 2.28, p = 0.03). Conclusion Tailored COVID-19 prevention strategies are beneficial as a feasible and acceptable implementation strategy with the potential to reduce disparities in vaccine acceptance among the subgroup of non-White individuals with mental disabilities. Trial registration ClinicalTrials.gov, NCT04726371, 27/01/2021. https://clinicaltrials.gov/study/NCT04726371 .
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