Summary Background Animals can act as a reservoir and source for the emergence of novel meticillin-resistant Staphylococcus aureus (MRSA) clones in human beings. Here, we report the discovery of a ...strain of S aureus (LGA251) isolated from bulk milk that was phenotypically resistant to meticillin but tested negative for the mecA gene and a preliminary investigation of the extent to which such strains are present in bovine and human populations. Methods Isolates of bovine MRSA were obtained from the Veterinary Laboratories Agency in the UK, and isolates of human MRSA were obtained from diagnostic or reference laboratories (two in the UK and one in Denmark). From these collections, we searched for mecA PCR-negative bovine and human S aureus isolates showing phenotypic meticillin resistance. We used whole-genome sequencing to establish the genetic basis for the observed antibiotic resistance. Findings A divergent mecA homologue ( mecALGA251 ) was discovered in the LGA251 genome located in a novel staphylococcal cassette chromosome mec element, designated type-XI SCC mec . The mecALGA251 was 70% identical to S aureus mecA homologues and was initially detected in 15 S aureus isolates from dairy cattle in England. These isolates were from three different multilocus sequence type lineages (CC130, CC705, and ST425); spa type t843 (associated with CC130) was identified in 60% of bovine isolates. When human mecA -negative MRSA isolates were tested, the mecALGA251 homologue was identified in 12 of 16 isolates from Scotland, 15 of 26 from England, and 24 of 32 from Denmark. As in cows, t843 was the most common spa type detected in human beings. Interpretation Although routine culture and antimicrobial susceptibility testing will identify S aureus isolates with this novel mecA homologue as meticillin resistant, present confirmatory methods will not identify them as MRSA. New diagnostic guidelines for the detection of MRSA should consider the inclusion of tests for mecALGA251. Funding Department for Environment, Food and Rural Affairs, Higher Education Funding Council for England, Isaac Newton Trust (University of Cambridge), and the Wellcome Trust.
Hair cells are mechanosensors for the perception of sound, acceleration, and fluid motion. Mechanotransduction channels in hair cells are gated by tip links, which connect the stereocilia of a hair ...cell in the direction of their mechanical sensitivity. The molecular constituents of the mechanotransduction channels of hair cells are not known. Here, we show that mechanotransduction is impaired in mice lacking the tetraspan TMHS. TMHS binds to the tip-link component PCDH15 and regulates tip-link assembly, a process that is disrupted by deafness-causing Tmhs mutations. TMHS also regulates transducer channel conductance and is required for fast channel adaptation. TMHS therefore resembles other ion channel regulatory subunits such as the transmembrane alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor regulatory proteins (TARPs) of AMPA receptors that facilitate channel transport and regulate the properties of pore-forming channel subunits. We conclude that TMHS is an integral component of the hair cell’s mechanotransduction machinery that functionally couples PCDH15 to the transduction channel.
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► TMHS is a component of the hair cell’s mechanotransduction machinery ► TMHS binds to the tip-link component PCDH15 and regulates tip-link assembly ► TMHS regulates transducer channel conductance and is required for adaptation ► TMHS is structurally similar to other ion channel regulatory subunits such as TARPs
The tetraspan TMHS is identified as an accessory subunit of the hair cell mechanotransducer channel. TMHS regulates transducer channel conductance and functionally couples the tip-link component protocadherin 15 to the transduction channel.
Accurate information on the growth rates of fish is crucial for fisheries stock assessment and management. Empirical life history parameters (von Bertalanffy growth) are widely fitted to ...cross-sectional size-at-age data sampled from fish populations. This method often assumes that environmental factors affecting growth remain constant over time. The current study utilized longitudinal life history information contained in otoliths from 412 juveniles and adults of gilthead seabream, Sparus aurata, a commercially important species fished and farmed throughout the Mediterranean. Historical annual growth rates over 11 consecutive years (2002-2012) in the Gulf of Lions (NW Mediterranean) were reconstructed to investigate the effect of temperature variations on the annual growth of this fish. S. aurata growth was modelled linearly as the relationship between otolith size at year t against otolith size at the previous year t-1. The effect of temperature on growth was modelled with linear mixed effects models and a simplified linear model to be implemented in a cohort Integral Projection Model (cIPM). The cIPM was used to project S. aurata growth, year to year, under different temperature scenarios. Our results determined current increasing summer temperatures to have a negative effect on S. aurata annual growth in the Gulf of Lions. They suggest that global warming already has and will further have a significant impact on S. aurata size-at-age, with important implications for age-structured stock assessments and reference points used in fisheries.
An interim analysis of a randomized trial in triple-negative breast cancer comparing the addition of pembrolizumab to neoadjuvant chemotherapy with chemotherapy alone and adjuvant pembrolizumab with ...placebo after definitive surgery was reported after 39 months of follow-up. Event-free survival at 3 years was 84.5% in the pembrolizumab group and 76.8% in the group that did not receive pembrolizumab.
Aims/hypothesis
Type 2 diabetes is a growing global public health challenge. Investigating quantitative traits, including fasting glucose, fasting insulin and HbA
1c
, that serve as early markers of ...type 2 diabetes progression may lead to a deeper understanding of the genetic aetiology of type 2 diabetes development. Previous genome-wide association studies (GWAS) have identified over 500 loci associated with type 2 diabetes, glycaemic traits and insulin-related traits. However, most of these findings were based only on populations of European ancestry. To address this research gap, we examined the genetic basis of fasting glucose, fasting insulin and HbA
1c
in participants of the diverse Population Architecture using Genomics and Epidemiology (PAGE) Study.
Methods
We conducted a GWAS of fasting glucose (
n
= 52,267), fasting insulin (
n
= 48,395) and HbA
1c
(
n
= 23,357) in participants without diabetes from the diverse PAGE Study (23% self-reported African American, 46% Hispanic/Latino, 40% European, 4% Asian, 3% Native Hawaiian, 0.8% Native American), performing transethnic and population-specific GWAS meta-analyses, followed by fine-mapping to identify and characterise novel loci and independent secondary signals in known loci.
Results
Four novel associations were identified (
p
< 5 × 10
−9
), including three loci associated with fasting insulin, and a novel, low-frequency African American-specific locus associated with fasting glucose. Additionally, seven secondary signals were identified, including novel independent secondary signals for fasting glucose at the known
GCK
locus and for fasting insulin at the known
PPP1R3B
locus in transethnic meta-analysis.
Conclusions/interpretation
Our findings provide new insights into the genetic architecture of glycaemic traits and highlight the continued importance of conducting genetic studies in diverse populations.
Data availability
Full summary statistics from each of the population-specific and transethnic results are available at NHGRI-EBI GWAS catalog (
https://www.ebi.ac.uk/gwas/downloads/summary-statistics
).
Graphical abstract
Alterations in DNA methylation have been implicated in the pathogenesis of myelodysplastic syndromes (MDS), although the underlying mechanism remains largely unknown. Methylation of CpG dinucleotides ...is mediated by DNA methyltransferases, including DNMT1, DNMT3A and DNMT3B. DNMT3A mutations have recently been reported in patients with de novo acute myeloid leukemia (AML), providing a rationale for examining the status of DNMT3A in MDS samples. In this study, we report the frequency of DNMT3A mutations in patients with de novo MDS, and their association with secondary AML. We sequenced all coding exons of DNMT3A using DNA from bone marrow and paired normal cells from 150 patients with MDS and identified 13 heterozygous mutations with predicted translational consequences in 12/150 patients (8.0%). Amino acid R882, located in the methyltransferase domain of DNMT3A, was the most common mutation site, accounting for 4/13 mutations. DNMT3A mutations were expressed in the majority of cells in all tested mutant samples regardless of myeloblast counts, suggesting that DNMT3A mutations occur early in the course of MDS. Patients with DNMT3A mutations had worse overall survival compared with patients without DNMT3A mutations (P=0.005) and more rapid progression to AML (P=0.007), suggesting that DNMT3A mutation status may have prognostic value in de novo MDS.
Anthropogenic drivers are flattening reef structure from 3-dimensional habitats composed of macroalgae and live branching corals towards low-profile turfing algae. Our current understanding of the ...consequences of widespread reef degradation currently fails to consider the responses of small mobile invertebrates (‘epifauna’) to patterns of change amongst reef structural elements (‘microhabitats’). Here, the taxonomic composition of 152 epifaunal assemblages was compared among 21 structurally diverse benthic microhabitats across an Australian temperate to tropical climatic gradient, spanning 28.6 degrees in latitude from Tasmania to the northern Great Barrier Reef. Epifauna varied consistently with different microhabitat types, and to a much lesser extent with latitude. Macroalgae, live branching coral and turfing algae represented 3 extremes for epifaunal community structure, with most microhabitats possessing epifaunal assemblages intermediate between these endpoints. Amongst structural characteristics, epifauna related primarily to the degree of branching and hardness of microhabitats. Mobile invertebrate communities are likely to transform in predictable ways with the collapse of large erect macroalgae and live coral towards low-lying turf-associated communities.
The multifunctional membrane glycoprotein CD36 is expressed in different types of cells and plays a key regulatory role in cellular lipid metabolism, especially in cardiac muscle. CD36 facilitates ...the cellular uptake of long-chain fatty acids, mediates lipid signaling, and regulates storage and oxidation of lipids in various tissues with active lipid metabolism. CD36 deficiency leads to marked impairments in peripheral lipid metabolism, which consequently impact on the cellular utilization of multiple different fuels because of the integrated nature of metabolism. The functional presence of CD36 at the plasma membrane is regulated by its reversible subcellular recycling from and to endosomes and is under the control of mechanical, hormonal, and nutritional factors. Aberrations in this dynamic role of CD36 are causally associated with various metabolic diseases, in particular insulin resistance, diabetic cardiomyopathy, and cardiac hypertrophy. Recent research in cardiac muscle has disclosed the endosomal proton pump vacuolar-type H
-ATPase (v-ATPase) as a key enzyme regulating subcellular CD36 recycling and being the site of interaction between various substrates to determine cellular substrate preference. In addition, evidence is accumulating that interventions targeting CD36 directly or modulating its subcellular recycling are effective for the treatment of metabolic diseases. In conclusion, subcellular CD36 localization is the major adaptive regulator of cellular uptake and metabolism of long-chain fatty acids and appears a suitable target for metabolic modulation therapy to mend failing hearts.
The obesity paradox in which overweight/obesity is associated with mortality benefits is believed to be explained by confounding and reverse causality rather than by a genuine clinical benefit of ...excess body weight. We aimed to gain deeper insights into the paradox through analyzing mortality relationships with several adiposity measures; assessing subgroups with type 2 diabetes, with coronary heart disease (CHD), with cancer, and by smoking status; and adjusting for several confounders.
We studied the general UK Biobank population (
= 502,631) along with three subgroups of people with type 2 diabetes (
= 23,842), CHD (
= 24,268), and cancer (
= 45,790) at baseline. A range of adiposity exposures were considered, including BMI (continuous and categorical), waist circumference, body fat percentage, and waist-to-hip ratio, and the outcome was all-cause mortality. We used Cox regression models adjusted for age, smoking status, deprivation index, education, and disease history.
For BMI, the obesity paradox was observed among people with type 2 diabetes (adjusted hazard ratio for obese vs. normal BMI 0.78 95% CI 0.65, 0.95) but not among those with CHD (1.00 0.86, 1.17). The obesity paradox was pronounced in current smokers, absent in never smokers, and more pronounced in men than in women. For other adiposity measures, there was less evidence for an obesity paradox, yet smoking status consistently modified the adiposity-mortality relationship.
The obesity paradox was observed in people with type 2 diabetes and is heavily modified by smoking status. The results of subgroup analyses and statistical adjustments are consistent with reverse causality and confounding.
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