Little is known about the microbial communities found in distribution centers (DCs), especially in those storing and handling food. As many foodborne bacteria are known to establish residence in food ...facilities, it is reasonable to assume that DCs handling foods are also susceptible to pathogen colonization. To investigate the microbial communities within DCs, 16S amplicon sequencing was completed on 317 environmental surface sponge swabs collected in DCs (
= 18) across the United States. An additional 317 swabs were collected in parallel to determine if any viable
species were also present at each sampling site. There were significant differences in median diversity measures (observed, Shannon, and Chao1) across individual DCs, and top genera across all reads were
_A,
,
_E,
, and
based on taxonomic classifications using the Genome Taxonomy Database. Of the 39 16S samples containing
ASVs, four of these samples had corresponding
positive microbiological samples. Data indicated a predominance of ASVs identified as cold-tolerant bacteria in environmental samples collected in DCs. Differential abundance analysis identified
,
, and
present at a significantly greater abundance in
positive microbiological compared to those negative for
. Additionally, microbiome composition varied significantly across groupings within variables (e.g., DC, season, general sampling location).
A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in NAFLD; however, these findings have not been consistently replicated in ...the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis.
We performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a random effects meta-analysis using recessive, additive and dominant genetic models.
Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations 95% CI 0.02–0.05, pz = 4.8×10–5) and diagnosis of NAFLD (odds ratio OR 1.17 95% CI 1.05–1.3, pz = 0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 95% CI 1.03–1.45, pz = 0.021) in Caucasian adults using a recessive model of inheritance (CC + CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (pz = 0.002) and lower serum triglycerides (pz = 1.5×10–4). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD.
Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent.
Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including ‘cirrhosis’). It is closely linked to obesity and diabetes, but some genes are also thought to be important. We did this study to see whether one specific change (‘variant’) in one gene (‘MBOAT7’) was linked to fatty liver disease. We took data from over 40 published studies and found that this variant near MBOAT7 is linked to more severe fatty liver disease. This means that drugs designed to work on MBOAT7 could be useful for treating fatty liver disease.
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•Meta-analysis of 42 studies (>1 million participants) to assess the role of rs641738C>T near MBOAT7 in NAFLD.•rs641738C>T positively associated with liver fat, ALT, fibrosis and HCC.•rs641738C>T negatively associated with serum triglycerides.•Consistent associations found in studies of Caucasian populations only.
IMPORTANCE: The National Pediatric Readiness Project is a US initiative to improve emergency department (ED) readiness to care for acutely ill and injured children. However, it is unclear whether ...high ED pediatric readiness is associated with improved survival in US trauma centers. OBJECTIVE: To evaluate the association between ED pediatric readiness, in-hospital mortality, and in-hospital complications among injured children presenting to US trauma centers. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study of 832 EDs in US trauma centers in 50 states and the District of Columbia was conducted using data from January 1, 2012, through December 31, 2017. Injured children younger than 18 years who were admitted, transferred, or with injury-related death in a participating trauma center were included in the analysis. Subgroups included children with an Injury Severity Score (ISS) of 16 or above, indicating overall seriously injured (accounting for all injuries); any Abbreviated Injury Scale (AIS) score of 3 or above, indicating at least 1 serious injury; a head AIS score of 3 or above, indicating serious brain injury; and need for early use of critical resources. EXPOSURES: Emergency department pediatric readiness for the initial ED visit, measured through the weighted Pediatric Readiness Score (range, 0-100) from the 2013 National Pediatric Readiness Project ED pediatric readiness assessment. MAIN OUTCOMES AND MEASURES: In-hospital mortality, with a secondary composite outcome of in-hospital mortality or complication. For the primary measurement tools used, the possible range of the AIS is 0 to 6, with 3 or higher indicating a serious injury; the possible range of the ISS is 0 to 75, with 16 or higher indicating serious overall injury. The weighted Pediatric Readiness Score examines and scores 6 domains; in this study, the lowest quartile included scores of 29 to 62 and the highest quartile included scores of 93 to 100. RESULTS: There were 372 004 injured children (239 273 64.3% boys; median age, 10 years interquartile range, 4-15 years), including 5700 (1.5%) who died in-hospital and 5018 (1.3%) who developed in-hospital complications. Subgroups included 50 440 children (13.6%) with an ISS of 16 or higher, 124 507 (33.5%) with any AIS score of 3 or higher, 57 368 (15.4%) with a head AIS score of 3 or higher, and 32 671 (8.8%) requiring early use of critical resources. Compared with EDs in the lowest weighted Pediatric Readiness Score quartile, children cared for in the highest ED quartile had lower in-hospital mortality (adjusted odds ratio aOR, 0.58; 95% CI, 0.45-0.75), but not fewer complications (aOR for the composite outcome 0.88; 95% CI, 0.74-1.04). These findings were consistent across subgroups, strata, and multiple sensitivity analyses. If all children cared for in the lowest-readiness quartiles (1-3) were treated in an ED in the highest quartile of readiness, an additional 126 lives (95% CI, 97-154 lives) might be saved each year in these trauma centers. CONCLUSIONS AND RELEVANCE: In this cohort study, injured children treated in high-readiness EDs had lower mortality compared with similar children in low-readiness EDs, but not fewer complications. These findings support national efforts to increase ED pediatric readiness in US trauma centers that care for children.
The Proteome of Hand Eczema Assessed by Tape Stripping Sølberg, Julie B.K.; Quaade, Anna S.; Drici, Lylia ...
Journal of investigative dermatology,
August 2023, 2023-08-00, 20230801, Letnik:
143, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Hand eczema (HE) is a prevalent skin disease. However, the classification of HE into different subtypes remains challenging. A limited number of previous studies have employed invasive biopsy–based ...strategies; yet, studies of the HE proteome using noninvasive tape-stripping methodology have not been reported. In this study, we wanted to assess whether global proteomic analysis of skin tape strip samples can be used for subclassification of patients with HE. Tape strips were collected from patients with HE and healthy skin. Liquid chromatography–mass spectrometry proteomics was performed, and the global protein expression was analyzed. We identified 2,919 proteins in stratum corneum–derived skin cells from tape strip samples. Compared with healthy skin, the lesional samples from patients with HE exhibited increased expression of immune-related markers and a decreased expression of structural barrier proteins. The difference between HE subtypes was restricted to the lesional skin areas and included an increased expression of skin barrier–related proteins independently of the concurrent AD. In conclusion, we found that the noninvasive tape strip method used in combination with liquid chromatography–mass spectrometry proteomics can be used for analysis of skin protein expression in patients with HE. Thus, the method shows potential for assessing the proteomic differences between subtypes of HE and biomarker discovery.
Abstract
During cancer and chronic viral infections, the persistence of antigen progressively causes CD8+ T cells to differentiate into a dysfunctional PD1+ “exhausted” state, with reduced production ...of inflammatory cytokines relative to effector cells that form during acute infections. Antigen and costimulation signals activate kinase cascades to induce distinct T cell transcription programs, but how T cells distinguish acute and chronic signals to program the exhausted or effector transcriptional states remains poorly understood. We found that members of the protein kinase C (PKC) family function together as a “molecular clock,” sensing acute or chronic agonism to drive distinct transcriptional programs. Continuous stimulation of PKC induces many features of T cell exhaustion, including a loss of production of the cytokines IFNγ and TNF, upregulation of inhibitory receptors and TOX, and altered expression of the proteins in the AP-1 family. Mechanistically, CD8+ T cells express several different PKC proteins, and chronic agonism of PKC leads to degradation of multiple family members and selective maintenance of only one PKC protein, PKC-η. This “PKC switch” alters downstream signaling to support the transcriptional reprogramming of T cells into a terminally exhausted state. In summary, continuous signaling through PKCs causes changes in the output from these kinases initially at the protein level, driving transcriptional changes downstream of PKC targets in the AP-1 transcription factor family and thus allowing further widespread transcriptional and functional changes that characterize T cell exhaustion.
Supported by a Damon Runyon Cancer Research Fellowship (DRG-2358-19) and an NIH training grant, T32-CA009370.
Antibody-based therapeutics and vaccines are essential to combat COVID-19 morbidity and mortality after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Multiple mutations in ...SARS-CoV-2 that could impair antibody defenses propagated in human-to-human transmission and spillover or spillback events between humans and animals. To develop prevention and therapeutic strategies, we formed an international consortium to map the epitope landscape on the SARS-CoV-2 spike protein, defining and structurally illustrating seven receptor binding domain (RBD)–directed antibody communities with distinct footprints and competition profiles. Pseudovirion-based neutralization assays reveal spike mutations, individually and clustered together in variants, that affect antibody function among the communities. Key classes of RBD-targeted antibodies maintain neutralization activity against these emerging SARS-CoV-2 variants. These results provide a framework for selecting antibody treatment cocktails and understanding how viral variants might affect antibody therapeutic efficacy.
OBJECTIVE:The aim of this study was to evaluate the association between common exonic variants in the leucine-rich repeat kinase 2 (LRRK2) gene and risk of multiple system atrophy (MSA).
METHODS:One ...series from the United States (92 patients with pathologically confirmed MSA, 416 controls) and a second series from the United Kingdom (85 patients with pathologically confirmed MSA, 352 controls) were included in this case-control study. We supplemented these data with those of 53 patients from the United States with clinically probable or possible MSA. Seventeen common LRRK2 exonic variants were genotyped and assessed for association with MSA.
RESULTS:In the combined series of 177 patients with pathologically confirmed MSA and 768 controls, there was a significant association between LRRK2 p.M2397T and MSA (odds ratio OR = 0.60, p = 0.002). This protective effect was observed more strongly in the US series (OR = 0.46, p = 0.0008) than the UK series (OR = 0.82, p = 0.41). We observed other noteworthy associations with MSA for p.G1624G (OR = 0.63, p = 0.006) and p.N2081D (OR = 0.15, p = 0.010). The p.G1624G-M2397T haplotype was significantly associated with MSA in the US series (p < 0.0001) and combined series (p = 0.003) but not the UK series (p = 0.67). Results were consistent when additionally including the US patients with clinical MSA, where the strongest single-variant association was again observed for p.M2397T (OR = 0.59, p = 0.0005).
CONCLUSIONS:These findings provide evidence that LRRK2 exonic variants may contribute to susceptibility to MSA. Validation in other series and meta-analytic studies will be important.
Abstract
Graded levels of molecular oxygen (O2) exist within developing mammalian embryos and can differentially regulate cellular specification pathways. During differentiation, cells acquire ...distinct epigenetic landscapes, which determine their function, however the mechanisms which regulate this are poorly understood. The demethylation of 5-methylcytosine (5mC) is achieved via successive oxidation reactions catalysed by the Ten-Eleven-Translocation (Tet) enzymes, yielding the 5-hydroxymethylcytosine (5hmC) intermediate. These require O2 as a co-factor, and hence may link epigenetic processes directly to O2 gradients during development. We demonstrate that the activities of Tet enzymes display distinct patterns of O2-dependency, and that Tet1 activity, specifically, is subject to differential regulation within a range of O2 which is physiologically relevant in embryogenesis. Further, differentiating embryonic stem cells displayed a transient burst of 5hmC, which was both dependent upon Tet1 and inhibited by low (1%) O2. A GC-rich promoter region within the Tet3 locus was identified as a significant target of this 5mC-hydroxylation. Further, this region was shown to associate with Tet1, and display the histone epigenetic marks, H3K4me3 and H3K27me3, which are characteristic of a bivalent, developmentally 'poised' promoter. We conclude that Tet1 activity, determined by O2 may play a critical role in regulating cellular differentiation and fate in embryogenesis.
Arctic warming is causing permafrost thaw and release of organic carbon (OC) to fluvial systems. Permafrost-derived OC can be transported downstream and degraded into greenhouse gases that may ...enhance climate warming. Susceptibility of OC to decomposition depends largely upon its source and composition, which vary throughout the seasonally distinct hydrograph. Most studies on carbon dynamics to date have focused on larger Arctic rivers, yet little is known about carbon cycling in lower-order rivers and streams. Here, we characterize the composition and sources of OC, focusing on less studied particulate OC (POC), in smaller waterways within the Kolyma River watershed. Additionally, we examine how watershed characteristics control carbon concentrations. In lower-order systems, we find rapid initiation of primary production in response to warm water temperatures during spring freshet, shown by decreasing δ13C-POC, in contrast to larger rivers. This results in CO2 uptake by primary producers and microbial degradation of mainly autochthonous OC. However, if terrestrially derived inorganic carbon is assimilated by primary producers, part of it is returned via CO2 emissions if the autochthonous OC pool is simultaneously degraded. As Arctic warming and hydrologic changes may increase OC transfer from smaller waterways to larger river networks, understanding carbon dynamics in smaller waterways is crucial.
A role of CD4+ T cells during the progression from nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) has been suggested, but which polarization state of these cells ...characterizes this progression and the development of fibrosis remain unclear. In addition, a gut-liver axis has been suggested to play a role in NASH, but the role of CD4+ T cells in this axis has just begun to be investigated. Combining single-cell RNA sequencing and multiple-parameter flow cytometry, we provide the first cell atlas to our knowledge focused on liver-infiltrating CD4+ T cells in patients with NAFLD and NASH, showing that NASH is characterized by a population of multicytokine-producing CD4+ T cells. Among these cells, only those with a Th17 polarization state were enriched in patients with advanced fibrosis. In parallel, we observed that Bacteroides appeared to be enriched in the intestine of NASH patients and to correlate with the frequency of multicytokine-producing CD4+ T cells. In short, we deliver a CD4+ T cell atlas of NAFLD and NASH, providing the rationale to target CD4+ T cells with a Th17 polarization state to block fibrosis development. Finally, our data offer an early indication to test whether multicytokine-producing CD4+ T cells are part of the gut-liver axis characterizing NASH.
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