Background Cardiovascular disease is a risk factor for cognitive impairment. Evidence links both lower and higher concentration of the circulating opioid pro-enkephalin A (PENK-A) with stroke risk. ...We studied the association of plasma PENK-A with incident cognitive impairment. Methods and Results REGARDS (Reasons for Geographic and Racial Differences in Stroke) is a prospective cohort study of 30 239 adults enrolled from 2003 to 2007. Baseline PENK-A was measured in a nested case-control study of 462 participants who developed cognitive impairment over 4.7 years, and 556 controls. Logistic regression and spline plots adjusted for confounders estimated odds ratios (ORs) of cognitive impairment by baseline PENK-A. Interaction terms tested for differences in associations by age, sex, and race. Baseline PENK-A was comparable between cases and controls. There were significant differences in the association of PENK-A with cognitive impairment by sex and age (adjusted
=0.003 and 0.06, respectively). In women but not men, spline plots showed that higher and lower PENK-A were associated with decreased odds of cognitive impairment (ORs for 10th and 90th percentiles versus median, 0.65 95% CI, 0.43-0.96 and 0.64 95% CI, 0.41-0.99), with no difference by age. In men ≥65 years of age but not younger men, higher PENK-A was associated with decreased odds for cognitive impairment (OR for fourth versus first quartile 0.47 95% CI, 0.22-0.99); this pattern was not confirmed with spline plotting. Conclusions High and low levels of circulating opioid PENK-A were associated with decreased odds of future cognitive impairment in specific subgroups. Additional research is warranted to understand the biology underlying this association and the observed differences by sex.
Several probiotic-derived factors have been identified as effectors of probiotics for exerting beneficial effects on the host. However, there is a paucity of studies to elucidate mechanisms of their ...functions. p40, a secretory protein, is originally isolated from a probiotic bacterium, Lactobacillus rhamnosus GG. Thus, this study aimed to apply structure-functional analysis to define the functional peptide of p40 that modulates the epigenetic program in intestinal epithelial cells for sustained prevention of colitis. In silico analysis revealed that p40 is composed of a signal peptide (1-28 residues) followed by a coiled-coil domain with uncharacterized function on the N-terminus, a linker region, and a β-sheet domain with high homology to CHAP on the C-terminus. Based on the p40 three-dimensional structure model, two recombinant p40 peptides were generated, p40N120 (28-120 residues) and p40N180 (28-180 residues) that contain first two and first three coiled coils, respectively. Compared to full-length p40 (p40F) and p40N180, p40N120 showed similar or higher effects on up-regulating expression of Setd1b (encoding a methyltransferase), promoting mono- and trimethylation of histone 3 on lysine 4 (H3K4me1/3), and enhancing Tgfb gene expression and protein production that leads to SMAD2 phosphorylation in human colonoids and a mouse colonic epithelial cell line. Furthermore, supplementation with p40F and p40N120 in early life increased H3K4me1, Tgfb expression and differentiation of regulatory T cells (Tregs) in the colon, and mitigated disruption of epithelial barrier and inflammation induced by DSS in adult mice. This study reveals the structural feature of p40 and identifies a functional peptide of p40 that could maintain intestinal homeostasis.
The challenge to link understanding and manipulation at the microscale to functional behaviour at the macroscale defines the frontiers of mesoscale science.
The risk of colon cancer is increased in patients with Crohn's disease and ulcerative colitis. Inflammation-induced DNA damage could be an important link between inflammation and cancer, although the ...pathways that link inflammation and DNA damage are incompletely defined. RAG2-deficient mice infected with Helicobacter hepaticus (Hh) develop colitis that progresses to lower bowel cancer. This process depends on nitric oxide (NO), a molecule with known mutagenic potential. We have previously hypothesized that production of NO by macrophages could be essential for Hh-driven carcinogenesis, however, whether Hh infection induces DNA damage in this model and whether this depends on NO has not been determined. Here we demonstrate that Hh infection of RAG2-deficient mice rapidly induces expression of iNOS and the development of DNA double-stranded breaks (DSBs) specifically in proliferating crypt epithelial cells. Generation of DSBs depended on iNOS activity, and further, induction of iNOS, the generation of DSBs, and the subsequent development of dysplasia were inhibited by depletion of the Hh-induced cytokine IL-22. These results demonstrate a strong association between Hh-induced DNA damage and the development of dysplasia, and further suggest that IL-22-dependent induction of iNOS within crypt epithelial cells rather than macrophages is a driving force in this process.
The pro-inflammatory cytokine interleukin-23 (IL-23) has been implicated in colorectal cancer (CRC). Yet, the cell-specific contributions of IL-23 receptor (IL-23R) signaling in CRC remain unknown. ...One of the cell types that highly expresses IL-23R are colonic regulatory T cells (Treg cells). The aim of this study was to define the contribution of Treg cell-specific IL-23R signaling in sporadic and inflammation-associated CRC.
In mice, the role of IL-23R in Treg cells in colitis-associated cancer (CAC) was investigated using azoxymethane/dextran sodium sulphate in wild-type Treg cell reporter mice (WT,
), and mice harboring a Treg cell-specific deletion of IL-23 (
). The role of IL-23R signaling in Treg cells in sporadic CRC was examined utilizing orthotopic injection of the syngeneic colon cancer cell line MC-38 submucosally into the colon/rectum of mice. The function of macrophages was studied using clodronate. Finally, single-cell RNA-seq of a previously published dataset in human sporadic cancer was reanalyzed to corroborate these findings.
In CAC,
mice had increased tumor size and increased dysplasia compared to WT mice that was associated with decreased tumor-infiltrating macrophages. In the sporadic cancer model,
mice had increased survival and decreased tumor size compared to WT mice. Additionally, MC-38 tumors of
mice exhibited a higher frequency of pro-inflammatory macrophages and IL-17 producing CD4
T cells. The decreased tumor size in
mice was macrophage-dependent. These data suggest that loss of IL-23R signaling in Treg cells permits IL-17 production by CD4
T cells that in turn promotes pro-inflammatory macrophages to clear tumors. Finally, analysis of TCGA data and single-cell RNA-seq analysis of a previously published dataset in human sporadic cancer, revealed that
was highly expressed in CRC compared to other cancers and specifically in tumor-associated Treg cells.
Inflammation in colorectal carcinogenesis differs with respect to the contribution of IL-23R signaling in regulatory T cells.
The formation of porous CRUD deposits on nuclear reactor fuel rods, a longstanding problem in the operation of pressurized water reactors (PWRs), is a significant challenge to science-based ...multiscale modeling and simulation. While existing, published studies have focused on individual or loosely coupled processes, such as heat transfer, fluid flow, and compound dissolution/precipitation, none have addressed their coupled effects sufficiently to enable a comprehensive, scientific understanding of CRUD. Here we present the formulation and results of a model, MAMBA-BDM, which begins to incorporate mechanistic details in describing CRUD in PWRs. CRUD is treated as a chemical deposition process in an environment of variable concentration, an arbitrary level of heating, and a complex fractal-based flow geometry. We present results on spatial distributions of temperature, pressure, velocity, and concentration that give insight into the interplay between these physical properties and geometrical parameters. We show the role of heat convection which has not been discussed previously. Furthermore, we suggest that the assumption of liquid saturation in the CRUD deserves scrutiny, as a result of our attempt to determine an effective CRUD thermal conductivity.
Beta-blockers remain underused in patients with chronic obstructive pulmonary disease (COPD) and cardiovascular disease.
We compared how different inhaled therapies affect tolerability of bisoprolol ...and carvedilol in moderate to severe COPD.
A randomized, open label, cross-over study.
We compared the cardiopulmonary interactions of bisoprolol 5 mg qd or carvedilol 12.5 mg bid for 6 weeks in conjunction with: (i) triple: inhaled corticosteroid/long acting beta-agonist/long acting muscarinic antagonist (ICS + LABA + LAMA), (ii) dual: ICS + LABA and (iii) ICS alone.
Eighteen patients completed, all ex-smokers, mean age 65 years, forced expiratory volume in 1 s (FEV1) 52% predicted. Bisoprolol and carvedilol produced comparable significant reduction in resting and exercise heart rate. FEV1, forced vital capacity and lung compliance (AX) were significantly lower with carvedilol vs. bisoprolol while taking concomitant ICS/LABA (P < 0.05) but not ICS/LABA/LAMA.
In summary, bisoprolol was better tolerated than carvedilol on pulmonary function at doses which produced equivalent cardiac beta-1 blockade. Worsening of pulmonary function with carvedilol was mitigated by concomitant inhaled LAMA (tiotropium) with LABA (formoterol), but not LABA alone. Registered at clinicaltrials.gov: NCT01656005.
Radiation-induced void swelling is a serious mode of degradation in nuclear structural materials. Much effort has been spent to predict swelling resistance, with the goal of increasing the void ...swelling incubation dose so as to postpone the consequences of radiation damage. However, this trial-and-error approach is highly inefficient due to the time- and resource-intensive nature of both experiments and physics-based multiscale simulations. In this work, as a first attempt, machine learning is applied to perform this prediction based on available experimental data. Of the multiple techniques applied, the gradient boosting ensemble method best predicts experimental onset doses for swelling in test datasets, and identifies the main contributing factors such as temperature, Fe and Cr content, and dose rate, which are consistent with established understanding. This work demonstrates the feasibility of machine learning to predict macroscale radiation effects based on material and environmental parameters, and has practical significance in guiding further material optimization for nuclear applications.
●First application of machine learning (ML) to predict the onset of swelling.●ML delivers promising results just based on material and environmental parameters.●Model determined key factors are consistent with established understandings.
Few studies in population biology have documented how structure and diversity of pathogens evolve over time at local scales. With the historical samples of Verticillium dahliae available from ...lettuce, we investigated the structure and diversity of this pathogen in time and space. Three hundred twenty-nine V. dahliae isolates from lettuce fields collected over 18 years were characterized with polymorphic microsatellite markers and polymerase chain reaction tests for race and mating type. Genetic variation within and among commercial lettuce fields in a single season was also investigated using an additional 146 isolates. Sixty-two haplotypes (HTs) were observed among the 329 isolates. A single HT was frequently observed over multiple years and locations (61.40%). Genetic diversity, allelic richness, and private allelic richness suggested a relatively recent clonal expansion. Race 1 (93.63%) and MAT1-2-1 (99.69%) were overwhelmingly represented among the isolates. Linkage disequilibrium was significant (P < 0.001) for all populations, suggesting limited sexual recombination in the sampled populations from lettuce. Populations from 2006, 2009, and 2010 had higher numbers of unique HTs, implying a recent introduction of novel HTs. We conclude that V. dahliae population from lettuce evaluated in this study is expanding clonally, consistent with an asexually reproducing pathogen, and the movement of clonal genotypes locally occurs over time.
Cysteine-rich receptor-like kinases (
) are a large subfamily of plant receptor-like kinases that play a critical role in disease resistance in plants. However, knowledge about the
gene family in ...cotton and its function against Verticillium wilt (VW), a destructive disease caused by
that significantly reduces cotton yields is lacking. In this study, we identified a total of 30 typical
in a
genome (
). Eleven of these (>30%) are located on the A06 and D06 chromosomes, and 18 consisted of 9 paralogous pairs encoded in the A and D subgenomes. Phylogenetic analysis showed that the
could be classified into four broad groups, the expansion of which has probably been driven by tandem duplication. Gene expression profiling of the
in resistant and susceptible cotton cultivars revealed that a phylogenetic cluster of nine of the
genes were up-regulated in response to
infection. Virus-induced gene silencing of each of these nine
independently revealed that the silencing of
was sufficient to compromise VW resistance in
. GbCRK18 expression could be induced by
infection or jasmonic acid, and displayed plasma membrane localization. Therefore, our expression analyses indicated that the
gene family is differentially regulated in response to Verticillium infection, while gene silencing experiments revealed that
in particular confers VW resistance in
.
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