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Background/Objectives: Activity-related energy expenditure (AEE) might be an important factor in the etiology of chronic diseases. However, measurement of free-living AEE is usually not feasible in large-scale epidemiological studies but instead has traditionally been estimated based on self-reported physical activity. Recently, accelerometry has been proposed for objective assessment of physical activity, but it is unclear to what extent this methods explains the variance in AEE. Subjects/Methods: We conducted a systematic review searching MEDLINE database (until 2014) on studies that estimated AEE based on accelerometry-assessed physical activity in adults under free-living conditions (using doubly labeled water method). Extracted study characteristics were sample size, accelerometer (type (uniaxial, triaxial), metrics (for example, activity counts, steps, acceleration), recording period, body position, wear time), explained variance of AEE ( R 2 ) and number of additional predictors. The relation of univariate and multivariate R 2 with study characteristics was analyzed using nonparametric tests. Results: Nineteen articles were identified. Examination of various accelerometers or subpopulations in one article was treated separately, resulting in 28 studies. Sample sizes ranged from 10 to 149. In most studies the accelerometer was triaxial, worn at the trunk, during waking hours and reported activity counts as output metric. Recording periods ranged from 5 to 15 days. The variance of AEE explained by accelerometer-assessed physical activity ranged from 4 to 80% (median crude R 2 =26%). Sample size was inversely related to the explained variance. Inclusion of 1 to 3 other predictors in addition to accelerometer output significantly increased the explained variance to a range of 12.5–86% (median total R 2 =41%). The increase did not depend on the number of added predictors. Conclusions: We conclude that there is large heterogeneity across studies in the explained variance of AEE when estimated based on accelerometry. Thus, data on predicted AEE based on accelerometry-assessed physical activity need to be interpreted cautiously.

Current mouse models of nonalcoholic steatohepatitis are limited, making identification and preclinical testing of new treatments challenging. Housing mice at thermoneutrality leads to less stress, a stronger immune response and better modeling of this condition. Nonalcoholic fatty liver disease (NAFLD), a common prelude to cirrhosis and hepatocellular carcinoma, is the most common chronic liver disease worldwide. Defining the molecular mechanisms underlying the pathogenesis of NAFLD has been hampered by a lack of animal models that closely recapitulate the severe end of the disease spectrum in humans, including bridging hepatic fibrosis. Here we demonstrate that a novel experimental model employing thermoneutral housing, as opposed to standard housing, resulted in lower stress-driven production of corticosterone, augmented mouse proinflammatory immune responses and markedly exacerbated high-fat diet (HFD)-induced NAFLD pathogenesis. Disease exacerbation at thermoneutrality was conserved across multiple mouse strains and was associated with augmented intestinal permeability, an altered microbiome and activation of inflammatory pathways that are associated with the disease in humans. Depletion of Gram-negative microbiota, hematopoietic cell deletion of Toll-like receptor 4 (TLR4) and inactivation of the IL-17 axis resulted in altered immune responsiveness and protection from thermoneutral-housing-driven NAFLD amplification. Finally, female mice, typically resistant to HFD-induced obesity and NAFLD, develop full disease characteristics at thermoneutrality. Thus, thermoneutral housing provides a sex-independent model of exacerbated NAFLD in mice and represents a novel approach for interrogation of the cellular and molecular mechanisms underlying disease pathogenesis.

Guanylyl Cyclase C (GCC) signaling via uroguanylin (UGN) and guanylin activation is a critical mediator of intestinal fluid homeostasis, intestinal cell proliferation/apoptosis, and tumorigenesis. As a mechanism for some of these effects, we hypothesized that GCC signaling mediates regulation of intestinal barrier function. Paracellular permeability of intestinal segments was assessed in wild type (WT) and GCC deficient (GCC-/-) mice with and without lipopolysaccharide (LPS) challenge, as well as in UGN deficient (UGN-/-) mice. IFNγ and myosin light chain kinase (MLCK) levels were determined by real time PCR. Expression of tight junction proteins (TJPs), phosphorylation of myosin II regulatory light chain (MLC), and STAT1 activation were examined in intestinal epithelial cells (IECs) and intestinal mucosa. The permeability of Caco-2 and HT-29 IEC monolayers, grown on Transwell filters was determined in the absence and presence of GCC RNA interference (RNAi). We found that intestinal permeability was increased in GCC-/- and UGN-/- mice compared to WT, accompanied by increased IFNγ levels, MLCK and STAT1 activation in IECs. LPS challenge promotes greater IFNγ and STAT1 activation in IECs of GCC-/- mice compared to WT mice. Claudin-2 and JAM-A expression were reduced in GCC deficient intestine; the level of phosphorylated MLC in IECs was significantly increased in GCC-/- and UGN-/- mice compared to WT. GCC knockdown induced MLC phosphorylation, increased permeability in IEC monolayers under basal conditions, and enhanced TNFα and IFNγ-induced monolayer hyperpermeability. GCC signaling plays a protective role in the integrity of the intestinal mucosal barrier by regulating MLCK activation and TJ disassembly. GCC signaling activation may therefore represent a novel mechanism in maintaining the small bowel barrier in response to injury.

The guanylate cyclase C (GC-C) receptor regulates electrolyte and water secretion into the gut following activation by the E. coli enterotoxin STa, or by weaker endogenous agonists guanylin and uroguanylin. Our previous work has demonstrated that GC-C plays an important role in controlling initial infection as well as carrying load of non-invasive bacterial pathogens in the gut. Here, we use Salmonella enterica serovar Typhimurium to determine whether GC-C signaling is important in host defense against pathogens that actively invade enterocytes. In vitro studies indicated that GC-C signaling significantly reduces Salmonella invasion into Caco2-BBE monolayers. Relative to controls, GC-C knockout mice develop severe systemic illness following oral Salmonella infection, characterized by disrupted intestinal mucus layer, elevated cytokines and organ CFUs, and reduced animal survival. In Salmonella -infected wildtype mice, oral gavage of GC-C agonist peptide reduced host/pathogen physical interaction and diminished bacterial translocation to mesenteric lymph nodes. These studies suggest that early life susceptibility to STa-secreting enterotoxigenic E. coli may be counter-balanced by a critical role of GC-C in protecting the mucosa from non-STa producing, invasive bacterial pathogens.

Low levels of physical activity (PA) are reported to contribute to the occurrence of non-communicable diseases over the life course. Although psychological factors have been identified as an important category concerning PA behavior, knowledge on psychological determinants of PA is still inconclusive. Therefore, the aim of this umbrella systematic literature review (SLR) was to summarize and synthesize the scientific evidence on psychological determinants of PA behavior across the life course. A systematic online search was conducted on MEDLINE, ISI Web of Science, Scopus, and SPORTDiscus databases. The search was limited to studies published in English from January 2004 to April 2016. SLRs and meta-analyses (MAs) of observational studies investigating the association of psychological variables and PA were considered eligible. Extracted data were evaluated based on importance of determinants, strength of evidence, and methodological quality. The full protocol is available from PROSPERO (Record ID: CRD42015010616). Twenty reviews (14 SLRs and 6 MAs), mostly of moderate methodological quality, were found eligible. Convincing evidence was found for self-efficacy (positive association with PA) in children and adolescents, and stress (negative association with PA) regardless of age. Most of the evidence revealing an association between psychological determinants and PA is probable and limited, mainly due to differences in the definition of PA and of psychological determinants across reviews. Thus, scholars are urged to reach a consensus on clear definitions of relevant psychological determinants of PA, subsuming cultural biases and allowing the possibility to obtain clear interpretations and generalizability of findings. Finally, most psychological determinants should be considered within a larger framework of other multi-level determinants that may interact or mediate some of the effects.

The question whether new genetic modification techniques (nGM) in plant development might result in non-negligible negative effects for the environment and/or health is significant for the discussion concerning their regulation. However, current knowledge to address this issue is limited for most nGMs, particularly for recently developed nGMs, like genome editing, and their newly emerging variations, e.g., base editing. This leads to uncertainties regarding the risk/safety-status of plants which are developed with a broad range of different nGMs, especially genome editing, and other nGMs such as cisgenesis, transgrafting, haploid induction or reverse breeding. A literature survey was conducted to identify plants developed by nGMs which are relevant for future agricultural use. Such nGM plants were analyzed for hazards associated either (i) with their developed traits and their use or (ii) with unintended changes resulting from the nGMs or other methods applied during breeding. Several traits are likely to become particularly relevant in the future for nGM plants, namely herbicide resistance (HR), resistance to different plant pathogens as well as modified composition, morphology, fitness (e.g., increased resistance to cold/frost, drought, or salinity) or modified reproductive characteristics. Some traits such as resistance to certain herbicides are already known from existing GM crops and their previous assessments identified issues of concern and/or risks, such as the development of herbicide resistant weeds. Other traits in nGM plants are novel; meaning they are not present in agricultural plants currently cultivated with a history of safe use, and their underlying physiological mechanisms are not yet sufficiently elucidated. Characteristics of some genome editing applications, e.g., the small extent of genomic sequence change and their higher targeting efficiency, i.e., precision, cannot be considered an indication of safety , especially in relation to novel traits created by such modifications. All nGMs considered here can result in unintended changes of different types and frequencies. However, the rapid development of nGM plants can compromise the detection and elimination of unintended effects. Thus, a case-specific premarket risk assessment should be conducted for nGM plants, including an appropriate molecular characterization to identify unintended changes and/or confirm the absence of unwanted transgenic sequences.

Polymeric immunoglobulin receptor (pIgR) transport of secretory immunoglobulin A (SIgA) to mucosal surfaces is thought to promote gut integrity and immunity to Salmonella enterica serovar Typhimurium (S. Typhimurium), an invasive pathogen in mice. To elucidate potential mechanisms, we assessed intestinal barrier function and both oral and systemic S. Typhimurium virulence in pIgR knockout (KO) and wildtype (WT) mice. In uninfected animals, we harvested jejunal segments for Ussing chamber analyses of transepithelial resistance (TER); mesenteric lymph nodes (mLN) for bacterial culture; and serum and stool for IgA. Separately, we infected mice either orally or intravenously (IV) with S. Typhimurium to compare colonization, tissue dynamics, and inflammation between KOs and WTs. Uninfected KOs displayed decreased TER and dramatically increased serum IgA and decreased fecal IgA vs. WT; however, KO mLNs yielded fewer bacterial counts. Remarkably, WTs challenged orally with S. Typhimurium exhibited increased splenomegaly, tissue colonization, and pro-inflammatory cytokines vs. pIgR KOs, which showed increased survival following either oral or IV infection. Absence of pIgR compromises gut integrity but does not exacerbate bacterial translocation nor S. Typhimurium infection. These findings raise the possibility that immune adaptation to increased gut permeability and elevated serum IgA in the setting of SIgA deficiency provides compensatory protection against invasive gut pathogens.

Guanylate Cyclase C (GC-C; Gucy2c) is a transmembrane receptor expressed in intestinal epithelial cells. Activation of GC-C by its secreted ligand guanylin stimulates intestinal fluid secretion. Familial mutations in GC-C cause chronic diarrheal disease or constipation and are associated with intestinal inflammation and infection. Here, we investigated the impact of GC-C activity on mucosal immune responses. We utilized intraperitoneal injection of lipopolysaccharide to elicit a systemic cytokine challenge and then measured pro-inflammatory gene expression in colonic mucosa. GC-C(+/+) and GC-C(-/-) mice were bred with interleukin (IL)-10 deficient animals and colonic inflammation were assessed. Immune cell influx and cytokine/chemokine expression was measured in the colon of wildtype, IL-10(-/-), GC-C(+/+)IL-10(-/-) and GC-C(-/-)IL-10(-/-) mice. GC-C and guanylin production were examined in the colon of these animals and in a cytokine-treated colon epithelial cell line. Relative to GC-C(+/+) animals, intraperitoneal lipopolysaccharide injection into GC-C(-/-) mice increased proinflammatory gene expression in both whole colon tissue and in partially purified colonocyte isolations. Spontaneous colitis in GC-C(-/-)IL-10(-/-) animals was significantly more severe relative to GC-C(+/+)IL-10(-/-) mice. Unlike GC-C(+/+)IL-10(-/-) controls, colon pathology in GC-C(-/-)IL-10(-/-) animals was apparent at an early age and was characterized by severely altered mucosal architecture, crypt abscesses, and hyperplastic subepithelial lesions. F4/80 and myeloperoxidase positive cells as well as proinflammatory gene expression were elevated in GC-C(-/-)IL-10(-/-) mucosa relative to control animals. Guanylin was diminished early in colitis in vivo and tumor necrosis factor α suppressed guanylin mRNA and protein in intestinal goblet cell-like HT29-18-N2 cells. The GC-C signaling pathway blunts colonic mucosal inflammation that is initiated by systemic cytokine burst or loss of mucosal immune cell immunosuppression. These data as well as the apparent intestinal inflammation in human GC-C mutant kindred underscore the importance of GC-C in regulating the response to injury and inflammation within the gut.

Objective To examine the association of meat consumption with diabetes risk in the Hawaii component of the Multiethnic Cohort and to assess effect modification by ethnicity. Design A prospective cohort study. Baseline information on diet and lifestyle was assessed by questionnaire. The cohort was followed up for incident cases of diabetes, which were identified through self-reports, medication questionnaires, or health plan linkages. Cox regression was used to calculate hazard ratios (HR) and 95 % confidence intervals for diabetes associated with quintile of meat consumption. Setting Hawaii, USA. Subjects A total of 29 759 Caucasian, 35 244 Japanese-American and 10 509 Native Hawaiian men and women, aged 45–75 years at baseline. Results During a mean follow-up time of 14 years, 8587 incident diabetes cases were identified. Intake of red meat was positively associated with diabetes risk in men (fifth v. first quintile: HR = 1·43; 95 % CI 1·29, 1·59) and women (fifth v. first quintile: HR = 1·30; 95 % CI 1·17, 1·45) in adjusted models. The respective HR for processed red meat intake were 1·57 (95 % CI 1·42, 1·75) and 1·45 (95 % CI 1·30, 1·62). The association for processed poultry was weaker than for processed red meat, and fresh poultry intake was not associated with diabetes risk. For men only, we observed significant interactions of ethnicity with the red and processed red meat associations, with Caucasians experiencing slightly higher risks than Japanese-Americans. Conclusions Our findings support the growing evidence that red and processed meat intake increase risk for diabetes irrespective of ethnicity and level of BMI.

Guanylin (GN) and uroguanylin (UGN), through activation of guanylyl cyclase C (GCC), serve to control intestinal fluid homeostasis. Both peptides are produced in the intestinal epithelium, but their cellular origin has not been fully charted. Using quantitative PCR and an improved in situ hybridization technique (RNAscope), we have assessed the expression of GN ( Guca2a ), UGN ( Guca2b ), and GCC ( Gucy2c ) in mouse intestine. In the crypts of Lieberkühn, expression of Guca2a and Guca2b was restricted to cells of secretory lineage, at the crypt’s base, and to a region above, previously identified as a common origin of cellular differentiation. In this compartment, comparatively uniform levels of Guca2a and Guca2b expression were observed throughout the length of the gut. In contrast, Guca2a and Guca2b expression in the villus–surface region was more variable, and reflected the distinct, but overlapping expression pattern observed previously. Accordingly, in jejunum and ileum, Guca2a and Guca2b were abundantly expressed by enterocytes, whereas in colon only Guca2a transcript was found in the surface region. In duodenum, only low levels of Guca2b transcript were observed in columnar cells, and Guca2a expression was restricted entirely to cells of the secretory lineage. Gucy2c was shown to be expressed relatively uniformly along the rostrocaudal and crypt–villus axes and was also found in the duodenal glands. Our study reveals novel aspects of the cellular localization of the GCC signaling axis that, apart from its role in the regulation of fluid balance, link it to pH regulation, cell cycle control, and host defense.