Ketogenesis is considered to occur primarily in liver to generate ketones as an alternative energy source for non-hepatic tissues when glucose availability/utilization is impaired. ...3-Hydroxy-3-methylglutaryl-CoA synthase-2 (HMGCS2) mediates the rate-limiting step in this mitochondrial pathway. Publicly available databases show marked down-regulation of HMGCS2 in colonic tissues in Crohn's disease and ulcerative colitis. This led us to investigate the expression and function of this pathway in colon and its relevance to colonic inflammation in mice. Hmgcs2 is expressed in cecum and colon. As global deletion of Hmgcs2 showed significant postnatal mortality, we used a conditional knockout mouse with enzyme deletion restricted to intestinal tract. These mice had no postnatal mortality. Fasting blood ketones were lower in these mice, indicating contribution of colonic ketogenesis to circulating ketones. There was also evidence of gut barrier breakdown and increased susceptibility to experimental colitis with associated elevated levels of IL-6, IL-1β, and TNF-α in circulation. Interestingly, many of these phenomena were mostly evident in male mice. Hmgcs2 expression in colon is controlled by colonic microbiota as evidenced from decreased expression in germ-free mice and antibiotic-treated conventional mice and from increased expression in a human colonic epithelial cell line upon treatment with aqueous extracts of cecal contents. Transcriptomic analysis of colonic epithelia from control mice and Hmgcs2-null mice indicated an essential role for colonic ketogenesis in the maintenance of optimal mitochondrial function, cholesterol homeostasis, and cell-cell tight-junction organization. These findings demonstrate a sex-dependent obligatory role for ketogenesis in protection against colonic inflammation in mice.
Abstract
Context
ANGPTL8 (A8) plays a key role in determining the tissue fate of circulating triglycerides (TGs). Plasma A8 levels are associated with several parameters of glucose and TG metabolism, ...but the causality of these relationships and the contribution of genetic variants to differences in A8 levels have not been explored.
Objective
To characterize the frequency distribution of plasma A8 levels in a diverse population using a newly-developed enzyme-linked immunosorbent assay (ELISA) and to identify genetic factors contributing to differences in plasma A8 levels.
Methods
We studied a population-based sample of Dallas County, comprising individuals in the Dallas Heart Study (DHS-1, n = 3538; DHS-2, n = 3283), including 2131 individuals with repeated measurements 7 to 9 years apart (age 18-85 years; >55% female; 52% Black; 29% White; 17% Hispanic; and 2% other). The main outcome measures were associations of A8 levels with body mass index (BMI), plasma levels of glucose, insulin, lipids, and hepatic TGs, as well as DNA variants identified by exome-wide sequencing.
Results
A8 levels varied over a 150-fold range (2.1-318 ng/mL; median, 13.3 ng/mL) and differed between racial/ethnic groups (Blacks > Hispanics > Whites). A8 levels correlated with BMI, fasting glucose, insulin, and TG levels. A variant in A8, R59W, accounted for 17% of the interindividual variation in A8 levels but was not associated with the metabolic parameters correlated with plasma A8 concentrations.
Conclusions
A8 levels were strongly associated with indices of glucose and TG metabolism, but the lack of association of genetic variants at the A8 locus that impact A8 levels with these parameters indicates that differences in A8 levels are not causally related to the associated metabolic phenotypes.
Silicon nitride (SiN
x
) thin films have been deposited by a new remote plasma deposition system HiTUS (High Target Utilisation Sputtering). The remote plasma geometry allows, pseudo separation of ...plasma/target-bias parameters, lower ion bombardment, and effectively eliminates poisoning, making it an attractive option for stable reactive sputtering of important electronic and photovoltaic films including silicon nitride. Transmission and absorbance measurements on glass were performed in order to evaluate the absorbance of the silicon nitride thin layer. The SiN
x
is produced by reactive sputtering from a silicon target in an Ar/N
2
atmosphere, negating the use of silane gas in difference to the more commonly used PECVD method. A deposition rates up to 0.7 nm/s have been obtained. Control of refractive index from 1.9 to 2.3 was achieved by varying the RF target bias, meeting the requirements for silicon passivation in PV applications, with a growth rate independent of refractive index across a wide range. The carrier life time over a range of specified minority carrier densities was measured using a contactless inductively coupled photoconductance tester for 50 ohm cm 〈100〉 oriented silicon wafers coated with different types of SiN
x
. We found that the passivation action of the silicon nitride increased the carrier lifetime over one order of magnitude.
Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2000.
Includes bibliographical references (leaves 114-117).
by Michael Kevin Bass.
S.M.
This is a replication and extension of the Bass and Coleman (1996) study. The current study extends the initial investigation through the use of a standardized instrument to assess whether the Sphinx ...club, a school-based Africentric intervention enhances academic achievement in African American middle school boys who are at risk for academic failure or underachievement. This intervention combined the principles of the rites of passage movement within African American communities and current thinking on the process of second culture acquisition to focus on developing the participants' sense of ethnic self as a precursor to academic performance. This investigation adds a Social Skills Intervention (Elliott & Gresham, 1991) for the control group and participants were randomly assigned to their treatment condition. Results from the Classroom Behavior Scale (Bass & Coleman, 1996), Grade Point Average, Academic Self-Efficacy Scale-AV (Coleman, 1996), Multigroup Ethnic Identity Measure (Phinney, 1992) Social Skills Rating System (Gresham & Elliott, 1990) and Disciplinary referrals indicated that culturally relevant interventions (Sphinx Club) can be as successful as monocultural interventions (Social Skills intervention). Based on the results of the investigation it appears that social skills development has a stronger relationship to students' attitude toward academic achievement, whereas increasing one's ethnic identity has a stronger relationship to student's actual academic achievement. It also adds to the body of empirical research, which is currently being conducted on culturally relevant interventions.
Ion-selective electrodes (ISE's) are routinely used to measure electrolyte concentrations in biological fluids such as blood and urine. The process involves the transduction of ion activity to a ...potential within a sensing membrane. This membrane typically consists of a plastic phase (e.g., plasticized PVC) impregnated with a highly specific ion-binding molecule. It is desirable to determine the relationship between formulation and function. Such knowledge would enable developers to achieve required performance specifications for sensor slope, longevity, and transient response. This research focused on the analysis of a planar format Na+ sensor, fabricated with the use of thick-film screen printing technology. A model was developed to interpret electrode responses in terms of fundamental physical processes. These processes included interfacial transport (kinetics, solubility), electrodiffusion (Nernst-Planck), and ion-ionophore complexation. Potentials were calculated from the Poisson equation using the resulting time-dependent concentration distributions. Model mechanisms were converted to mathematical expressions and discretized for computer simulation. Experimental design techniques were used to efficiently determine the significance of model input parameters. Results from this exercise specified membrane formulations to be fabricated, tested, and compared to the model. Both model and laboratory sensors revealed a diffusion controlled "warm-up" conditioning phase upon sample exposure. When membrane formulations and thicknesses were varied, electrode responses were altered in the direction predicted by the model. It was concluded that the model could predict the direction of "warm-up" and transient responses with regard to voltage and time as a result of changing inputs. Such correlation between model and laboratory advocates that sensor performance is determined by the physical and chemical parameters of the membrane; hence, formulation and thickness. In addition, the research showed that membrane function is not limited to the electrode/electrolyte interface; rather, it also depends on processes within the membrane bulk. However, because of the disparity between model and laboratory electrodes for voltage spans and response times, it was concluded that the model was neglecting essential mechanisms such as ion-exchange and water interactions.
Patients with mammographically dense breast tissue have a greatly increased risk of developing breast cancer. Dense breast tissue contains more stromal collagen, which contributes to increased matrix ...stiffness and alters normal cellular responses. Stromal collagen within and surrounding mammary tumors is frequently aligned and reoriented perpendicular to the tumor boundary. We have shown that aligned collagen predicts poor outcome in breast cancer patients, and postulate this is because it facilitates invasion by providing tracks on which cells migrate out of the tumor. However, the mechanisms by which alignment may promote migration are not understood. Here, we investigated the contribution of matrix stiffness and alignment to cell migration speed and persistence. Mechanical measurements of the stiffness of collagen matrices with varying density and alignment were compared with the results of a 3D microchannel alignment assay to quantify cell migration. We further interpreted the experimental results using a computational model of cell migration. We find that collagen alignment confers an increase in stiffness, but does not increase the speed of migrating cells. Instead, alignment enhances the efficiency of migration by increasing directional persistence and restricting protrusions along aligned fibers, resulting in a greater distance traveled. These results suggest that matrix topography, rather than stiffness, is the dominant feature by which an aligned matrix can enhance invasion through 3D collagen matrices.
Rifaximin treatment in hepatic encephalopathy Bass, Nathan M; Mullen, Kevin D; Sanyal, Arun ...
New England journal of medicine/The New England journal of medicine,
03/2010, Letnik:
362, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Hepatic encephalopathy is a chronically debilitating complication of hepatic cirrhosis. The efficacy of rifaximin, a minimally absorbed antibiotic, is well documented in the treatment of acute ...hepatic encephalopathy, but its efficacy for prevention of the disease has not been established.
In this randomized, double-blind, placebo-controlled trial, we randomly assigned 299 patients who were in remission from recurrent hepatic encephalopathy resulting from chronic liver disease to receive either rifaximin, at a dose of 550 mg twice daily (140 patients), or placebo (159 patients) for 6 months. The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy. The key secondary end point was the time to the first hospitalization involving hepatic encephalopathy.
Rifaximin significantly reduced the risk of an episode of hepatic encephalopathy, as compared with placebo, over a 6-month period (hazard ratio with rifaximin, 0.42; 95% confidence interval CI, 0.28 to 0.64; P<0.001). A breakthrough episode of hepatic encephalopathy occurred in 22.1% of patients in the rifaximin group, as compared with 45.9% of patients in the placebo group. A total of 13.6% of the patients in the rifaximin group had a hospitalization involving hepatic encephalopathy, as compared with 22.6% of patients in the placebo group, for a hazard ratio of 0.50 (95% CI, 0.29 to 0.87; P=0.01). More than 90% of patients received concomitant lactulose therapy. The incidence of adverse events reported during the study was similar in the two groups, as was the incidence of serious adverse events.
Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo. Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy. (ClinicalTrials.gov number, NCT00298038.)
PDF
