ADGRL4/ELTD1 is an orphan adhesion GPCR (aGPCR) expressed in endothelial cells that regulates tumour angiogenesis. The majority of aGPCRs are orphan receptors. The Stachel Hypothesis proposes a ...mechanism for aGPCR activation, in which aGPCRs contain a tethered agonist (termed Stachel) C-terminal to the GPCR-proteolytic site (GPS) cleavage point which, when exposed, initiates canonical GPCR signalling. This has been shown in a growing number of aGPCRs. We tested this hypothesis on ADGRL4/ELTD1 by designing full length (FL) and C-terminal fragment (CTF) ADGRL4/ELTD1 constructs, and a range of potential Stachel peptides. Constructs were transfected into HEK293T cells and HTRF FRET, luciferase-reporter and Alphascreen GPCR signalling assays were performed. A stable ADGRL4/ELTD1 overexpressing HUVEC line was additionally generated and angiogenesis assays, signalling assays and transcriptional profiling were performed. ADGRL4/ELTD1 has the lowest GC content in the aGPCR family and codon optimisation significantly increased its expression. FL and CTF ADGRL4/ELTD1 constructs, as well as Stachel peptides, did not activate canonical GPCR signalling. Furthermore, stable overexpression of ADGRL4/ELTD1 in HUVECs induced sprouting angiogenesis, lowered in vitro anastomoses, and decreased proliferation, without activating canonical GPCR signalling or MAPK/ERK, PI3K/AKT, JNK, JAK/HIF-1α, beta catenin or STAT3 pathways. Overexpression upregulated ANTXR1, SLC39A6, HBB, CHRNA, ELMOD1, JAG1 and downregulated DLL4, KIT, CCL15, CYP26B1. ADGRL4/ELTD1 specifically regulates the endothelial tip-cell phenotype through yet undefined signalling pathways.
LTPCI (low temperature premixed compression ignition) strategies are capable of causing simultaneous reduction in NOx and PM (particulate matter) emissions and increment in HC (hydrocarbon) and CO ...(carbon monoxide) emission with more cyclic variation. In this study, the combustion characteristics, performance and exhaust emissions of the RCCI (reactivity controlled compression ignition) engine dual fueled CNG (compressed natural gas)/biodiesel were investigated experimentally at various load conditions. The results revealed that waste fish oil biodiesel as a high reactivity fuel in dual fuel mode led to a higher in-cylinder pressure with shorter heat release rate duration as compared to conventional combustion. CNG/biodiesel dual fuel was more stable with little cycle-to-cycle variations compared to CNG/diesel, especially for high engine loads. Also, the CNG/biodiesel dual fuel mode has about 1.6% more gross thermal efficiency and 2% lower combustion loss as compared to the CNG/diesel mode, averaged on all engine loads. CO emission concentration for CNG/biodiesel mode reached the same level as conventional combustion for high engine load conditions and its UHC (unburned hydrocarbon) emission reduced to about 32.5% compared to CNG/diesel case, averaged on all engine loads. Even though NOx emission amount for CNG/biodiesel case was higher than CNG/diesel, it was still much lower than conventional combustion with diesel or biodiesel fuels.
•CNG/Biodiesel leads to higher cylinder pressure together with shorter heat release.•The combustion in CNG/biodiesel is more stable than CNG/diesel at high engine loads.•Gross efficiency in CNG/biodiesel is 1.6% higher than CNG/diesel averagely.•CO emission in CNG/biodiesel mode reached the same level as CC at high engine load.•UHC reduces to about 32.5% compared to CNG/diesel, averaged on all engine loads.
Background
Catheter ablation is proven to be an effective strategy for drug refractory ventricular tachycardia (VT) in ischemic cardiomyopathy. However, the appropriate timing of VT ablation and ...identifying the group of patients that may receive the greatest benefit remains uncertain. There is limited data on the effect on prophylactic catheter ablation (PCA) in the prevention of implantable cardioverter defibrillator (ICD) therapy, electrical storm, and mortality.
Methods
We performed a comprehensive literature search through November 1, 2017, for all eligible studies comparing PCA + ICD versus ICD only in eligible patients with ischemic cardiomyopathy. Clinical outcomes included all ICD therapies including ICD shocks and electrical storm. Additional outcomes included all-cause mortality, cardiovascular mortality, and complications.
Results
Three randomized controlled trials (RCTs) (
N
= 346) met inclusion criteria. PCA was associated with a significantly lower ICD therapies (OR 0.49; CI 0.28 to 0.87;
p
= 0.01) including ICD shocks OR 0.38; CI 0.22 to 0.64;
p
= 0.0003) and electrical storm (OR 0.55; CI 0.30 to 1.01;
p
= 0.05) when compared with ICD only. There was no significant difference in all-cause mortality (OR 0.77; CI 0.41 to 1.46;
p
= 0.42), cardiovascular mortality (OR 0.49; CI 0.16 to 1.50;
p
= 0.21), and major adverse events (OR 1.45; CI 0.52 to 4.01;
p
= 0.47) between two groups.
Conclusion
These results suggest prophylactic catheter ablation decreases ICD therapies, including shocks and electrical storm with no improvement in overall mortality. There is a need for future carefully designed randomized clinical trials.
Since lifestyle changes are main therapies for non-alcoholic fatty liver disease (NAFLD), changing dietary components (nutritional or bioactive) may play a parallel important role. Few studies have ...assessed the effects of curcumin on NAFLD (mainly antioxidant and anti-inflammatory effects). We aimed to determine the effects of nano-curcumin (NC) on overweight/obese NAFLD patients by assessing glucose, lipids, inflammation, insulin resistance, and liver function indices, especially through nesfatin.
This double-blind, randomized, placebo-controlled clinical trial was conducted in the Oil Company Central Hospital, Tehran. 84 overweight/obese patients with NAFLD diagnosed using ultrasonography were recruited according to the eligibility criteria (age 25-50 yrs., body mass index BMI 25-35 kg/m
). The patients were randomly divided into two equal NC (
= 42) and placebo (n = 42) groups. Interventions were two 40 mg capsules/day after meals for 3 months. Lifestyle changes were advised. A general questionnaire, a 24-h food recall (at the beginning, middle and end), and the short-form international physical activity questionnaire (at the beginning and end) were completed. Also, blood pressure, fatty liver degree, anthropometrics, fasting blood sugar (FBS) and insulin (FBI), glycated hemoglobin (HbA1c), homeostasis model assessment-insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), tumor necrosis factor-alpha (TNF-α), high sensitive c-reactive protein (hs-CRP), interleukin-6 (IL-6), liver transaminases, and nesfatin were determined at the beginning and end.
NC compared with placebo significantly increased HDL, QUICKI, and nesfatin and decreased fatty liver degree, liver transaminases, waist circumference (WC), FBS, FBI, HbA1c, TG, TC, LDL, HOMA-IR, TNF-α, hs-CRP, and IL-6 (
< 0.05). The mean changes in weight, BMI, body composition (BC), and blood pressure were not significant (
> 0.05). After adjustment for confounders, the changes were similar to the unadjusted model.
NC supplementation in overweight/obese NAFLD patients improved glucose indices, lipids, inflammation, WC, nesfatin, liver transaminases, and fatty liver degree. Accordingly, the proposed mechanism for ameliorating NAFLD with NC was approved by the increased serum nesfatin and likely consequent improvements in inflammation, lipids, and glucose profile. Further trials of nano-curcumin's effects are suggested.
Iranian Registry of Clinical Trials, IRCT2016071915536N3. Registered 2016-08-02.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Recent technical advances have greatly facilitated G-protein coupled receptors crystallography as evidenced by the number of successful x-ray structures that have been reported recently. These ...technical advances include novel detergents, specialised crystallography techniques as well as protein engineering solutions such as fusions and conformational thermostabilisation. Using conformational thermostabilisation, it is possible to generate variants of GPCRs that exhibit significantly increased stability in detergent micelles whilst preferentially occupying a single conformation. In this paper we describe for the first time the application of this technique to a member of a class B GPCR, the corticotropin releasing factor receptor 1 (CRF1R). Mutational screening in the presence of the inverse agonist, CP-376395, resulted in the identification of a construct with twelve point mutations that exhibited significantly increased thermal stability in a range of detergents. We further describe the subsequent construct engineering steps that eventually yielded a crystallisation-ready construct which recently led to the solution of the first x-ray structure of a class B receptor. Finally, we have used molecular dynamic simulation to provide structural insight into CRF1R instability as well as the stabilising effects of the mutants, which may be extended to other class B receptors considering the high degree of structural conservation.
•In relation to the probiotic treatment process, it should not be recommended that probiotics could be used as a single treatment for H. pylori eradication.•However, use of probiotics as a supplement ...will increase eradication and reduce side effects associated with treatment.•It is widely believed that probiotics could improve the eradication of H. pylori and reduce side effects during standard treatment, but some probiotic bacterial species could be useful with drug therapy.•Generally, probiotic supplements could increase the eradication rate of H. pylori infections and reduced the side effects of antibiotics.
Chronic infection with Helicobacter pylori (H. pylori) is a known risk factor for gastric cancer. Eradication rate of H. pylori infection by the classic triple treatment of PPIs and antibiotics is low. Therefore, probiotics are a useful tool for improving the rate of eradication and reduction of side effects. Several studies in animal models showed that Lactobacillus spp. alone and in combination with other probiotic strains have inhibitory effects on growth and suppression of inflammatory responses in H. pylori infections. However, some studies showed significant effects of Pediococcus strains on suppression, survival, and eradication of H. pylori infections. Therefore, it is suggested that in the treatment of H. pylori infections along with the usual probiotic strains, different strains of Pediococcus could be used. Recent studies showed that Lactobacillus reuteri and Lactobacillus gasseri alone with PPIs in human have a high eradication effect on H. pylori infections and it is suggested as the probiotic treatment of patient's in future therapeutic protocols. In relation to the probiotic treatment process, it should not be recommended that probiotics could be used as a single treatment for H. pylori eradication. However, use of probiotics as a supplement will increase eradication and reduce side effects associated with treatment. It is widely believed that probiotics could improve the eradication of H. pylori and reduce side effects during standard treatment, but some probiotic bacterial species could be useful with drug therapy. Generally, probiotic supplements could increase the eradication rate of H. pylori infections and reduced the side effects of antibiotics.
James L. Januzzi, Jr., MD, FACC Chair, ACC Task Force on Expert Consensus Decision Pathways1 Abstract Tobacco use, especially cigarette smoking, is a major risk factor for cardiovascular morbidity ...and mortality and is the leading preventable cause of death worldwide. Patients who use any tobacco product should receive clear advice to stop tobacco use and be offered a brief intervention that includes prescriptions for proven pharmacological smoking cessation aids and proactive connection to evidence-based behavioral support based in the healthcare system and/or the community. Clinically, tobacco smoking increases the risk of coronary heart disease (CHD) (including myocardial infarction MI and sudden death), cerebrovascular disease (stroke), peripheral artery disease, and abdominal aortic aneurysm (10,12,13). Experimental, epidemiological, and clinical studies demonstrate a nonlinear dose effect of cigarette smoke exposure on CV function and CVD such that a low level of cigarette use is associated with a disproportionately large excess in CV risk (10,11,20–22).
The aim of this study is to apply the artificial neural network to identify the mathematical model of the combustion of a reactivity-controlled compression ignition (RCCI) engine fueled with natural ...gas and diesel oil. In this study, a single-cylinder heavy-duty diesel engine is set on operation at 9.4 bar gross indicated mean effective pressure. To implement the identification process, the effects of three control factors, namely the intake temperature, the intake pressure (both at the intake valve closing time), and the single-stage diesel fuel injection timing on the engine performance are assessed. Based on the design of experiments–fractional factorial concept, the randomized treatment combinations of chosen levels from the three selected control factors are employed to simulate the RCCI combustion. According to the engine’s responses derived from the RCCI combustion’s simulation, an artificial neural network is trained directly to identify the mathematical model of the RCCI combustion. The results show that the fractional factorial method is capable to produce an appropriate database for the artificial neural network’s training. Moreover, this method can predict more efficient scenarios in which the engine operation under the RCCI combustion has a desirable behavior. Also, artificial neural network as a powerful tool is effectively capable to predict the range of the excessive combustion noise occurrence, misfire occurrence, and the desirable engine load.
The first intracellular loop (ICL1) of G protein-coupled receptors (GPCRs) has received little attention, although there is evidence that, with the 8
helix (H8), it is involved in early ...conformational changes following receptor activation as well as contacting the G protein β subunit. In class B1 GPCRs, the distal part of ICL1 contains a conserved R
KLRCxR
motif that extends into the base of the second transmembrane helix; this is weakly conserved as a R/H
KLR/H motif in class A GPCRs. In the current study, the role of ICL1 and H8 in signaling through cAMP,
Ca
and ERK1/2 has been examined in two class B1 GPCRs, using mutagenesis and molecular dynamics. Mutations throughout ICL1 can either enhance or disrupt cAMP production by CGRP at the CGRP receptor. Alanine mutagenesis identified subtle differences with regard elevation of
Ca
, with the distal end of the loop being particularly sensitive. ERK1/2 activation displayed little sensitivity to ICL1 mutation. A broadly similar pattern was observed with the glucagon receptor, although there were differences in significance of individual residues. Extending the study revealed that at the CRF1 receptor, an insertion in ICL1 switched signaling bias between
Ca
and cAMP. Molecular dynamics suggested that changes in ICL1 altered the conformation of ICL2 and the H8/TM7 junction (ICL4). For H8, alanine mutagenesis showed the importance of E390
for all three signal transduction pathways, for the CGRP receptor, but mutations of other residues largely just altered ERK1/2 activation. Thus, ICL1 may modulate GPCR bias
interactions with ICL2, ICL4 and the Gβ subunit.
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