Background Identifying predictive markers for future atherosclerotic cardiovascular diseases may be helpful to motivate young adults to promote healthy lifestyle. We sought to determine the ...association between persistently elevated low‐density lipoprotein‐cholesterol (LDL‐C) and/or triglyceride levels and the atherosclerotic cardiovascular diseases risks in young adults. Methods and Results We conducted a nationwide population‐based cohort study of 1 887 853 statin‐naive adults aged 20 to 39 years, with LDL‐C <190 mg/dL, using the Korean National Health Insurance Service database. Persistently elevated LDL‐C and triglyceride levels were defined by ≥3 measurements of ≥160 and ≥175 mg/dL, respectively. The primary outcome was a composite of stroke and myocardial infarction. Among the study population, 11 121 (0.59%) and 167 373 (8.87%) had persistently elevated LDL‐C and triglycerides, respectively. During a median follow‐up of 5.2 years, 2170 and 1537 incidences of stroke (0.16%) and myocardial infarction (0.23%) occurred. Persistently elevated LDL‐C levels were significantly associated with increased risks of the primary outcome, with an adjusted hazard ratio (HR) of 1.396 (95% CI, 1.005–1.940). This association was independent of high‐density lipoprotein cholesterol. Persistently elevated triglycerides were significantly associated with increased risks of the primary outcome (HR, 1.120; 95% CI, 1.015–1.236), but attenuated after adjustment for high‐density lipoprotein cholesterol. Conclusions Persistently elevated LDL‐C and triglyceride levels were associated with atherosclerotic cardiovascular diseases risk in young Korean adults without severe hypercholesterolemia. These lipid abnormalities should be considered risk factors in young adults since their effects on lifetime atherosclerotic cardiovascular diseases risk may become more pronounced over the life course.
mTOR, which can form mTOR Complex 1 (mTORC1) or mTOR Complex 2 (mTORC2) depending on its binding partners, is frequently deregulated in the pulmonary neoplastic conditions and interstitial lung ...diseases of the patients treated with rapalogs. In this study, we investigated the relationship between mTOR signaling and epithelial mesenchymal transition (EMT) by dissecting mTOR pathways.
Components of mTOR signaling pathway were silenced by shRNA in a panel of non-small cell lung cancer cell lines and protein expression of epithelial and mesenchymal markers were evaluated by immunoblotting and immunocytochemistry. mRNA level of the E-cadherin repressor complexes were evaluated by qRT-PCR.
IGF-1 treatment decreased expression of the E-cadherin and rapamycin increased its expression, suggesting hyperactivation of mTOR signaling relates to the loss of E-cadherin. Genetic ablation of rapamycin-insensitive companion of mTOR (Rictor), a component of mTORC2, did not influence E-cadherin expression, whereas genetic ablation of regulatory-associated protein of mTOR (Raptor), a component of mTORC1, led to a decrease in E-cadherin expression at the mRNA level. Increased phosphorylation of AKT at Ser473 and GSK-3β at Ser9 were observed in the Raptor-silenced NSCLC cells. Of the E-cadherin repressor complexes tested, Snail, Zeb2, and Twist1 mRNAs were elevated in raptor-silenced A549 cells, and Zeb2 and Twist1 mRNAs were elevated in Raptor-silenced H2009 cells. These findings were recapitulated by treatment with the GSK-3β inhibitor, LiCl. Raptor knockdown A549 cells showed increased expression of N-cadherin and vimentin with mesenchymal phenotypic changes.
In conclusion, selective inhibition of mTORC1 leads to hyperactivation of the AKT/GSK-3β pathway, inducing E-cadherin repressor complexes and EMT. These findings imply the existence of a feedback inhibition loop of mTORC1 onto mTORC2 that plays a role in the homeostasis of E-cadherin expression and EMT, requiring caution in the clinical use of rapalog and selective mTORC1 inhibitors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Currently, many children undergo precocious puberty, resulting in short stature due to premature closure of the growth plate. Pulsed electromagnetic field (PEMF) stimulation induces cell ...proliferation of articular chondrocytes. We developed a method for growth promotion using equipment with PEMF. In this study, we aimed to evaluate the effects of PEMF on the growth rate of growth plates using an animal model. An experimental study was conducted on 16 3-week-old rats to validate the effects of the growth care device on growth and development by PEMF stimulation at 28 Hz and 20 Gauss. The tibia bones of the groups with and without PEMF administration were dissected after 10 days, and then, the length of the growth plate of the knee and levels of insulin-like growth factor (IGF)-1 hormone in serum were measured. The length of the growth plate on the tibia bone and the levels of circulating IGF-1 were significantly increased by 25.6% and 13.6%, respectively, in the experimental group to which PEMF was applied compared to those of the control group, without any side effects. These results suggest that PEMF can safely stimulate growth of the growth plate in a non-invasive manner to promote bone growth.
OBJECTIVESHepatocellular carcinoma can develop after hepatitis C virus eradication. We developed a new hepatocellular carcinoma risk score (HCC-SVR score) based on independent predictors for chronic ...hepatitis C after sustained virological response.
METHODSBetween 2003 and 2016, a total of 1193 patients with chronic hepatitis C who achieved sustained virological response through antiviral therapy were included (669 for training cohort and 524 for validation cohort). The HCC-SVR score was developed using multivariate Cox proportional hazards regression modelling.
RESULTSHepatocellular carcinoma (n = 19) occurred more frequently in older, male patients and was associated with liver cirrhosis; hypertension; diabetes; lower platelet count; higher alpha-fetoprotein, aspartate, and alanine aminotransferase; lower total cholesterol; and higher fibrosis-4 index (FIB-4) (all P < 0.05). FIB-4 (hazard ratio = 1.080), male gender (hazard ratio = 8.189), and higher alpha-fetoprotein (hazard ratio = 1.060) independently predicted hepatocellular carcinoma (all P < 0.05). HCC-SVR score successfully predicted hepatocellular carcinoma development risk area under receiver operating characteristic curve (AUC) = 0.771, 0.857, and 0.911 at 2, 4, and 6 years, respectively. The cumulative incidence rate of hepatocellular carcinoma differed significantly among groups stratified by HCC-SVR risk score (0–2 points, low; 3–7 points, intermediate; 8–9 points, high risk) (all P < 0.05 by log-rank test). HCC-SVR score was maintained in a validation cohort (n = 524) (AUC = 0.728 at 2 years, 0.737 at 4 years, and 0.809 at 6 years).
CONCLUSIONThe HCC-SVR score enables risk stratification for hepatocellular carcinoma development at sustained virological response in patients with chronic hepatitis C.
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•The QD2s which showed 500 times stronger photo- luminescence than individual QDs were successfully applied a virus detection with a broad dynamic range and high ...sensitivity.•Streptavidin was detected within a range of 10zM to 10nM in the system via biotin–streptavidin interaction.•Clinical applicability was examined using the avian virus with a detection range of 4.76×10-4∼3.2HAU/mL, which is comparable to PCR and approximately 2100 times higher sensitivity than the conventional hemagglutination method.•The QD2 based system could detect target molecules with high sensitivity without requiring an amplification step.
As virus spread can lead to severe epidemics and pandemics associated with high mortality, it is necessary to have a highly sensitive detection method for viruses. Although various detection methods have been developed so far, current methods in detecting a virus require preprocessing and involve quite intricate processes of low sensitivity. Here, we have developed a virus detection method with a broad dynamic range and high sensitivity, based on immuno-complex formation between quantum dot (QD)-embedded silica nanoparticles (QD2) and magnetic beads. The multiple QD- containing QD2s showed 500 times stronger photoluminescence than individual QDs. When biotin was immobilized as a ligand, streptavidin was detected in a range of 10zM to 10nM. The clinical applicability of the QD2-based system was examined using the avian virus (i.e., H1N1 influenza virus), and it showed a detection range of 4.76×10−4< span class="xps_thinspace"> ∼3.2 hemagglutination unit/mL. This result is comparable to the polymerase chain reaction method, and is approximately 2100 times more sensitive than the conventional hemagglutination method. Since the QD2-based system could detect target molecules with high sensitivity without requiring an amplification step, it can be applied in various biomedical and clinical fields.
Transforming growth factor-β1 (TGF-β1) induces the differentiation of human adipose tissue-derived mesenchymal stem cells (hASCs) into smooth muscle cells. Lipid rafts are cholesterol-rich ...microdomains in cell membranes that reportedly play a key role in receptor-mediated signal transduction and cellular responses. In order to clarify whether lipid rafts are involved in TGF-β1-induced differentiation of hASCs into smooth muscle cells, we analyzed the lipid raft proteome of hASCs.
Pretreatment of hASCs with the lipid raft disruptor methyl-β-cyclodextrin abrogated TGF-β1-induced expression of α-smooth muscle actin, a smooth muscle cell marker, suggesting a pivotal role of lipid rafts in TGF-β1-induced differentiation of hASCs to smooth muscle cells. Sucrose density gradient centrifugation along with a shotgun proteomic strategy using liquid chromatography-tandem mass spectrometry identified 1002 individual proteins as the lipid raft proteome, and 242 of these were induced by TGF-β1 treatment. ADAM12, a disintegrin and metalloproteases family member, was identified as the most highly up-regulated protein in response to TGF-β1 treatment. TGF-β1 treatment of hASCs stimulated the production of both ADAM12 protein and mRNA. Silencing of endogenous ADAM12 expression using lentiviral small hairpin RNA or small interfering RNA abrogated the TGF-β1-induced differentiation of hASCs into smooth muscle cells.
These results suggest a pivotal role for lipid raft-associated ADAM12 in the TGF-β1-induced differentiation of hASCs into smooth muscle cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Environmental disinfection with continuously antimicrobial surfaces could offer superior control of surface bioburden. We sought to decide the efficacy of photocatalyst antimicrobial coating in ...reducing methicillin-resistant Staphylococcus aureus (MRSA) acquisition in high incidence setting.
We performed prospective cohort study involving patients hospitalized in medical intensive care unit. A titanium dioxide-based photocatalyst was coated on high touch surfaces and walls. Five months of pre-intervention data were compared with five months of post-intervention data. The incidence rates of multidrug-resistant organism acquisition and the rates of hospital-acquired blood stream infection, pneumonia, urinary tract infection, and Clostridium difficile-associated diseases were compared using Cox proportional hazards regression analysis.
In total, 621 patients were included. There was significant decrease in MRSA acquisition rate after photocatalyst coating (hazard ratio, 0.37; 95% confidence interval, 0.14-0.99; p = 0.04). However, clinical identification of vancomycin-resistant Enterococcus spp. and multidrug-resistant Acinetobacter baumannii did not decrease significantly. The hazard of contracting hospital-acquired pneumonia during the intervention period compared to baseline period was 0.46 (95% confidence interval, 0.23-0.94; p = 0.03).
In conclusion, MRSA rate was significantly reduced after photocatalyst coating. We provide evidence that photocatalyst disinfection can be an adjunctive measure to control MRSA acquisition in high-incidence settings.
ISRCTN Registry ( ISRCTN31972004 ). Registered retrospectively on November 19, 2018.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dyslipidaemia is a modifiable cardiovascular risk factor with prognostic implications. Current strategies for lipid management in young adults are largely based on expert recommendations. We ...investigated the risks of death and cardiovascular disease in relation to each lipid component to establish evidence for primary prevention in young adults.
In this nationwide population-based cohort study, we analysed 5,688,055 statin-naïve subjects, aged 20-39 years, undergoing general health check-ups between 2009 and 2014. The endpoint was a composite of clinical events including death, myocardial infarction (MI), and stroke. We compared the incidence and risk of clinical events according to each lipid variable.
During follow-up (median 7.1 years), clinical events occurred in 30,330 subjects (0.53%): 16,262 deaths (0.29%), 8578 MIs (0.15%), and 5967 strokes (0.10%). The risk of clinical events gradually increased with increasing total cholesterol (TC) and triglycerides and decreasing high-density lipoprotein cholesterol (HDL-C), largely driven by MI. Low-density lipoprotein cholesterol (LDL-C) had a J-shaped association with clinical events, showing the lowest risk for LDL-C of 84-101 mg/dL. Among lipid variables, triglycerides remained the sole independent predictor (adjusted hazard ratio, 1.20;
< 0.001) after adjusting for conventional risk factors.
For statin-naïve young adults, the risk of clinical events was proportional to lipid levels, positively with TC and triglycerides, negatively with HDL-C, and J-shaped with LDL-C. Triglycerides had an independent and the strongest association with the clinical events. Screening and intervention for abnormal lipid levels, particularly triglycerides, from an early age might be of clinical value.
We report the fabrication and DC and microwave characteristics of 0.5μm AlGaN/GaN high electron mobility transistors using double plasma treatment process. Silicon nitride layers 700 and 150Å thick ...were deposited by plasma-enhanced chemical vapor deposition at 260°C to protect the device and to define the gate footprint. The double plasma process was carried out by two different etching techniques to obtain enhancement-mode AlGaN/GaN high electron mobility transistors with 0.5μm gate lengths. The enhancement-mode AlGaN/GaN high electron mobility transistor was prepared in parallel to the depletion-mode AlGaN/GaN high electron mobility transistor device on one wafer. Completed double plasma treated 0.5μm AlGaN/GaN high electron mobility transistor devices fabricated by dry etching exhibited a peak transconductance, gm, of 330mS/mm, a breakdown voltage of 115V, a current-gain cutoff frequency (fT) of 18GHz, and a maximum oscillation frequency (fmax) of 66GHz.
•The double plasma process was carried out by two different etching techniques.•Double plasma treated device exhibited a transconductance of 330mS/mm.•Completed 0.5μm gate device exhibited a current-gain cutoff frequency of 18GHz.•The off-state breakdown voltage of 115V for 0.5μm gate device was obtained.•Continuous-wave output power density of 4.3W/mm was obtained at 2.4GHz.
Several studies have shown that dysfunction of macroautophagy/autophagy is associated with many human diseases, including neurodegenerative disease and cancer. To explore the molecular mechanisms of ...autophagy, we performed a cell-based functional screening with SH-SY5Y cells stably expressing GFP-LC3, using an siRNA library and identified TMED10 (transmembrane p24 trafficking protein 10), previously known as the γ-secretase-modulating protein, as a novel regulator of autophagy. Further investigations revealed that depletion of TMED10 induced the activation of autophagy. Interestingly, protein-protein interaction assays showed that TMED10 directly binds to ATG4B (autophagy related gene 4B cysteine peptidase), and the interaction is diminished under autophagy activation conditions such as rapamycin treatment and serum deprivation. In addition, inhibition of TMED10 significantly enhanced the proteolytic activity of ATG4B for LC3 cleavage. Importantly, the expression of TMED10 in AD (Alzheimer disease) patients was considerably decreased, and downregulation of TMED10 increased amyloid-β (Aβ) production. Treatment with Aβ increased ATG4B proteolytic activity as well as dissociation of TMED10 and ATG4B. Taken together, our results suggest that the AD-associated protein TMED10 negatively regulates autophagy by inhibiting ATG4B activity.Abbreviations: Aβ: amyloid-β; AD: Alzheimer disease; ATG: autophagy related; BECN1: beclin 1; BiFC: bimolecular fluorescence complementation; CD: cytosolic domain; GFP: green fluorescent protein; GLUC: Gaussia luciferase; IP: immunoprecipitation; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LD: luminal domain; PD: Parkinson disease; ROS: reactive oxygen species; siRNA: small interfering RNA; SNP: single-nucleotide polymorphisms; TD: transmembrane domain; TMED10: transmembrane p24 trafficking protein 10; VC: C terminus of Venus fluorescent protein; VN: N terminus of Venus fluorescent protein.
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