Modeling of mPGES-1 Three-Dimensional Structures: Applications in Drug Design and Discovery

This invention relates to representations of prostaglandin synthase three-dimensional structures. Such representations are suitable for designing agents that modulate the activity of the enzyme by binding to the substrate binding domain

The Long-Term Effects of Blood Urea Nitrogen Levels on Cardiovascular Disease and All-Cause Mortality in Diabetes: A Prospective Cohort Study

BACKGROUND: The long-term effects of blood urea nitrogen(BUN) in patients with diabetes remain unknown. Current studies reporting the target BUN level in patients with diabetes are also limited. Hence, this prospective study aimed to explore the relationship of BUN with all-cause and cardiovascular mortalities in patients with diabetes. METHODS: In total, 10,507 participants with diabetes from the National Health and Nutrition Examination Survey (1999-2018) were enrolled. The causes and numbers of deaths were determined based on the National Death Index mortality data from the date of NHANES interview until follow-up (December 31, 2019). Multivariate Cox proportional hazard regression models were used to calculate the hazard ratios (HRs) and 95% confidence interval (CIs) of mortality. RESULTS: Of the adult participants with diabetes, 4963 (47.2%) were female. The median (interquartile range) BUN level of participants was 5 (3.93-6.43) mmol/L. After 86,601 person-years of follow-up, 2,441 deaths were documented. After adjusting for variables, the HRs of cardiovascular disease (CVD) and all-cause mortality in the highest BUN level group were 1.52 and 1.35, respectively, compared with those in the lowest BUN level group. With a one-unit increment in BUN levels, the HRs of all-cause and CVD mortality rates were 1.07 and 1.08, respectively. The results remained robust when several sensitivity and stratified analyses were performed. Moreover, BUN showed a nonlinear association with all-cause and CVD mortality. Their curves all showed that the inflection points were close to the BUN level of 5 mmol/L. CONCLUSION: BUN had a nonlinear association with all-cause and CVD mortality in patients with diabetes. The inflection point was at 5 mmol/L

Ruin Probabilities in the Mixed Claim Frequency Risk Models

We consider two mixed claim frequency risk models. Some important probabilistic properties are obtained by probability-theory methods. Some important results about ruin probabilities are obtained by martingale approach

Receptor-Interacting Protein 1 and 3 Kinase Activity Are Required for High-Fat Diet Induced Liver Injury in Mice

BACKGROUND: The RIP1-RIP3-MLKL-mediated cell death pathway is associated with progression of non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH). Previous work identified a critical role for MLKL, the key effector regulating necroptosis, but not RIP3, in mediating high fat diet-induced liver injury in mice. RIP1 and RIP3 have active N-terminus kinase domains essential for activation of MLKL and subsequent necroptosis. However, little is known regarding domain-specific roles of RIP1/RIP3 kinase in liver diseases. Here, we hypothesized that RIP1/RIP3 kinase activity are required for the development of high fat diet-induced liver injury. METHODS:Rip1K45A/K45A and Rip3K51A/K51A kinase-dead mice on a C57BL/6J background and their littermate controls (WT) were allowed free access to a diet high in fat, fructose and cholesterol (FFC diet) or chow diet. RESULTS: Both Rip1K45A/K45A and Rip3K51A/K51A mice were protected against FFC diet-induced steatosis, hepatocyte injury and expression of hepatic inflammatory cytokines and chemokines. FFC diet increased phosphorylation and oligomerization of MLKL and hepatocyte death in livers of WT, but not in Rip3K51A/K51A, mice. Consistent with in vivo data, RIP3 kinase deficiency in primary hepatocytes prevented palmitic acid-induced translocation of MLKL to the cell surface and cytotoxicity. Additionally, loss of Rip1 or Rip3 kinase suppressed FFC diet-mediated formation of crown-like structures (indicators of dead adipocytes) and expression of mRNA for inflammatory response genes in epididymal adipose tissue. Moreover, FFC diet increased expression of multiple adipokines, including leptin and plasminogen activator inhibitor 1, in WT mice, which was abrogated by Rip3 kinase deficiency. DISCUSSION: The current data indicate that both RIP1 and RIP3 kinase activity contribute to FFC diet-induced liver injury. This effect of RIP1 and RIP3 kinase deficiency on injury is consistent with the protection of protection in Rip3-/- mice. Taken together with previous reports, our data suggest that other domains of RIP3 likely counteract the effect of RIP3 kinase in response to high fat diets

Green Fluorescent Protein GFP-Chromophore-Based Probe for the Detection of Mitochondrial Viscosity in Living Cells

Viscosity is a pivotal factor for indicating the dysfunction of the mitochondria. To date, most of the fluorescent probes developed for mitochondrial viscosity have been designed using BODIPY, hemicyanine, or pyridine-based molecular rotors as part of the core structure. Our aim with this research was to extend the range of suitable fluorophores available for the construction of such fluorescent molecular rotors for evaluating the viscosity of mitocondria. Herein, we have developed a green fluorescent protein (GFP)-chromophore-based fluorescent probe (MIT-V) for the detection of mitochondrial viscosity in live cells. MIT-V exhibited a high sensitivity toward viscosity (from 7.9 cP to 438.4 cP). The "off-on"sensing mechanism of MIT-V was ascribed to the restricted rotation of single bonds and excited-state C= C double bonds of MIT-V. Cell studies indicated that MIT-V targets the mitochondria and that it was able to monitor real-time changes in the viscosity of live HeLa cell mitochondria. Therefore, we propose that MIT-V can be used as an effective chemosensor for the real-time imaging of mitochondrial viscosity in live cells. Our results clearly demonstrate the utility of such GFP-chromophore-based derivatives for the development of viscosity-sensitive systems.</p

Capability of four sigmoidoscopy-based screening strategies to predict proximal neoplasia in an asymptomatic Chinese population

Background and Aim: A proper colonoscopy referral criterion is essential for flexible sigmoidoscopy‐based colorectal cancer screening. We aimed to compare the predictive capability of four existing criteria to detect proximal neoplasia (PN) and advanced proximal neoplasia (APN) in a Chinese population. Methods: Asymptomatic Chinese participants aged 50–75 years, who received screening colonoscopy, were consecutively recruited. The four criteria included (i) UK flexible sigmoidoscopy; (ii) Italian Screening for COlon REctum; (iii) NORwegian Colorectal Cancer Prevention trial; and (iv) US clinical index. The sensitivity, specificity, positive/negative predictive value, and the number of subjects needed to screen (NNS)/refer (NNR) to detect one APN/PN were examined. The area under receiver operating characteristic curve was evaluated. Results: Among 5833 subjects, 749 (12.8%) and 151 (2.6%) cases were found to have PN and APN, respectively. US criteria achieved the highest sensitivity for PN (49%) and APN (66%), while UK criteria attained the highest specificity (93%) for PN/APN. The lowest NNS was required by US criteria for PN (16 vs 19–38) and APN (58 vs 69–86), while the lowest NNR was required by UK criteria for PN (3.2 vs 4.0–4.8) and APN (7 vs 10–16). The receiver operating characteristic of all four criteria was 0.57–0.61 for PN and 0.68–0.70 for APN. Conclusions: Among all the four criteria, US criteria had the highest sensitivity and lowest NNS, while UK criteria achieved the highest specificity and lowest NNR. Their limited discriminatory capability highlighted the need for a new score to predict PN/APN in Chinese populations

An algorithm to predict advanced proximal colorectal neoplasia in Chinese asymptomatic population

This study aims to develop and validate a new algorithm that incorporates distal colonoscopic findings to predict advanced proximal neoplasia (APN) in a Chinese asymptomatic population. We collected age, gender, and colonoscopic findings from a prospectively performed colonoscopy study between 2013 and 2015 in a large hospital-based endoscopy unit in Shanghai, China. Eligible subjects were allocated to a derivation group (n = 3,889) and validation group (n = 1,944) by random sampling. A new index for APN and its cut-off level were evaluated from the derivation cohort by binary logistic regression. The model performance was tested in the validation cohort using area under the curve (AUC). Age, gender, and distal finding were found to be independent predictors of APN in the derivation cohort (p &lt; 0.001). Subjects were categorized into Average Risk (AR) and High Risk (HR) based on a cut-off score of 2. The AUC of the derivation and validation cohorts were 0.801 (0.754–0.847) and 0.722 (0.649–0.794), respectively. In the validation cohort, those in the HR group had a 3.57 fold higher risk of APN when compared with the AR group (P &lt; 0.001), requiring 18 (95% CI = 12–28) follow-up colonoscopies to detect 1 APN. This new clinical index is useful to stratify APN risk in Chinese population

Green Fluorescent Protein GFP-Chromophore-Based Probe for the Detection of Mitochondrial Viscosity in Living Cells

Viscosity is a pivotal factor for indicating the dysfunction of the mitochondria. To date, most of the fluorescent probes developed for mitochondrial viscosity have been designed using BODIPY, hemicyanine, or pyridine-based molecular rotors as part of the core structure. Our aim with this research was to extend the range of suitable fluorophores available for the construction of such fluorescent molecular rotors for evaluating the viscosity of mitocondria. Herein, we have developed a green fluorescent protein (GFP)-chromophore-based fluorescent probe (MIT-V) for the detection of mitochondrial viscosity in live cells. MIT-V exhibited a high sensitivity toward viscosity (from 7.9 cP to 438.4 cP). The "off-on"sensing mechanism of MIT-V was ascribed to the restricted rotation of single bonds and excited-state C= C double bonds of MIT-V. Cell studies indicated that MIT-V targets the mitochondria and that it was able to monitor real-time changes in the viscosity of live HeLa cell mitochondria. Therefore, we propose that MIT-V can be used as an effective chemosensor for the real-time imaging of mitochondrial viscosity in live cells. Our results clearly demonstrate the utility of such GFP-chromophore-based derivatives for the development of viscosity-sensitive systems.</p