Block of Tetrodotoxin-resistant Na+ Channel Pore by Multivalent Cations: Gating Modification and Na+ Flow Dependence

Tetrodotoxin-resistant (TTX-R) Na+ channels are much less susceptible to external TTX but more susceptible to external Cd2+ block than tetrodotoxin-sensitive (TTX-S) Na+ channels. Both TTX and Cd2+ seem to block the channel near the “DEKA” ring, which is probably part of a multi-ion single-file region adjacent to the external pore mouth and is involved in the selectivity filter of the channel. In this study we demonstrate that other multivalent transitional metal ions such as La3+, Zn2+, Ni2+, Co2+, and Mn2+ also block the TTX-R channels in dorsal root ganglion neurons. Just like Cd2+, the blocking effect has little intrinsic voltage dependence, but is profoundly influenced by Na+ flow. The apparent dissociation constants of the blocking ions are always significantly smaller in inward Na+ currents than those in outward Na+ current, signaling exit of the blocker along with the Na+ flow and a high internal energy barrier for “permeation” of these multivalent blocking ions through the pore. Most interestingly, the activation and especially the inactivation kinetics are slowed by the blocking ions. Moreover, the gating changes induced by the same concentration of a blocking ion are evidently different in different directions of Na+ current flow, but can always be correlated with the extent of pore block. Further quantitative analyses indicate that the apparent slowing of channel activation is chiefly ascribable to Na+ flow–dependent unblocking of the bound La3+ from the open Na+ channel, whereas channel inactivation cannot happen with any discernible speed in the La3+-blocked channel. Thus, the selectivity filter of Na+ channel is probably contiguous to a single-file multi-ion region at the external pore mouth, a region itself being nonselective in terms of significant binding of different multivalent cations. This region is “open” to the external solution even if the channel is “closed” (“deactivated”), but undergoes imperative conformational changes during the gating (especially the inactivation) process of the channel

An Effective Cold Start Recommendaton Method Using A Web Of Trust

Cold start recommendations are important because they help build user loyalty, which is the key to the success of e-services and e-commerce systems. Recommending useful information for new users generally creates a sense of belonging and loyalty, and encourages them to visit e-commerce systems frequently. However, as new users take time to become familiar with recommendation systems, the systems usually have limited information about newcomers and have difficulty providing appropriate recommendations. The cold start phenomenon has a serious impact on the performance of recommendation systems. To address the problem, we propose a cold start recommendation method that integrates a web of trust with a user model to identify trustworthy users. The suggestions of those users are then aggregated to provide useful recommendations for cold start users. Experiments based on the well-known Epinions dataset demonstrate that the proposed method is effective and efficient, and outperforms well-known recommendation methods by a significant margin

Effect of Multifactorial Treatment Targets and Relative Importance of Hemoglobin A1c, Blood Pressure, and Low‐Density Lipoprotein‐Cholesterol on Cardiovascular Diseases in Chinese Primary Care Patients With Type 2 Diabetes Mellitus: A Population‐Based Retrospective Cohort Study

published_or_final_versio

Prediction of new onset of end stage renal disease in Chinese patients with type 2 diabetes mellitus – a population-based retrospective cohort study

published_or_final_versio

Age-specific associations between Systolic Blood Pressure and Cardiovascular Disease: A 10-years diabetes cohort study

Abstract: Background The relationship between systolic blood pressure (SBP) and cardiovascular disease (CVD) among patients with diabetes mellitus remains unclear. The study aimed to explore age‐specific associations between SBP and CVD. Methods and Results: A population‐based retrospective cohort study was conducted on 180 492 Chinese adults with type 2 diabetes mellitus in 2008–2010, with follow‐up to 2017. Age‐specific associations (<50, 50–59, 60–69, and 70–79 years) between the average SBP in the previous 2 years and CVD risk were assessed by adjusted Cox proportional hazards regression with age‐specific regression dilution ratios and patient characteristics stratified by subgroups. During a median follow‐up of 9.3 years (1.5 million person‐years), 32 545 patients developed a CVD, with an incidence rate of 23.4 per 1000 person‐years. A positive and log‐linear association between SBP and CVD risk was observed among the 4 age groups without evidence of a threshold down to 120 mm Hg, but the magnitude of SBP effect on CVD attenuated with increased age. The CVD risk in the age group <50 years was ≈22% higher than the age group 70 to 79 years (hazard ratio [HR], 1.33 [95% CI, 1.26–1.41] versus HR, 1.09 [95% CI, 1.07–1.11]). Each 10‐mm Hg higher SBP was associated with 12% (HR, 1.12 [95% CI, 1.10–1.13]), 11% (HR, 1.11 [95% CI, 1.10–1.13]), and 20% (HR, 1.20 [95% CI, 1.17–1.22]) higher risk of all composite CVD events, individual CVD, and CVD mortality, respectively. Conclusions: There is a significant log‐linear relationship between baseline SBP and the risk of CVD among patients with diabetes mellitus in China. The risk increases from an SBP of 120 mm Hg onward. Age influences this relationship significantly, with younger patients (<50 years) having a greater risk of CVD for a similar rise in SBP as compared with those who are older. These findings suggest that differential target blood pressures stratified by age maybe usefu

The impact of cardiovascular disease and chronic kidney disease on life expectancy and direct medical cost in a 10-year diabetes cohort study

Objective: The relative effects of various cardiovascular diseases (CVD) and varying severity of chronic kidney disease (CKD) on mortality risk, direct medical cost and life expectancy in patients with diabetes mellitus (DM) are unclear. The aim of this study was to evaluate these associations. / Research Design and Methods: This was a retrospective cohort study that included 208,792 adults with diabetes stratified into 12 disease status groups with varying combinations of heart disease, stroke, moderate CKD (eGFR:30-59ml/min/1.73m2) and severe CKD (eGFR: <30ml/min/1.73m2) in 2008-2010. The effect of risk mortality, annual direct medical costs and life expectancy were assessed using Cox regression, Gamma generalized linear with log link function, and flexible parametric survival models. / Results: Over a median follow-up of 8.5 years (1.6 million patient-years), 50,154 deaths were recorded. Mortality risks for patients with only a single condition among heart disease, stroke and moderate CKD were similar. The mortality risks were 1.75 times, 2.63 times and 3.58 times greater for patients with one, two and all three conditions (consisting of stroke, heart disease and moderate CKD), compared with patients without these diseases, suggesting an independent and individually additive effect for any combination. A similar trend was observed in annual public healthcare costs with 2.91, 3.90 and 3.88 fold increased costs for patients with one, two and three conditions, respectively. Increases in the number of conditions reduced life expectancy greatly, particularly in younger patients. Reduction in life expectancy for a 40-year-old with one, two and three conditions were 20, 25, 30 years for men and 25, 30, 35 years for women. A similar trend of greater magnitude was observed for severe CKD. / Conclusion: The effect of heart diseases, stroke, CKD and the combination of these conditions on all-cause mortality and direct medical costs are independent and cumulative. CKD, especially severe CKD, appears to have a particularly significant impact on life expectancy and direct medical costs in patients with diabetes. These finding supports the importance of preventing both CVD and CKD in patients with DM

Greater variability in lipid measurements associated with kidney diseases in patients with type 2 diabetes mellitus in a 10-year diabetes cohort study.

This study aimed to evaluate the associations between variability of lipid parameters and the risk of kidney disease in patients with type 2 diabetes mellitus. Low-density lipoprotein-cholesterol, total cholesterol to high-density lipoprotein-cholesterol ratio and triglyceride were specifically addressed in this study. This retrospective cohort study included 105,552 patients aged 45-84 with type 2 diabetes mellitus and normal kidney function who were managed under Hong Kong public primary care clinics during 2008-2012. Those with kidney disease (estimated glomerular filtration rate < 60 mL/min/1.73 m2 or urine albumin to creatinine ratio ≥ 3 mg/mmol) were excluded. Variabilities of low-density lipoprotein-cholesterol, total cholesterol to high-density lipoprotein-cholesterol ratio and triglyceride were determined using the standard deviation of the respective parameter obtained from a mixed effects model to minimize regression dilution bias. The associations between lipid variability and renal outcomes including incident kidney disease, renal function decline defined as ≥ 30% reduction in estimated glomerular filtration rate since baseline, and end-stage renal disease (estimated glomerular filtration rate < 15 mL/min/1.73 m2) were evaluated by multivariable Cox regression. After a median follow-up of 66.5 months (0.5 million person-years in total), 49,653 kidney disease, 29,358 renal function decline, and 1765 end-stage renal disease cases were recorded. Positive linear associations between low-density lipoprotein-cholesterol and total cholesterol to high-density lipoprotein-cholesterol ratio variabilities and the risk of all renal outcomes were demonstrated. However, no association between triglyceride variability and any outcome was found. Each mmol/L increase in low-density lipoprotein-cholesterol variability was associated with 20% (Hazard ratio 1.20 [95% CI 1.15-1.25]), 38% (Hazard ratio 1.37 [95% CI 1.30-1.45]), and 108% (Hazard ratio 2.08 [95% CI 1.74-2.50]) higher risk in incident kidney disease, renal function decline and end-stage renal disease respectively. Similarly, each unit increase in total cholesterol to high-density lipoprotein-cholesterol ratio variability was associated with 35% (Hazard ratio 1.15 [95% CI 1.10-1.20]), 33% (Hazard ratio 1.33 [95% CI 1.26-1.40]), and 75% (Hazard ratio 1.75 [95% CI 1.46-2.09]) heightened risk in incident kidney disease, renal function decline and end-stage renal disease respectively. Cholesterol variability may potentially be a useful predictor of kidney diseases in patients with type 2 diabetes mellitus. Attention should be drawn to cholesterol variability when managing diabetic patients and further research is warranted to investigate the modifiable risk factors for lipid variability

Age-Specific Associations of Usual Blood Pressure Variability With Cardiovascular Disease and Mortality: 10-Year Diabetes Mellitus Cohort Study

BACKGROUND: The detrimental effects of increased variability in systolic blood pressure (SBP) on cardiovascular disease (CVD) and mortality risk in patients with diabetes mellitus remains unclear. This study evaluated age‐specific association of usual SBP visit‐to‐visit variability with CVD and mortality in patients with type 2 diabetes mellitus. METHODS AND RESULTS: A retrospective cohort study investigated 155 982 patients with diabetes mellitus aged 45 to 84 years without CVD at baseline (2008–2010). Usual SBP variability was estimated using SBP SD obtained from a mixed‐effects model. Age‐specific associations (45–54, 55–64, 65–74, 75–84 years) between usual SBP variability, CVD, and mortality risk were assessed by Cox regression adjusted for patient characteristics. After a median follow‐up of 9.7 years, 49 816 events (including 34 039 CVD events and 29 211 mortalities) were identified. Elevated SBP variability was independently, positively, and log‐linearly associated with higher CVD and mortality risk among all age groups, with no evidence of any threshold effects. The excess CVD and mortality risk per 5 mm Hg increase in SBP variability within the 45 to 54 age group is >3 times higher than the 70 to 79 age group (hazard ratio, 1.66; 95% CI, 1.49–1.85 versus hazard ratio, 1.19; 95% CI, 1.15–1.23). The significant associations remained consistent among all subgroups. Patients with younger age had a higher association of SBP variability with event outcomes. CONCLUSIONS: The findings suggest that SBP visit‐to‐visit variability was strongly associated with CVD and mortality with no evidence of a threshold effect in a population with diabetes mellitus. As well as controlling overall blood pressure levels, SBP visit‐to‐visit variability should be monitored and evaluated in routine practice, in particular for younger patients

Probing the DNA kink structure induced by the hyperthermophilic chromosomal protein Sac7d

Sac7d, a small, abundant, sequence-general DNA-binding protein from the hyperthermophilic archaeon Sulfolobus acidocaldarius, causes a single-step sharp kink in DNA (∼60°) via the intercalation of both Val26 and Met29. These two amino acids were systematically changed in size to probe their effects on DNA kinking. Eight crystal structures of five Sac7d mutant–DNA complexes have been analyzed. The DNA-binding pattern of the V26A and M29A single mutants is similar to that of the wild-type, whereas the V26A/M29A protein binds DNA without side chain intercalation, resulting in a smaller overall bending (∼50°). The M29F mutant inserts the Phe29 side chain orthogonally to the C2pG3 step without stacking with base pairs, inducing a sharp kink (∼80°). In the V26F/M29F-GCGATCGC complex, Phe26 intercalates deeply into DNA bases by stacking with the G3 base, whereas Phe29 is stacked on the G15 deoxyribose, in a way similar to those used by the TATA box-binding proteins. All mutants have reduced DNA-stabilizing ability, as indicated by their lower T(m) values. The DNA kink patterns caused by different combinations of hydrophobic side chains may be relevant in understanding the manner by which other minor groove-binding proteins interact with DNA

Enhancing performance of ZnO dye-sensitized solar cells by incorporation of multiwalled carbon nanotubes

A low-temperature, direct blending procedure was used to prepare composite films consisting of zinc oxide [ZnO] nanoparticles and multiwalled carbon nanotubes [MWNTs]. The mesoporous ZnO/MWNT films were fabricated into the working electrodes of dye-sensitized solar cells [DSSCs]. The pristine MWNTs were modified by an air oxidation or a mixed acid oxidation treatment before use. The mixed acid treatment resulted in the disentanglement of MWNTs and facilitated the dispersion of MWNTs in the ZnO matrix. The effects of surface property and loading of MWNTs on DSSC performance were investigated. The performance of DSSCs was found to depend greatly on the type and the amount of MWNTs incorporated. At a loading of 0.01 wt%, the acid-treated MWNTs were able to increase the power conversion efficiency of fabricated cells from 2.11% (without MWNTs) to 2.70%