Mechanical Constraint Effect on DNA Persistence Length.

Persistence length is a significant criterion to characterize the semi-flexibility of DNA molecules. The mechanical constraints applied on DNA chains in new single-molecule experiments play a complex role in measuring DNA persistence length; however, there is a difficulty in quantitatively characterizing the mechanical constraint effects due to their complex interactions with electrostatic repulsions and thermal fluctuations. In this work, the classical buckling theory of Euler beam and Manning's statistical theories of electrostatic force and thermal fluctuation force are combined for an isolated DNA fragment to formulate a quantitative model, which interprets the relationship between DNA persistence length and critical buckling length. Moreover, this relationship is further applied to identify the mechanical constraints in different DNA experiments by fitting the effective length factors of buckled fragments. Then, the mechanical constraint effects on DNA persistence lengths are explored. A good agreement among the results by theoretical models, previous experiments, and present molecular dynamics simulations demonstrates that the new superposition relationship including three constraint-dependent terms can effectively characterize changes in DNA persistence lengths with environmental conditions, and the strong constraint-environment coupling term dominates the significant changes of persistence lengths; via fitting effective length factors, the weakest mechanical constraints on DNAs in bulk experiments and stronger constraints on DNAs in single-molecule experiments are identified, respectively. Moreover, the consideration of DNA buckling provides a new perspective to examine the bendability of short-length DNA.

Influence of Microscopic Interactions on the Flexible Mechanical Properties of Viral DNA.

During the packaging and ejection of viral DNA, its mechanical properties play an essential role in viral infection. Some of these mechanical properties originate from different microscopic interactions of the encapsulated DNA in the capsid. Based on an updated mesoscopic model of the interaction potential by Parsegian et al., an alternative continuum elastic model of the free energy of the confined DNA in the capsid is developed in this work. With this model, we not only quantitatively identify the respective contributions from hydration repulsion, electrostatic repulsion, entropy and elastic bending but also predict the ionic effect of viral DNA's mechanical properties during the packaging and ejection. The relevant predictions are quantitively or qualitatively consistent with the existing experimental results. Furthermore, the nonmonotonous or monotonous changes in the respective contributions of microscopic interactions to the ejection force and free energy at different ejection stages are revealed systematically. Among these, the nonmonotonicity in the entropic contribution implies a transition of viral DNA structure from order to disorder during the ejection.

Increased risk of kidney damage among Chinese adults with simple renal cyst.

BACKGROUND: The presence of simple renal cyst (SRC) has been related to hypertension, the early and long-term allograft function, and aortic disease, but the relationship with kidney damage was still controversial. Accordingly, we conducted a large sample cross-sectional study to explore the association of SRC with indicators of kidney damage among Chinese adults. METHODS: A total of 42,369 adults (aged 45.8 ± 13.67 years, 70.6% males) who visited the Health Checkup Clinic were consecutively enrolled. SRC was assessed by ultrasonography according to Bosniak category. Multiple regression models were applied to explore the relationships between SRC and indicators of kidney damage [proteinuria (dipstick urine protein ≥ 1+) and decreased estimated glomerular filtration rate (DeGFR) < 60 ml/min/1.73 m2]. RESULTS: Among all participants in the study, the prevalence of SRC was 10.5%. As a categorical outcome, participants with more 1 cyst and with 1 cyst had higher percentage of proteinuria [53 (5.3%) and 93 (2.7%) vs. 596 (1.6%), p < 0.001] and DeGFR [57 (5.7%) and 85 (2.5%) vs. 278 (0.7%), p < 0.001] compared with participants with no cyst. SRC significantly correlated with proteinuria [OR 1.59 (95% CI 1.30-1.95)] and DeGFR [OR 1.97 (95% CI 1.56-2.47)] after adjusting for potential confounders. Furthermore, the results also demonstrated that maximum diameter (per 1 cm increase), bilateral location, and multiple cysts significantly correlated with DeGFR in the multiple logistic regression analysis. CONCLUSIONS: The study revealed that SRC significantly correlated with kidney damage and special attention should be paid among Chinese adults with SRC.

Increasing Body Mass Index Predicts Rapid Decline in Renal Function: A 5 Year Retrospective Study.

While obesity is a recognized risk factor for chronic kidney disease, it remains unclear whether change in body mass index (ΔBMI ) is independently associated with decline in renal function (evaluated by the change in estimated glomerular filtration rate, ΔeGFR) over time. Accordingly, to help clarify this we conducted a retrospective study to measure the association of ΔBMI with decline in renal function in Chinese adult population. A total of 4007 adults (aged 45.3±13.7 years, 68.6% male) without chronic kidney disease at baseline were enrolled between 2008 and 2013. Logistic regression models were applied to explore the relationships between baseline BMI and ΔBMI, and rapid decline in renal function (defined as the lowest quartile of ΔeGFR ). During 5 years of follow-up, the ΔBMI and ΔeGFR were 0.47±1.6 (kg/m2) and -3.0±8.8 (ml/min/1.73 m2), respectively. After adjusted for potential confounders, ΔBMI (per 1 kg/m2 increase) was independently associated with the rapid decline in renal function [with a fully adjusted OR of 1.12 (95% CI, 1.05 to 1.20). By contrast, the baseline BMI was not associated with rapid decline in renal function [OR=1.05 (95% CI, 0.98 to 1.13)]. The results were robust among 2948 hypertension-free and diabetes-free participants, the adjusted ORs of ΔBMI and baseline BMI were 1.14 (95% CI, 1.05 to 1.23) and 1.0 (95% CI, 0.96 to 1.04) for rapid decline in renal function, respectively. The study revealed that increasing ΔBMI predicts rapid decline in renal function.

The pH-dependent elastic properties of nanoscale DNA films and the resultant bending signals for microcantilever biosensors.

The diverse mechanical properties of nanoscale DNA films on solid substrates have a close correlation with complex detection signals of micro-/nano-devices. This paper is devoted to formulating several multiscale models to study the effect of pH-dependent ionic inhomogeneity on the graded elastic properties of nanoscale DNA films and the resultant bending deflections of microcantilever biosensors. First, a modified inverse Debye length is introduced to improve the classical Poisson-Boltzmann equation for the electrical potential of DNA films to consider the inhomogeneous effect of hydrogen ions. Second, the graded characteristics of the particle distribution are taken into consideration for an improvement in Parsegian's mesoscopic potential for both attraction-dominated and repulsion-dominated films. Third, by the improved interchain interaction potential and the thought experiment about the compression of a macroscopic continuum DNA bar, we investigate the diversity of the elastic properties of single-stranded DNA (ssDNA) films due to pH variations. The relevant theoretical predictions quantitatively or qualitatively agree well with the relevant DNA experiments on the electrical potential, film thickness, condensation force, elastic modulus, and microcantilever deflections. The competition between attraction and repulsion among the fixed charges and the free ions endows the DNA film with mechanical properties such as a remarkable size effect and a non-monotonic behavior, and a negative elastic modulus is first revealed in the attraction-dominated ssDNA film. There exists a transition between the pH-sensitive parameter interval and the pH-insensitive one for the bending signals of microcantilevers, which is predominated by the initial stress effect in the DNA film.

Effects of triptolide on pharmacokinetics of amlodipine in rats by using LC-MS/MS.

CONTEXT: Triptolide and amlodipine are often simultaneously used for reducing urine protein excretion after renal transplantation in China clinics. OBJECTIVE: This study investigated the effects of triptolide on the pharmacokinetics of amlodipine in male Sprague-Dawley rats. MATERIALS AND METHODS: The pharmacokinetics of amlodipine (1 mg/kg) with or without triptolide pre-treatment (2 mg/kg/day for seven days) were investigated using a sensitive and reliable LC-MS/MS method. Additionally, the inhibitory effects of triptolide on the metabolic stability of amlodipine were investigated using rat liver microsome incubation systems. RESULTS: The results indicated that when the rats were pre-treated with triptolide, the Cmax of amlodipine increased from 13.78 ± 3.57 to 19.96 ± 4.56 ng/mL (p < 0.05), the Tmax increased from 4.04 ± 1.15 to 5.89 ± 1.64 h (p < 0.05), and the AUC0-t increased by approximately 104% (p < 0.05), which suggested that the pharmacokinetic behaviour of amlodipine was affected after oral co-administration of triptolide. Additionally, the metabolic half-life was prolonged from 22.5 ± 4.26 to 36.8 ± 6.37 min (p < 0.05) with the pre-treatment of triptolide. CONCLUSIONS: In conclusion, these results indicated that triptolide could affect the pharmacokinetics of amlodipine, possibly by inhibiting the metabolism of amlodipine in rat liver when they are co-administered.

Clustering of major cardiovascular risk factors is associated with arterial stiffness in adults.

OBJECTIVE: Cardiovascular disease (CVD) is the leading cause of mortality and morbidity worldwide. Previous studies have indicated that clustering of major CVD risk factors is common. We aimed to explore the association of clustering of CVD risk factors with arterial stiffness in adults. METHODS: A total of 9984 adults were enrolled. We investigated clustering of four major CVD risk factors (defined as two or more of the following: hypertension, diabetes, dyslipidemia, and high body mass index) and their association with arterial stiffness. Arterial stiffness was evaluated using the carotid-femoral pulse wave velocity (cfPWV). RESULTS: In the study group (52.2% men, the mean age was 55.4 ± 10.5 years; only 11.9% of participants were free of any pre-defined CVD risk factors and 61.8% of participants had clustering of CVD risk factors. The cfPWV was significantly higher in the clustered risk factors group than in the no risk factor or the single risk factor groups (16.1 ± 3.1, 13.4 ± 2.2, and 14.3 ± 2.6 m/s, respectively; P < 0.001). Multiple linear regression analysis revealed that age, gender, clustering of CVD risk factors, serum uric acid, and decreased renal function positively correlated with cfPWV. For a categorical outcome, the highest cfPWV quartile (cfPWV ≥ 16.9 m/s) was compared with the lower three quartiles. After adjusting for potential confounders, clustering of CVD risk factors significantly correlated with increased cfPWV compared with that in the no risk factor group, with an odds ratio of 5.76 (95% confidence interval: 4.46-7.44). CONCLUSIONS: Clustering of CVD risk factors significantly correlated with arterial stiffness; this confirms the importance of lifestyle modification to reduce the burden of CVD.

Hyperhomocysteinemia increases the risk of chronic kidney disease in a Chinese middle-aged and elderly population-based cohort.

BACKGROUND: Patients either with hyperhomocysteinemia or chronic kidney disease (CKD) have an increased risk of cardiovascular disease. Little is known regarding whether hyperhomocysteinemia can increase the risk of CKD in a Chinese middle-aged and elderly population. To help clarify this we conducted a prospective cohort study to measure the association of hyperhomocysteinemia with CKD. METHODS: A total of 5917 adults aged 56.4 ± 9.6 years without CKD at baseline were enrolled. The highest homocysteine quartile (≥15 µmol/L) was defined as hyperhomocysteinemia. CKD was defined as decreased estimated glomerular filtration rate (eGFR < 60 mL/min/1.73 m2) or presence of proteinuria (urine protein ≥ 1+) assessed using a repeated dipstick method. RESULTS: During 3 years of follow-up, 143 (2.4%) patients developed CKD, 85 (1.4%) patients with proteinuria and 59 (1.0%) patients with decreased eGFR. After adjusted for potential confounders, both homocysteine (per 1 µmol/L increase) and hyperhomocysteinemia were independently associated with increased risk of decreased eGFR [with a fully adjusted OR of 1.07 (95% CI 1.04-1.10) and 3.05 (95% CI 1.71-5.46)] and CKD [with a fully adjusted OR of 1.04 (95% CI 1.02-1.07) and 1.62 (95% CI 1.11-2.35)], respectively. By contrast, neither homocysteine (per 1 µmol/L increase) nor hyperhomocysteinemia were associated with proteinuria in the multivariable logistic regression analysis. CONCLUSIONS: The study revealed that hyperhomocysteinemia increases the risk of decreased eGFR. This suggests that homocysteine could be considered as a useful molecular markers for delaying the development of CKD.

Long-Term Outcomes of Total Parathyroidectomy With or Without Autoimplantation for Hyperparathyroidism in Chronic Kidney Disease: A Meta-Analysis.

The aim of the present study was to compare total parathyroidectomy without autotransplantation (TPTX) versus total parathyroidectomy with autotransplantation (TPTX + AT) for renal hyperparathyroidism (RHPT) with respect to long-term outcomes. A literature search was undertaken using Medline and EMBASE from inception to December 2013. Data were analyzed using Review Manager version 5.0. A total of seven cohort studies comprising 931 patients were identified. Compared with TPTX + AT, patients in the TPTX group have lower "recurrence" (odds ratio (OR) 0.08, confidence interval (CI) 0.03 to 0.21; P < 0.00001), lower "recurrence or persistence"(OR 0.11, 95% CI 0.05 to 0.25; P < 0.00001), lower "requiring reoperation because of recurrence or persistence" (OR 0.17, CI 0.06 to 0.54; P = 0.002), and higher "hypoparathyroidism" (OR 2.97, CI 1.09 to 8.08; P = 0.03). None of the patients in these seven studies were recorded as having severe hypocalcemia or adynamic bone disease. Compared with TPTX + AT, TPTX is associated with lower "requiring reoperation because of recurrence or persistence" and without severe hypocalcemia or adynamic bone disease.