Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis.

BACKGROUND: Mirikizumab, a p19-directed antibody against interleukin-23, showed efficacy in the treatment of ulcerative colitis in a phase 2 trial. METHODS: We conducted two phase 3, randomized, double-blind, placebo-controlled trials of mirikizumab in adults with moderately to severely active ulcerative colitis. In the induction trial, patients were randomly assigned in a 3:1 ratio to receive mirikizumab (300 mg) or placebo, administered intravenously, every 4 weeks for 12 weeks. In the maintenance trial, patients with a response to mirikizumab induction therapy were randomly assigned in a 2:1 ratio to receive mirikizumab (200 mg) or placebo, administered subcutaneously, every 4 weeks for 40 weeks. The primary end points were clinical remission at week 12 in the induction trial and at week 40 (at 52 weeks overall) in the maintenance trial. Major secondary end points included clinical response, endoscopic remission, and improvement in bowel-movement urgency. Patients who did not have a response in the induction trial were allowed to receive open-label mirikizumab during the first 12 weeks of the maintenance trial as extended induction. Safety was also assessed. RESULTS: A total of 1281 patients underwent randomization in the induction trial, and 544 patients with a response to mirikizumab underwent randomization again in the maintenance trial. Significantly higher percentages of patients in the mirikizumab group than in the placebo group had clinical remission at week 12 of the induction trial (24.2% vs. 13.3%, P<0.001) and at week 40 of the maintenance trial (49.9% vs. 25.1%, P<0.001). The criteria for all the major secondary end points were met in both trials. Adverse events of nasopharyngitis and arthralgia were reported more frequently with mirikizumab than with placebo. Among the 1217 patients treated with mirikizumab during the controlled and uncontrolled periods (including the open-label extension and maintenance periods) in the two trials, 15 had an opportunistic infection (including 6 with herpes zoster infection) and 8 had cancer (including 3 with colorectal cancer). Among the patients who received placebo in the induction trial, 1 had herpes zoster infection and none had cancer. CONCLUSIONS: Mirikizumab was more effective than placebo in inducing and maintaining clinical remission in patients with moderately to severely active ulcerative colitis. Opportunistic infection or cancer occurred in a small number of patients treated with mirikizumab. (Funded by Eli Lilly; LUCENT-1 and LUCENT-2 ClinicalTrials.gov numbers, NCT03518086 and NCT03524092, respectively.).

Dietary Factors and the Risk of Colorectal Cancer: A Mendelian Randomization Study.

OBJECTIVE: To examine the causal association between 15 dietary factors and the incidence of colorectal cancer through the application of Mendelian randomization methodology. METHODS: The data associated with 15 dietary factors were derived from the IEU OPEN GWAS database, and the colorectal cancer data were sourced from the FinnGen database. The Inverse Variance Weighting method was the principal research method. Sensitivity analyses were implemented to affirm the robustness of the findings. Additionally, we conducted multivariable Mendelian randomization analyses to adjust for the intake of ω-3 and ω-6 polyunsaturated fatty acids. RESULTS: In our research, we observed suggestive causal relationships between genetically predicted water intake and the reduced risk of colorectal cancer (OR = 0.54; 95% CI= 0.31 ∼ 0.93; p = 0.028); genetically predicted ω-3 PUFA intake (OR = 1.17; 95% CI= 1.05 ∼ 1.30; p = 0.005) were suggestively associated with the increased risk of colorectal cancer. In the multivariable Mendelian randomization analysis, the effect of ω-3 PUFA intake remains significant after adjusting for the influence of ω-6 PUFA intake. Horizontal pleiotropy was not present in this study. CONCLUSIONS: There exists a suggestive causal association between increased water intake and decreased risk of colorectal cancer, while ω-3 PUFA intake are suggestive linked to the increased risk of colorectal cancer.

Impact of non-alcoholic fatty liver disease and fibrosis on mortality and kidney outcomes in patients with type 2 diabetes and chronic kidney disease: A multi-cohort longitudinal study.

AIM: To evaluate the impact of non-alcoholic fatty liver disease (NAFLD) presence and fibrosis risk on adverse outcomes in patients with type 2 diabetes and chronic kidney disease. METHODS: Data were sourced from two longitudinal cohorts: 1172 patients from the National Health and Nutrition Examination Survey (NHANES) and 326 patients from the kidney biopsy cohort at the West China Hospital of Sichuan University. Cox regression estimated hazard ratios (HRs) for NAFLD and liver fibrosis concerning adverse clinical outcomes. Subsequently, a two-sample Mendelian randomization study using genome-wide association study statistics explored NAFLD's potential causal link to cardio-cerebrovascular events. RESULTS: In the NHANES cohort, NAFLD stood as an independent risk factor for various outcomes: overall mortality [HR 1.53 (95% confidence interval, CI 1.21-1.95)], mortality because of cardio-cerebrovascular diseases [HR 1.63 (95% CI 1.12-2.37)], heart disease [HR 1.58 (95% CI 1.00-2.49)], and cerebrovascular disease [HR 3.95 (95% CI 1.48-10.55)]. Notably, advanced liver fibrosis, identified by a fibrosis-4 (FIB-4) score >2.67, exhibited associations with overall mortality, cardio-cerebrovascular disease mortality and heart disease mortality. Within the kidney biopsy cohort, NAFLD correlated with future end-stage kidney disease [ESKD; HR 2.17 (95% CI 1.41-3.34)], while elevated FIB-4 or NAFLD Fibrosis Scores predicted future ESKD, following full adjustment. Liver fibrosis was positively correlated with renal interstitial fibrosis and tubular atrophy in biopsies. Further Mendelian randomization analysis supported a causal relationship between NAFLD and cardio-cerebrovascular events. CONCLUSIONS: In patients with type 2 diabetes and chronic kidney disease, the NAFLD presence and elevated FIB-4 scores link to heightened mortality risk and ESKD susceptibility. Moreover, NAFLD shows a causal relationship with cardio-cerebrovascular events.

Geochemical characteristics and health risks of heavy metals in agricultural soils and crops from a coal mining area in Anhui province, China.

Soil contamination by heavy metals (HMs) in mining areas is a major issue because of its significant impact on the environmental quality and physical health of residents. Mining of minerals used in energy production, particularly coal, has led to HMs entering the surrounding soil through geochemical pathways. In this study, a total of 166 surface soil and 100 wheat grain samples around the Guobei coal mine in southeast China were collected, and trace metal levels were determined via inductively coupled plasma mass spectrometry (ICP-MS). The average HMs (Ni, As, Cr, Cu, Pb, Cd, and Zn) concentrations were lower than the screening values in China (GB 15618-2018) but higher than the soil background values in the Huaibei Bozhou area of Anhui Province (except Zn), indicating HMs enrichment. Based on the geoaccumulation index (Igeo) and ecological risk index (IER), Cd pollution levels were low, while for the other metals the samples were pollution-free, and therefore no ecological risk warning was issued for the mining area. Both Cr and Pb had a higher noncarcinogenic health risks for adults and children. The lifetime carcinogenic risks (LCR) of Cr, Pb, and Cd were within acceptable levels. A positive matrix factorization (PMF) model identified two factors that could explain the HMs sources: factor 1 for Zn, Cd, and Pb, factor 2 for Ni, As, Cr, and Cu. Furthermore, HMs enrichment was observed in surface soil and the Carboniferous-Permian coal seams in the Guobei coal mine, which may suggest that coal mining is an important source for HMs enrichment in surface soil. Overall, this study provides a theoretical basis for undertaking the management and assessment of soil HMs pollution around a coal mine.

The spatiotemporal matching pattern of Ezrin/Periaxin involved in myoblast differentiation and fusion and Charcot-Marie-Tooth disease-associated muscle atrophy.

BACKGROUND: Clinically, Charcot-Marie-Tooth disease (CMT)-associated muscle atrophy still lacks effective treatment. Deletion and mutation of L-periaxin can be involved in CMT type 4F (CMT4F) by destroying the myelin sheath form, which may be related to the inhibitory role of Ezrin in the self-association of L-periaxin. However, it is still unknown whether L-periaxin and Ezrin are independently or interactively involved in the process of muscle atrophy by affecting the function of muscle satellite cells. METHOD: A gastrocnemius muscle atrophy model was prepared to mimic CMT4F and its associated muscle atrophy by mechanical clamping of the peroneal nerve. Differentiating C2C12 myoblast cells were treated with adenovirus-mediated overexpression or knockdown of Ezrin. Then, overexpression of L-periaxin and NFATc1/c2 or knockdown of L-periaxin and NFATc3/c4 mediated by adenovirus vectors were used to confirm their role in Ezrin-mediated myoblast differentiation, myotube formation and gastrocnemius muscle repair in a peroneal nerve injury model. RNA-seq, real-time PCR, immunofluorescence staining and Western blot were used in the above observation. RESULTS: For the first time, instantaneous L-periaxin expression was highest on the 6th day, while Ezrin expression peaked on the 4th day during myoblast differentiation/fusion in vitro. In vivo transduction of adenovirus vectors carrying Ezrin, but not Periaxin, into the gastrocnemius muscle in a peroneal nerve injury model increased the numbers of muscle myosin heavy chain (MyHC) I and II type myofibers, reducing muscle atrophy and fibrosis. Local muscle injection of overexpressed Ezrin combined with incubation of knockdown L-periaxin within the injured peroneal nerve or injection of knockdown L-periaxin into peroneal nerve-injured gastrocnemius muscle not only increased the number of muscle fibers but also recovered their size to a relatively normal level in vivo. Overexpression of Ezrin promoted myoblast differentiation/fusion, inducing increased MyHC-I+ and MyHC-II + muscle fiber specialization, and the specific effects could be enhanced by the addition of adenovirus vectors for knockdown of L-periaxin by shRNA. Overexpression of L-periaxin did not alter the inhibitory effects on myoblast differentiation and fusion mediated by knockdown of Ezrin by shRNA in vitro but decreased myotube length and size. Mechanistically, overexpressing Ezrin did not alter protein kinase A gamma catalytic subunit (PKA-γ cat), protein kinase A I alpha regulatory subunit (PKA reg Iα) or PKA reg Iß levels but increased PKA-α cat and PKA reg II α levels, leading to a decreased ratio of PKA reg I/II. The PKA inhibitor H-89 remarkably abolished the effects of overexpressing-Ezrin on increased myoblast differentiation/fusion. In contrast, knockdown of Ezrin by shRNA significantly delayed myoblast differentiation/fusion accompanied by an increased PKA reg I/II ratio, and the inhibitory effects could be eliminated by the PKA reg activator N6-Bz-cAMP. Meanwhile, overexpressing Ezrin enhanced type I muscle fiber specialization, accompanied by an increase in NFATc2/c3 levels and a decrease in NFATc1 levels. Furthermore, overexpressing NFATc2 or knocking down NFATc3 reversed the inhibitory effects of Ezrin knockdown on myoblast differentiation/fusion. CONCLUSIONS: The spatiotemporal pattern of Ezrin/Periaxin expression was involved in the control of myoblast differentiation/fusion, myotube length and size, and myofiber specialization, which was related to the activated PKA-NFAT-MEF2C signaling pathway, providing a novel L-Periaxin/Ezrin joint strategy for the treatment of muscle atrophy induced by nerve injury, especially in CMT4F.

Structural and dynamical properties of concentrated alkali- and alkaline-earth metal chloride aqueous solutions.

Concentrated ionic aqueous electrolytes possess a diverse array of applications across various fields, particularly in the field of energy storage. Despite extensive examination, the intricate relationships and numerous physical mechanisms underpinning diverse phenomena remain incompletely understood. Molecular dynamics simulations are employed to probe the attributes of aqueous solutions containing LiCl, NaCl, KCl, MgCl2, and CaCl2, spanning various solute fractions. The primary emphasis of the simulations is on unraveling the intricate interplay between these attributes and the underlying physical mechanisms. The configurations of cation-Cl- and Cl--Cl- pairs within these solutions are disclosed. As the solute fraction increases, consistent trends manifest regardless of solute type: (i) the number of hydrogen bonds formed by the hydration water surrounding ions decreases, primarily attributed to the growing presence of counter ions in proximity to the hydration water; (ii) the hydration number of ions exhibits varying trends influenced by multiple factor; and (iii) the diffusion of ions slows down, attributed to the enhanced confinement and rebound of cations and Cl- ions from the surrounding atoms, concurrently coupled with the changes in ion vibration modes. In our analysis, we have, for the first time, clarified the reasons behind the slowing down of the diffusion of the ions with increasing solute fraction. Our research contributes to a better understanding and manipulation of the attributes of ionic aqueous solutions and may help designing high-performance electrolytes.

[Regularity of prescriptions for sick sinus syndrome based on latent structure combined with association rules].

This study aims to mine the regularity of traditional Chinese medicine(TCM) prescriptions for sick sinus syndrome(SSS) and provide a reference for clinical syndrome differentiation and treatment. The relevant papers were retrieved from CNKI, Wanfang, VIP, and SinoMed with the time interval from inception to January 31, 2023. The relevant information from qualified papers was extracted to establish a library. Lantern 5.0 and Rstudio were used to analyze the latent structure and association rules of TCMs with the frequency ≥3%, which combined with frequency descriptions, were used to explore the rules of TCM prescriptions for SSS. A total of 192 TCM prescriptions were included, involving 115 TCMs with the cumulative frequency of 1 816. High-frequency TCMs include Aconiti Lateralis Radix Praeparata, Ginseng Radix et Rhizoma, Glycyrrhizae Radix et Rhizoma, Astragali Radix, and Salviae Miltiorrhizae Radix et Rhizoma. The high-frequency medicines mainly had the effects of tonifying, releasing exterior with pungent-warm, and activating blood and resolving stasis. The analysis of the latent structure model yielded 13 hidden variables, 26 hidden classes, 8 comprehensive cluster models, and 21 core prescriptions. Accordingly, the common syndromes of SSS were inferred as heart-Yang Qi deficiency, heart-spleen Yang deficiency, heart-kidney Yang deficiency, Yang deficiency and blood stasis, both Qi and Yin deficiency and blood stasis, and Yin and Yang deficiency. The analysis of association rules predicted 30 strong association rules, among which Ginseng Radix et Rhizoma-Aconiti Lateralis Radix Praeparata had the highest support. SSS is a syndrome with Yang deficiency and Qi deficiency as the root causes and cold, phlegm, and stasis as the manifestations. The clinical treatment of SSS should focus on warming Yang and replenishing Qi, which should be supplemented with the therapies of activating blood and resolving stasis, warming interior and dissipating cold, or regulating Qi movement for resolving phlegm according to the patients' syndromes.

Regulating evaporation of a water nanofilm by applying a terahertz alternating electric field.

The evaporation of water nanofilms on a solid surface is a widespread and important process in many fields. Herein, we utilize molecular dynamics simulations to demonstrate that the evaporation of a water nanofilm is regulated by applying an alternating electric field (AEF). An AEF at a specific frequency can be resonantly absorbed by the water film. Consequently, the AEF with sufficient strength significantly increases the evaporation rate of the water film (R). In contrast, an AEF of a different frequency and polarization direction decreases R sharply, which is closely related to the strengthened hydrogen bond network and the reduced kinetic energy of the outermost water of the water film. When the maximum amplitude of the AEFs is 0.9 V/nm, which is achievable in a laboratory setting, R spans six orders of magnitude. The effects of applying the AEFs are quite distinct from those of changing the temperature. Notably, the polarization direction of the AEF plays an important role in the water evaporation. To the best of our knowledge, this is the first report on regulating the evaporation rate of a water film, showing that it is possible to use AEFs to tune the properties of nanoscaled water, such as the wettability.

Machine learning can identify the sources of heavy metals in agricultural soil: A case study in northern Guangdong Province, China.

Source tracing of heavy metals in agricultural soils is of critical importance for effective pollution control and targeting policies. It is a great challenge to identify and apportion the complex sources of soil heavy metal pollution. In this study, a traditional analysis method, positive matrix fraction (PMF), and three machine learning methodologies, including self-organizing map (SOM), conditional inference tree (CIT) and random forest (RF), were used to identify and apportion the sources of heavy metals in agricultural soils from Lianzhou, Guangdong Province, China. Based on PMF, the contribution of the total loadings of heavy metals in soil were 19.3% for atmospheric deposition, 65.5% for anthropogenic and geogenic sources, and 15.2% for soil parent materials. Based on SOM model, As, Cd, Hg, Pb and Zn were attributed to mining and geogenic sources; Cr, Cu and Ni were derived from geogenic sources. Based on CIT results, the influence of altitude on soil Cr, Cu, Hg, Ni and Zn, as well as soil pH on Cd indicated their primary origin from natural processes. Whereas As and Pb were related to agricultural practices and traffic emissions, respectively. RF model further quantified the importance of variables and identified potential control factors (altitude, soil pH, soil organic carbon) in heavy metal accumulation in soil. This study provides an integrated approach for heavy metals source apportionment with a clear potential for future application in other similar regions, as well as to provide the theoretical basis for undertaking management and assessment of soil heavy metal pollution.

Quantifying the influencing factors and multi-factor interactions affecting cadmium accumulation in limestone-derived agricultural soil using random forest (RF) approach.

Cadmium (Cd) is a highly toxic heavy metal that occurs widely in the environment and poses extensive threats to human health, animals, and plants. This study aims to identify and apportion multi-source and multi-phase Cd pollution from natural and anthropogenic inputs using ensemble models that include random forest (RF) in agricultural soils on Karst areas. The contributions of natural and anthropogenic factors to Cd accumulation were quantitatively assessed using the RF machine learning method. The results revealed that the main influencing factors were pH, organic carbon (Corg), and elevation. Moreover, the interaction effects of pH and Corg on distance and elevation were also quantified and visualised. It is observed that pH and Corg had stronger effects on soil Cd concentration than that of distance when pH > 7.02 and Corg > 1.53. In other words, higher Cd content in the soil along roadways may be caused by the interaction of distance, pH and Corg, with pH and Corg playing the dominant role in our case. Moreover, the maximum contribution of a single factor, elevation, to Cd concentration was about 0.13 mg/kg, and its interactions reached 1.082 mg/kg and 0.83 mg/kg, respectively, when combined with pH and Corg at 194.0 m. However, with increasing elevation, pH and Corg gradually took over the leading roles. This result not only gives us a quantitative understanding of the relationship between the factors that affect soil cadmium accumulation, but also provides an accurate method for source apportionment of heavy metals in soil.

Status of mercury accumulation in agricultural soils across China (1976-2016).

Soil contamination with mercury (Hg) is a serious and widespread issue in China, with particularly severe effects on the quality of agricultural soils. To analyse long-term, nation-wide trends in Hg contamination of agriculture soil, we conducted a review of Hg concentrations in agricultural soils over four decades, based on 791 studies comprising 1411 sites, published between 1976 and 2016. We assessed spatiotemporal variations in Hg concentration, along with ecological and health risks. While Hg concentrations in agricultural soils showed an increasing trend between 1979 and 2010, they declined thereafter. Moreover, Hg concentrations in agricultural soils were generally high in western (e.g. Guizhou), southern (e.g. Hunan) and north-eastern provinces (e.g. Liaoning), where mining activities were concentrated. Using the geoaccumulation index (Igeo) and other ecological and health risk indices, we found most sampling sites to be uncontaminated, or to have a low level of contamination, although some mining sites showed moderate to extreme Hg contamination. The noncarcinogenic risk to exposure groups followed the order of children (4.42) > adult females (2.71) > adult males (2.45). Therefore, children were identified as the priority risk group. Noncarcinogenic risk values exceeded 100 in some areas in Guizhou and Hunan provinces; these areas should be prioritised for Hg control measures. This review examined Hg pollution in Chinese agricultural soils to provide insight to policymakers for the development of targeted contamination prevention measures.

KPC1 alleviates hypoxia/reoxygenation-induced apoptosis in rat cardiomyocyte cells though BAX degradation.

Bax triggers cell apoptosis by permeabilizing the outer mitochondrial membrane, leading to membrane potential loss and cytochrome c release. However, it is unclear if proteasomal degradation of Bax is involved in the apoptotic process, especially in heart ischemia-reperfusion (I/R)-induced injury. In the present study, KPC1 expression was heightened in left ventricular cardiomyocytes of patients with coronary heart disease (CHD), in I/R-myocardium in vivo and in hypoxia and reoxygenation (H/R)-induced cardiomyocytes in vitro. Overexpression of KPC1 reduced infarction size and cell apoptosis in I/R rat hearts. Similarly, the forced expression of KPC1 restored mitochondrial membrane potential (MMP) and cytochrome c release driven by H/R in H9c2 cells, whereas reducing cell apoptosis, and knockdown of KPC1 by short-hairpin RNA (shRNA) deteriorated cell apoptosis induced by H/R. Mechanistically, forced expression of KPC1 promoted Bax protein degradation, which was abolished by proteasome inhibitor MG132, suggesting that KPC1 promoted proteasomal degradation of Bax. Furthermore, KPC1 prevented basal and apoptotic stress-induced Bax translocation to mitochondria. Bax can be a novel target for the antiapoptotic effects of KPC1 on I/R-induced cardiomyocyte apoptosis and render mechanistic penetration into at least a subset of the mitochondrial effects of KPC1.

VEGF-A and VEGF-B Coordinate the Arteriogenesis to Repair the Infarcted Heart with Vagus Nerve Stimulation.

BACKGROUND/AIMS: Vagus nerve stimulation (VNS) suppresses arrhythmic activity and minimizes cardiomyocyte injury. However, how VNS affects angiogenesis/arteriogenesis in infarcted hearts, is poorly understood. METHODS: Myocardial infarction (MI) was achieved by ligation of the left anterior descending coronary artery (LAD) in rats. 7 days after LAD, stainless-steel wires were looped around the left and right vagal nerve in the neck for vagus nerve stimulation (VNS). The vagal nerve was stimulated with regular pulses of 0.2ms duration at 20 Hz for 10 seconds every minute for 4 hours, and then ACh levels by ELISA in cardiac tissue and serum were evaluated for its release after VNS. Three and 14 days after VNS, Real-time PCR, immunostaining and western blot were respectively used to determine VEGF-A/B expressions and α-SMA- and CD31-postive vessels in VNS-hearts with pretreatment of α7-nAChR blocker mecamylamine (10 mg/kg, ip) or mACh-R blocker atropine (10 mg/kg, ip) for 1 hour. The coronary function and left ventricular performance were analyzed by Langendorff system and hemodynamic parameters in VNS-hearts with pretreatment of VEGF-A/B-knockdown or VEGFR blocker AMG706. Coronary arterial endothelial cells proliferation, migration and tube formation were evaluated for angiogenesis following the stimulation of VNS in coronary arterial smooth muscle cells (VSMCs). RESULTS: VNS has been shown to stimulate VEGF-A and VEGF-B expressions in coronary arterial smooth muscle cells (VSMCs) and endothelial cells (ECs) with an increase of α-SMA- and CD31-postive vessel number in infarcted hearts. The VNS-induced VEGF-A/B expressions and angiogenesis were abolished by m-AChR inhibitor atropine and α7-nAChR blocker mecamylamine in vivo. Interestingly, knockdown of VEGF-A by shRNA mainly reduced VNS-mediated formation of CD31+ microvessels. In contrast, knockdown of VEGF-B powerfully abrogated VNS-induced formation of α-SMA+ vessels. Consistently, VNS-induced VEGF-A showed a greater effect on EC tube formation as compared to VNS-induced VEGF-B. Moreover, VEGF-A promoted EC proliferation and VSMC migration while VEGF-B induced VSMC proliferation and EC migration in vitro. Mechanistically, vagal neurotransmitter acetylcholine stimulated VEGF-A/B expressions through m/nACh-R/PI3K/Akt/Sp1 pathway in EC. Functionally, VNS improved the coronary function and left ventricular performance. However, blockade of VEGF receptor by antagonist AMG706 or knockdown of VEGF-A or VEGF-B by shRNA significantly diminished the beneficial effects of VNS on ventricular performance. CONCLUSION: VNS promoted angiogenesis/arteriogenesis to repair the infracted heart through the synergistic effects of VEGF-A and VEGF-B.

Ambulatory Blood Pressure Reactivity as a Moderator in the Association Between Daily Life Psychosocial Stress and Carotid Artery Atherosclerosis.

OBJECTIVE: We examined whether associations between daily psychosocial stressor exposures and carotid artery intima-medial thickness (IMT) may be stronger among those showing larger stress-related cardiovascular reactivity (CVR) during the course of daily living. METHODS: A total of 474 healthy working adults (ages 30-54 years) collected ambulatory blood pressure and recorded their daily experiences, using electronic diaries, during two 2-day periods for a week. Measures of mean momentary task strain and social conflict were used as indices of stressor exposure, and partial regression coefficients linking momentary strain and conflict with ambulatory blood pressure fluctuations were used as measures of CVR. IMT was assessed in the carotid arteries using B-mode ultrasound. RESULTS: After covariate adjustment, associations between mean task strain exposure and IMT were significant among those high in CVR to strain (for systolic blood pressure, p = .006, for diastolic blood pressure, p = .011) but not among those low in strain CVR. Similarly, associations involving mean conflict exposure were significant among those high in CVR to social conflict (p < .001 for systolic blood pressure, p = .001 for diastolic blood pressure) but not among low social conflict reactors. Significant moderation effects were more consistently shown for task strain than for social conflict, but the overall pattern of results was robust across two different types of statistical modeling procedures. CONCLUSIONS: Individual differences in CVR may moderate the effects of daily psychosocial stress on subclinical CVD among healthy employed adults. Using ecological momentary assessment to measure stress exposure as well as stress reactivity may facilitate our ability to detect these effects.

Structural and dynamic properties of water molecules in a uniformly charged nanopore.

The structural and dynamic properties of water molecules in a uniformly charged nanopore have been studied using the method of classical molecular dynamics simulation. When confined in an uncharged nanopore with an appropriate radius, water molecules are aligned along the nanopore axis and form a single-file structure with the dipole vectors pointing toward the same end of the nanopore. We demonstrate here that when the nanopore is uniformly charged, the water molecules in the nanopore pack more tightly and the water molecules near the two ends of the nanopore are no longer aligned along the nanopore axis but tend to be aligned perpendicularly to the nanopore axis. The water dipole vectors do not point toward the same nanopore end. When the nanopore is positively charged, the water molecules in the nanopore align with their oxygen atoms pointing to the center of the nanopore. The central water molecule forms an L-defect. However for a negatively charged nanopore, the water molecules in the nanopore take up the opposite orientation. A D-defect is formed at the center of the nanopore. Furthermore, the water molecules in the negatively charged nanopore with moderate atomic partial charges diffuse and transport more quickly than the water molecules in an uncharged nanopore.

S100B promotes injury-induced vascular remodeling through modulating smooth muscle phenotype.

S100B is a biomarker of nervous system injury, but it is unknown if it is also involved in vascular injury. In the present study, we investigated S100B function in vascular remodeling following injury. Balloon injury in rat carotid artery progressively induced neointima formation while increasing S100B expression in both neointimal vascular smooth muscle (VSMC) and serum along with an induction of proliferating cell nuclear antigen (PCNA). Knockdown of S100B by its shRNA delivered by adenoviral transduction attenuated the PCNA expression and neointimal hyperplasia in vivo and suppressed PDGF-BB-induced VSMC proliferation and migration in vitro. Conversely, overexpression of S100B promoted VSMC proliferation and migration. Mechanistically, S100B altered VSMC phenotype by decreasing the contractile protein expression, which appeared to be mediated by NF-κB activity. S100B induced NF-κB-p65 gene transcription, protein expression and nuclear translocation. Blockade of NF-κB activity by its inhibitor reversed S100B-mediated downregulation of VSMC contractile protein and increase in VSMC proliferation and migration. It appeared that S100B regulated NF-κB expression through, at least partially, the Receptor for Advanced Glycation End products (RAGE) because RAGE inhibitor attenuated S100B-mediated NF-κB promoter activity as well as VSMC proliferation. Most importantly, S100B secreted from VSMC impaired endothelial tube formation in vitro, and knockdown of S100B promoted re-endothelialization of injury-denuded arteries in vivo. These data indicated that S100B is a novel regulator for vascular remodeling following injury and may serve as a potential biomarker for vascular damage or drug target for treating proliferative vascular diseases.

[Luminescence Characteristics of Scintillator Y2SiO5∶Ce].

Cerium doped Y2SiO5 (YSO) is an important scintillator material due to its high density, non-hygroscopic, excellent light output and fast decay time nature. in the paper, Y2SiO5∶Ce3+0.2%(YSO∶Ce) was grown with high-temperature solid-phase method. The time-resolved excitation and emission spectra and fluorescent decay curves at low temperature and room temperature (RT) were measured and discussed. There were two types of luminescence, one was the crystal defect emission, the center at 320 nm; the other one was doped Ce3+ ions 5d→4f emission, the center at 440 nm. Only when the excitation energy (Ex) was greater than the band gap width (Eg), the crystal defect emission can be observed corresponding to slow process, and the emission intensity was higher at low temperature. The crystals defect emission was hardly observed in the time-resolved emission spectra when the temperature rose to room temperature because of temperature quenching. Regions from 60~300 nm corresponding to emission due to 5d→4f transitions in the activator Ce3+ ions peaks at 440 nm, a plurality of excitation peaks were observed. Among them, the excitation with energy less than 6.1 eV(Ex

Autoinducer-2 regulates Pseudomonas aeruginosa PAO1 biofilm formation and virulence production in a dose-dependent manner.

BACKGROUND: Pseudomonas aeruginosa is an opportunistic pathogen that is the leading cause of iatrogenic infections in critically ill patients, especially those undergoing mechanical ventilation. In this study, we investigated the effects of the universal signaling molecule autoinducer-2 (AI-2) in biofilm formation of P. aeruginosa PAO1. RESULTS: The addition of 0.1 nM, 1 nM, and 10 nM exogenous AI-2 to P. aeruginosa PAO1 increased biofilm formation, bacterial viability, and the production of virulence factors. However, compared to the 10 nM AI-2 group, higher concentrations of AI-2 (100 nM and 1 µM) reduced biofilm formation, bacterial viability, and the production of virulence factors. Consistent with the changes in morphology, gene expression analysis revealed that AI-2 up-regulated the expression of quorum sensing-associated genes and genes encoding virulence factors at lower concentrations and down-regulated these genes at higher concentrations. CONCLUSIONS: Our study demonstrated that exogenous AI-2 acted in a dose-dependent manner to regulate P. aeruginosa biofilm formation and virulence factors secretion via modulating the expression of quorum sensing-associated genes and may be targeted to treat P. aeruginosa biofilm infections.

Domain Motions and Functionally-Key Residues of L-Alanine Dehydrogenase Revealed by an Elastic Network Model.

Mycobacterium tuberculosis L-alanine dehydrogenase (L-MtAlaDH) plays an important role in catalyzing L-alanine to ammonia and pyruvate, which has been considered to be a potential target for tuberculosis treatment. In the present work, the functional domain motions encoded in the structure of L-MtAlaDH were investigated by using the Gaussian network model (GNM) and the anisotropy network model (ANM). The slowest modes for the open-apo and closed-holo structures of the enzyme show that the domain motions have a common hinge axis centered in residues Met133 and Met301. Accompanying the conformational transition, both the 1,4-dihydronicotinamide adenine dinucleotide (NAD)-binding domain (NBD) and the substrate-binding domain (SBD) move in a highly coupled way. The first three slowest modes of ANM exhibit the open-closed, rotation and twist motions of L-MtAlaDH, respectively. The calculation of the fast modes reveals the residues responsible for the stability of the protein, and some of them are involved in the interaction with the ligand. Then, the functionally-important residues relevant to the binding of the ligand were identified by using a thermodynamic method. Our computational results are consistent with the experimental data, which will help us to understand the physical mechanism for the function of L-MtAlaDH.