Analysis of multivariate recurrent event data with time‐dependent covariates and informative censoring

Multivariate recurrent event data are usually encountered in many clinical and longitudinal studies in which each study subject may experience multiple recurrent events. For the analysis of such data, most existing approaches have been proposed under the assumption that the censoring times are noninformative, which may not be true especially when the observation of recurrent events is terminated by a failure event. In this article, we consider regression analysis of multivariate recurrent event data with both time‐dependent and time‐independent covariates where the censoring times and the recurrent event process are allowed to be correlated via a frailty. The proposed joint model is flexible where both the distributions of censoring and frailty variables are left unspecified. We propose a pairwise pseudolikelihood approach and an estimating equation‐based approach for estimating coefficients of time‐dependent and time‐independent covariates, respectively. The large sample properties of the proposed estimates are established, while the finite‐sample properties are demonstrated by simulation studies. The proposed methods are applied to the analysis of a set of bivariate recurrent event data from a study of platelet transfusion reactions.     

Cellulose microfibril angle variation in Picea crassifolia tree rings improves climate signals on the Tibetan plateau

Microfibril angle (MFA) is an important factor in determining the mechanical properties of individual cells and wood as a whole. While some studies have described the variation of MFA within trees, little work has been done on the extent to which MFA is influenced by climate, despite it being known to respond to climatic events. Year-to-year variation in MFA and ring width was measured at high resolution by SilviScan-3^? on 30 dated Picea crassifolia trees growing in the northeastern Tibetan plateau. The climate signals registered in MFA and ring width were analyzed using dendroclimatological methods. The response function of MFA accounted for 67% of total variance, of which 60% was explained by climate elements. The response function of ring width explained 57% total variance, 37% of which was explained by climate variables. MFA significantly responded to July–August temperatures, and to precipitation in March, May and September. Over the period 1987–2009 temperatures generally increase and appeared to have a greater influence on MFA. A decrease in the strength of the relationship between MFA and ring width over the period 1987–2009 was also observed. MFA offers the potential to build robust climate proxies. The strong climate sensitivity of MFA to increasing temperature or the observed changes in the MFA–ring width relationship may contribute to resolving the “divergence problem” in temperature reconstructions. As far as we are aware, this study is the first to show a strong climate response in MFA and suggests that it might be a useful climate proxy.     

Food restriction and refeeding have no effect on cellular and humoral immunity in Mongolian gerbils (Meriones unguiculatus)

Small mammals in the temperate area often face fluctuations in food availability. Changes in food availability may have a great influence on an animals' immunity, which is important to their survival. We tested the hypothesis that cellular and humoral immunity would be suppressed by food restriction and restored to control levels by refeeding in Mongolian gerbils Meriones unguiculatus. Forty adult male gerbils were randomly divided into food-restricted (80% of baseline food intake) and food ad lib. groups. Similarly, another 40 adult male gerbils were also randomly assigned to two groups: a group for which food was restricted for 36 d and then provided ad lib. and a group that was continuously fed ad lib. Half of the gerbils in each group were injected with phytohemagglutinin (PHA) and keyhole limpet hemocyanin solution to assess cellular and humoral immunity, respectively; the others were injected with sterile saline as control groups. Food-restricted gerbils had significantly lower body mass, body fat mass, dry thymus mass, wet and dry spleen mass, and serum leptin levels than those of the controls, whereas refeeding restored these parameters to the controls. Both food restriction and refeeding had no significant effect on PHA response indicative of cellular immunity, immunoglobulin G and immunoglobulin M concentrations, and white blood cells. We also found that food restriction decreased corticosterone levels in food-restricted gerbils, while refeeding increased corticosterone levels in refed gerbils compared with the controls. Our results suggest that cellular and humoral immunity were not affected by food restriction and refeeding in gerbils.     

Microbial diversity in deep-sea sediment from the cobalt-rich crust deposit region in the Pacific Ocean

Cobalt-rich crusts are important metallic mineral resources with great economic potential, usually distributed on seamounts located in the Pacific Ocean. Microorganisms are believed to play a role in the formation of crusts as well as in metal cycling. To explore the microbial diversity related to cobalt-rich crusts, 16S ribosomal RNA gene clone libraries were constructed from three consecutive sediment layers. In total, 417 bacterial clones were obtained from three bacterial clone libraries, representing 17 distinct phylogenetic groups. Proteobacteria dominated in the bacterial communities, followed by Acidobacteria and Planctomycetes. Compared with high bacterial diversity, archaea showed a remarkably low diversity, with all 137 clones belonging to marine archaeal group I except one novel euryarchaeotal clone. The microbial communities were potentially involved in sulfur, nitrogen and metal cycling in the area of cobalt-rich crusts. Sulfur oxidation and metal oxidation were potentially major sources of energy for this ecosystem. This is the first reported investigation of microbial diversity in sediments associated with cobalt-rich crusts, and it casts fresh light on the microbial ecology of these important ecosystems.     

ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling

Mutations in VPS13C cause early-onset, autosomal recessive Parkinson’s disease (PD). We have established that VPS13C encodes a lipid transfer protein localized to contact sites between the ER and late endosomes/lysosomes. In the current study, we demonstrate that depleting VPS13C in HeLa cells causes an accumulation of lysosomes with an altered lipid profile, including an accumulation of di-22:6-BMP, a biomarker of the PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation. In addition, the DNA-sensing cGAS-STING pathway, which was recently implicated in PD pathogenesis, is activated in these cells. This activation results from a combination of elevated mitochondrial DNA in the cytosol and a defect in the degradation of activated STING, a lysosome-dependent process. These results suggest a link between ER-lysosome lipid transfer and innate immune activation in a model human cell line and place VPS13C in pathways relevant to PD pathogenesis.     

An NMR-based identification of a peptide fragment from the beta-subunit of a G-protein showing specific interactions with the GBB domain of the Ste20 kinase in budding yeast

In mitogen-activated protein kinase (MAPK) cascades of budding yeast, pheromone-induced mating signal is transmitted by interactions between the beta-subunit of a G-protein (G-beta) and the G-beta binding (GBB) domain of Ste20 kinase. Previously, mutational analyses of the beta-subunit of G-protein had identified two critical mutations which abrogate binding of the GBB domain of Ste20. In this work, we have identified, by use of NMR spectroscopy, a peptide fragment from the G-beta that shows specific interactions with the isolated GBB domain of Ste20. A model structure of the Ste20/G-beta complex reveals that the interface of the hetero-complex may be sustained by parallel orientation of two potentially interacting helical segments that are further stabilized by ionic, hydrogen bond, and helix macro-dipole interactions.     

Aspirin Use and Lung Cancer Risk: A Possible Relationship? Evidence from an Updated Meta-Analysis

Background and Purpose

Growing evidence has emerged and controversial results reported on possible relationship between aspirin use and lung cancer risk. We, therefore, conducted this updated and comprehensive meta-analysis to evaluate this issue, with focus on dose-risk and duration-risk relationships.

Methods

We searched electronic databases including PUBMED, EMBASE and Cochrane library to identify eligible studies. Relative risk (RR) and its 95% confidence interval (CI) were used for cohort studies, while odds ratio (OR) were employed for case-control studies. The random effects and fixed effects models were used for analyses.

Results

18 studies were identified including 19835 lung cancer cases, which were eligible for inclusion in the present meta-analysis. Pooled data from case-control studies showed a significant inverse association between regular aspirin use and lung cancer risk. But for cohort studies, insignificant association was detected with little evidence of heterogeneity (RR: 1.05, 95%CI: 0.95 – 1.16; I²: 10.3%, p value: 0.351). In case-control studies, standard aspirin use (>325mg) was related to lower lung cancer incidence, compared with low-dose aspirin use (75–100mg). A similar trend was observed in cohort studies. Besides, when analysis was restricted to long time regular aspirin use (>5 years), insignificant results were reported in both cohort and case-control studies. Finally, regular aspirin use might result in higher reduction of non-small cell lung cancer incidence among men.

Conclusions

Our findings do not support the protective effect of regular aspirin use on lung cancer risk. Long time aspirin use, sex, dose and type of lung cancer might alter the effect of aspirin use on lung cancer risk. More well-designed studies are needed to further clarify these associations.     

Hydrocortisone modulates the effect of estradiol on endothelial nitric oxide synthase expression in human endothelial cells.

The interaction between hydrocortisone and estradiol on the regulation of endothelial nitric oxide synthase (eNOS) expression was investigated in human umbilical vein endothelial cells (HUVECs). Following incubation in medium containing dextran-coated-charcoal-stripped serum (DCC-stripped medium) for 4 days, incubation of HUVECs with 0.1 nM estradiol for 24 hr in the absence of hydrocortisone increased levels of eNOS mRNA measured by ribonuclease protection assay above control (0 nM estradiol). 2 microM hydrocortisone applied for 24 hr preceding and during estradiol application inhibited the estradiol-elicited increase in eNOS mRNA levels, reducing mRNA levels from 134% +/- 14% of control to 85% +/- 5% of control. Significant (ANOVA, p<0.01) reductions of estradiol-mediated increases of mRNA levels occurred over a range of hydrocortisone concentrations (10 nM, p<0.05; 2 microM, p<0.05; n=3-12). In the presence of 2 microM hydrocortisone, 10 nM estradiol significantly reduced eNOS mRNA levels to 59% +/- 3% of control. The ability of hydrocortisone to block or reverse the estradiol-mediated increase in eNOS mRNA levels may provide a link between elevated hydrocortisone levels and decreased NO production, potentially contributing to the development of hypertension and cardiovascular disease in vivo and antagonizing cardioprotective effects of estrogens.