E3 Ligase Subunit Fbxo15 and PINK1 Kinase Regulate Cardiolipin Synthase 1 Stability and Mitochondrial Function in Pneumonia

Acute lung injury (ALI) is linked to mitochondrial injury, resulting in impaired cellular oxygen utilization; however, it is unknown how these events are linked on the molecular level. Cardiolipin, a mitochondrial-specific lipid, is generated by cardiolipin synthase (CLS1). Here, we show that S.aureus activates a ubiquitin E3 ligase component, Fbxo15, that is sufficient to mediate proteasomal degradation of CLS1 in epithelia, resulting in decreased cardiolipin availability and disrupted mitochondrial function. CLS1 is destabilized by the phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), which binds CLS1 to phosphorylate and regulates CLS1 disposal. Like Fbxo15, PINK1 interacts with and regulates levels of CLS1 through a mechanism dependent upon Thr219. S.aureus infection upregulates this Fbxo15-PINK1 pathway to impair mitochondrial integrity, and Pink1 knockout mice are less prone to S.aureus-induced ALI. Thus, ALI-associated disruption of cellular bioenergetics involves bioeffectors that utilize a phosphodegron to elicit ubiquitin-mediated disposal of a key mitochondrial enzyme. © 2014 The Authors

Estimating the health burden of aflatoxin attributable stunting among children in low income countries of Africa

Numerous population-based studies have documented high prevalence of aflatoxin associated childhood stunting in low income countries. We provide an estimate of the disease burden of aflatoxin related stunting using data from the four African countries. For this empirical analysis, we obtained blood aflatoxin albumin adduct biomarker based exposure data as measured using ELISA technique and anthropometric measurement data from surveys done over a 12-year period from 2001 to 2012 in four low income countries in Africa. We used these data to calculate population attributable risk (PAR), life time disease burden for children under five by comparing two groups of stunted children using both prevalence and incidence-based approaches. We combined prevalence estimates with a disability weight, measuring childhood stunting and co-occurrence of stunting-underweight to produce years lived with disability. Using a previously reported mortality, years of life lost were estimated. We used probabilistic analysis to model these associations to estimate the disability-adjusted life-years (DALYs), and compared these with those given by the Institute for Health Metrics and Evaluation’s Global Burden of Disease (GBD) 2016 study. The PAR increased from 3 to 36% for aflatoxin-related stunting and 14–50% for co-occurrence of stunting and underweight. Using prevalence-based approach, children with aflatoxin related stunting resulted in 48,965.20 (95% uncertainty interval (UI): 45,868.75–52,207.53) DALYs per 100,000 individuals. Children with co-occurrence of stunting and underweight due to exposure to aflatoxin resulted in 40,703.41 (95% UI: 38,041.57–43,517.89) DALYs per 100,000 individuals. Uncertainty analysis revealed that reducing aflatoxin exposure in high exposure areas upto non-detectable levels could save the stunting DALYs up to 50%. The burden of childhood all causes stunting is greater in countries with higher aflatoxin exposure such as Benin. In high exposure areas, these results might help guide research protocols and prioritisation efforts and focus aflatoxin exposure reduction. HEFCE Global Challenge Research Fund Aflatoxin project

Searching Ultra-compact Pulsar Binaries with Abnormal Timing Behavior

published_or_final_versio

Pituitary tumor transforming gene-1 haplotypes and risk of pituitary adenoma: a case-control study

<p>Abstract</p> <p>Background</p> <p>It has been suggested that pituitary adenoma results from accumulation of multiple genetic and/or epigenetic aberrations, which may be identified through association studies. As pituitary tumor transforming gene-1 (<it>PTTG1</it>)/securin plays a critical role in promoting genomic instability in pituitary neoplasia, the present study explored the association of <it>PTTG1 </it>haplotypes with the risk of pituitary adenoma.</p> <p>Methods</p> <p>We genotyped five <it>PTTG1 </it>haplotype-tagging SNPs (htSNP) by PCR-RFLP assays in a case-control study, which included 280 Han Chinese patients diagnosed with pituitary adenoma and 280 age-, gender- and geographically matched Han Chinese controls. Haplotypes were reconstructed according to the genotyping data and linkage disequilibrium status of the htSNPs.</p> <p>Results</p> <p>No significant differences in allele and genotype frequencies of the htSNPs were observed between pituitary adenoma patients and controls, indicating that none of the individual <it>PTTG1 </it>SNPs examined in this study is associated with the risk of pituitary adenoma. In addition, no significant association was detected between the reconstructed <it>PTTG1 </it>haplotypes and pituitary adenoma cases or the controls.</p> <p>Conclusions</p> <p>Though no significant association was found between <it>PTTG1 </it>haplotypes and the risk of pituitary adenoma, this is the first report on the association of individual <it>PTTG1 </it>SNPs or <it>PTTG1 </it>haplotypes with the risk of pituitary adenoma based on a solid study; it will provide an important reference for future studies on the association between genetic alterations in <it>PTTG1 </it>and the risk of pituitary adenoma or other tumors.</p

Disparities and risks of sexually transmissible infections among men who have sex with men in China: a meta-analysis and data synthesis.

BACKGROUND: Sexually transmitted infections (STIs), including Hepatitis B and C virus, are emerging public health risks in China, especially among men who have sex with men (MSM). This study aims to assess the magnitude and risks of STIs among Chinese MSM. METHODS: Chinese and English peer-reviewed articles were searched in five electronic databases from January 2000 to February 2013. Pooled prevalence estimates for each STI infection were calculated using meta-analysis. Infection risks of STIs in MSM, HIV-positive MSM and male sex workers (MSW) were obtained. This review followed the PRISMA guidelines and was registered in PROSPERO. RESULTS: Eighty-eight articles (11 in English and 77 in Chinese) investigating 35,203 MSM in 28 provinces were included in this review. The prevalence levels of STIs among MSM were 6.3% (95% CI: 3.5-11.0%) for chlamydia, 1.5% (0.7-2.9%) for genital wart, 1.9% (1.3-2.7%) for gonorrhoea, 8.9% (7.8-10.2%) for hepatitis B (HBV), 1.2% (1.0-1.6%) for hepatitis C (HCV), 66.3% (57.4-74.1%) for human papillomavirus (HPV), 10.6% (6.2-17.6%) for herpes simplex virus (HSV-2) and 4.3% (3.2-5.8%) for Ureaplasma urealyticum. HIV-positive MSM have consistently higher odds of all these infections than the broader MSM population. As a subgroup of MSM, MSW were 2.5 (1.4-4.7), 5.7 (2.7-12.3), and 2.2 (1.4-3.7) times more likely to be infected with chlamydia, gonorrhoea and HCV than the broader MSM population, respectively. CONCLUSION: Prevalence levels of STIs among MSW were significantly higher than the broader MSM population. Co-infection of HIV and STIs were prevalent among Chinese MSM. Integration of HIV and STIs healthcare and surveillance systems is essential in providing effective HIV/STIs preventive measures and treatments. TRIAL REGISTRATION: PROSPERO NO: CRD42013003721

Cascading signaling pathways improve the fidelity of a stochastically and deterministically simulated molecular RS latch

<p>Abstract</p> <p>Background</p> <p>While biological systems have often been compared with digital systems, they differ by the strong effect of crosstalk between signals due to diffusivity in the medium, reaction kinetics and geometry. Memory elements have allowed the creation of autonomous digital systems and although biological systems have similar properties of autonomy, equivalent memory mechanisms remain elusive. Any such equivalent memory system, however, must silence the effect of crosstalk to maintain memory fidelity.</p> <p>Results</p> <p>Here, we present a system of enzymatic reactions that behaves like an RS latch (a simple memory element in digital systems). Using both a stochastic molecular simulator and ordinary differential equation simulator, we showed that crosstalk between two latches operating in the same spatial localization disrupts the memory fidelity of both latches. Crosstalk was reduced or silenced when simple reaction loops were replaced with multiple step or cascading reactions, showing that cascading signaling pathways are less susceptible to crosstalk.</p> <p>Conclusion</p> <p>Thus, the common biological theme of cascading signaling pathways is advantageous for maintaining the fidelity of a memory latch in the presence of crosstalk. The experimental implementation of such a latch system will lead to novel approaches to cell control using synthetic proteins and will contribute to our understanding of why cells behave differently even when given the same stimulus.</p

The retroviral oncoprotein Tax targets the coiled-coil centrosomal protein TAX1BP2 to induce centrosome overduplication

Emerging evidence suggests that supernumerary centrosomes drive genome instability and oncogenesis. Human T-cell leukaemia virus type I (HTLV-I) is etiologically associated with adult T-cell leukaemia (ATL). ATL cells are aneuploid, but the causes of aneuploidy are incompletely understood. Here, we show that centrosome amplification is frequent in HTLV-I-transformed cells and that this phenotype is caused by the viral Tax oncoprotein. We also show that the fraction of Tax protein that localizes to centrosomes interacts with TAX1BP2, a novel centrosomal protein composed almost entirely of coiled-coil domains. Overexpression of TAX1BP2 inhibited centrosome duplication, whereas depletion of TAX1BP2 by RNAi resulted in centrosome hyperamplification. Our findings suggest that the HTLV-I Tax oncoprotein targets TAX1BP2 causing genomic instability and aneuploidy. © 2006 Nature Publishing Group.postprin