Gene Expression Pattern in Transmitochondrial Cytoplasmic Hybrid Cells Harboring Type 2 Diabetes-Associated Mitochondrial DNA Haplogroups

Decreased mitochondrial function plays a pivotal role in the pathogenesis of type 2 diabetes mellitus (T2DM). Recently, it was reported that mitochondrial DNA (mtDNA) haplogroups confer genetic susceptibility to T2DM in Koreans and Japanese. Particularly, mtDNA haplogroup N9a is associated with a decreased risk of T2DM, whereas haplogroups D5 and F are associated with an increased risk. To examine functional consequences of these haplogroups without being confounded by the heterogeneous nuclear genomic backgrounds of different subjects, we constructed transmitochondrial cytoplasmic hybrid (cybrid) cells harboring each of the three haplogroups (N9a, D5, and F) in a background of a shared nuclear genome. We compared the functional consequences of the three haplogroups using cell-based assays and gene expression microarrays. Cell-based assays did not detect differences in mitochondrial functions among the haplogroups in terms of ATP generation, reactive oxygen species production, mitochondrial membrane potential, and cellular dehydrogenase activity. However, differential expression and clustering analyses of microarray data revealed that the three haplogroups exhibit a distinctive nuclear gene expression pattern that correlates with their susceptibility to T2DM. Pathway analysis of microarray data identified several differentially regulated metabolic pathways. Notably, compared to the T2DM-resistant haplogroup N9a, the T2DM-susceptible haplogroup F showed down-regulation of oxidative phosphorylation and up-regulation of glycolysis. These results suggest that variations in mtDNA can affect the expression of nuclear genes regulating mitochondrial functions or cellular energetics. Given that impaired mitochondrial function caused by T2DM-associated mtDNA haplogroups is compensated by the nuclear genome, we speculate that defective nuclear compensation, under certain circumstances, might lead to the development of T2DM

Quantum capacity of an amplitude-damping channel with memory

We calculate the quantum capacity of an amplitude-damping channel with time correlated Markov noise, for two channel uses. Our results show that memory of the channel increases it's ability to transmit quantum information significantly. We analyze and compare our findings with earlier numerical results on amplitude-damping channel with memory. An upper bound on the amount of quantum information transmitted over the channel in presence of memory, for an arbitrary number of channel uses is also presented.Comment: 17 Pages, 5 Figure

Impact of nine common type 2 diabetes risk polymorphisms in Asian Indian Sikhs: PPARG2 (Pro12Ala), IGF2BP2, TCF7L2 and FTO variants confer a significant risk

<p>Abstract</p> <p>Background</p> <p>Recent genome-wide association (GWA) studies have identified several unsuspected genes associated with type 2 diabetes (T2D) with previously unknown functions. In this investigation, we have examined the role of 9 most significant SNPs reported in GWA studies: [peroxisome proliferator-activated receptor gamma 2 (<it>PPARG2</it>; rs 1801282); insulin-like growth factor two binding protein 2 (<it>IGF2BP2</it>; rs 4402960); cyclin-dependent kinase 5, a regulatory subunit-associated protein1-like 1 (<it>CDK5</it>; rs7754840); a zinc transporter and member of solute carrier family 30 (<it>SLC30A8</it>; rs13266634); a variant found near cyclin-dependent kinase inhibitor 2A (<it>CDKN2A</it>; rs10811661); hematopoietically expressed homeobox (<it>HHEX</it>; rs 1111875); transcription factor-7-like 2 (<it>TCF7L2</it>; rs 10885409); potassium inwardly rectifying channel subfamily J member 11(<it>KCNJ11</it>; rs 5219); and fat mass obesity-associated gene (<it>FTO</it>; rs 9939609)].</p> <p>Methods</p> <p>We genotyped these SNPs in a case-control sample of 918 individuals consisting of 532 T2D cases and 386 normal glucose tolerant (NGT) subjects of an Asian Sikh community from North India. We tested the association between T2D and each SNP using unconditional logistic regression before and after adjusting for age, gender, and other covariates. We also examined the impact of these variants on body mass index (BMI), waist to hip ratio (WHR), fasting insulin, and glucose and lipid levels using multiple linear regression analysis.</p> <p>Results</p> <p>Four of the nine SNPs revealed a significant association with T2D; <it>PPARG2 </it>(Pro12Ala) [odds ratio (OR) 0.12; 95% confidence interval (CI) (0.03–0.52); p = 0.005], <it>IGF2BP2 </it>[OR 1.37; 95% CI (1.04–1.82); p = 0.027], <it>TCF7L2 </it>[OR 1.64; 95% CI (1.20–2.24); p = 0.001] and <it>FTO </it>[OR 1.46; 95% CI (1.11–1.93); p = 0.007] after adjusting for age, sex and BMI. Multiple linear regression analysis revealed significant association of two of nine investigated loci with diabetes-related quantitative traits. The 'C' (risk) allele of <it>CDK5 </it>(rs 7754840) was significantly associated with decreased HDL-cholesterol levels in both NGT (p = 0.005) and combined (NGT and T2D) (0.005) groups. The less common 'C' (risk) allele of <it>TCF7L2 </it>(rs 10885409) was associated with increased LDL-cholesterol (p = 0.010) in NGT and total and LDL-cholesterol levels (p = 0.008; p = 0.003, respectively) in combined cohort.</p> <p>Conclusion</p> <p>To our knowledge, this is first study reporting the role of some recently emerged loci with T2D in a high risk population of Asian Indian origin. Further investigations are warranted to understand the pathway-based functional implications of these important loci in T2D pathophysiology in different ethnicities.</p

Evaluating the implementation related challenges of Shasthyo Suroksha Karmasuchi (health protection scheme) of the government of Bangladesh: a study protocol

Background Rapidly increasing healthcare costs and the growing burden of noncommunicable diseases have increased the out-of-pocket (OOP) spending (63.3% of total health expenditure) in Bangladesh. This increasing OOP spending for healthcare has catastrophic economic impact on households. To reduce this burden, the Health Economics Unit (HEU) of the Ministry of Health and Family Welfare has developed the Shasthyo Surokhsha Karmasuchi (SSK) health protection scheme for the below-poverty line (BPL) population. The key actors in the scheme are HEU, contracted scheme operator and hospital. Under this scheme, each enrolled household is provided 50,000 BDT (620 USD) coverage per year for healthcare services against a government financed premium of 1000 BDT (12 USD). This initiative faces some challenges e.g., delays in scheme activities, registering the targeted population, low utilization of services, lack of motivation of the providers, and management related difficulties. It is also important to estimate the financial requirement for nationwide scale-up of this project. We aim to identify these implementation-related challenges and provide feedback to the project personnel. Methods This is a concurrent process documentation using mixed-method approaches. It will be conducted in the rural Kalihati Upazila where the SSK is being implemented. To validate the BPL population selection process, we will estimate the positive predictive value. A community survey will be conducted to assess the knowledge of the card holders about SSK services. From the SSK information management system, numbers of different services utilized by the card holders will be retrieved. Key-informant interviews with personnel from three key actors will be conducted to understand the barriers in the implementation of the project as per plan and gather their suggestions. To estimate the project costs, all inputs to be used will be identified, quantified and valued. The nationwide scale-up cost of the project will be estimated by applying economic modeling. Discussion SSK is the first ever government initiated health protection scheme in Bangladesh. The study findings will enable decision makers to gain a better understanding of the key challenges in implementation of such scheme and provide feedback towards the successful implementation of the program

The LUX-ZEPLIN (LZ) Experiment

We describe the design and assembly of the LUX-ZEPLIN experiment, a direct detection search for cosmic WIMP dark matter particles. The centerpiece of the experiment is a large liquid xenon time projection chamber sensitive to low energy nuclear recoils. Rejection of backgrounds is enhanced by a Xe skin veto detector and by a liquid scintillator Outer Detector loaded with gadolinium for efficient neutron capture and tagging. LZ is located in the Davis Cavern at the 4850' level of the Sanford Underground Research Facility in Lead, South Dakota, USA. We describe the major subsystems of the experiment and its key design features and requirements

The LUX-ZEPLIN (LZ) radioactivity and cleanliness control programs

LUX-ZEPLIN (LZ) is a second-generation direct dark matter experiment with spin-independent WIMP-nucleon scattering sensitivity above 1.4×10−48cm2 for a WIMP mass of 40GeV/c2 and a 1000days exposure. LZ achieves this sensitivity through a combination of a large 5.6t fiducial volume, active inner and outer veto systems, and radio-pure construction using materials with inherently low radioactivity content. The LZ collaboration performed an extensive radioassay campaign over a period of six years to inform material selection for construction and provide an input to the experimental background model against which any possible signal excess may be evaluated. The campaign and its results are described in this paper. We present assays of dust and radon daughters depositing on the surface of components as well as cleanliness controls necessary to maintain background expectations through detector construction and assembly. Finally, examples from the campaign to highlight fixed contaminant radioassays for the LZ photomultiplier tubes, quality control and quality assurance procedures through fabrication, radon emanation measurements of major sub-systems, and bespoke detector systems to assay scintillator are presented

Quantification of In Situ Denitrification Rates in Groundwater Below an Arable and a Grassland System

peer-reviewedUnderstanding denitrification rates in groundwater ecosystems can help predict where agricultural reactive nitrogen (N) contributes to environmental degradation. In situ groundwater denitrification rates were determined in subsoil, at the bedrock-interface and in bedrock at two sites, grassland and arable, using an in situ ‘push-pull’ method with 15N labelled nitrate (NO3--N). Measured groundwater denitrification rates ranged from 1.3 to 469.5 µg N kg-1d-1. Exceptionally high denitrification rates observed at the bedrock-interface at grassland site (470±152µg N kg-1d-1; SE, standard error) suggest that deep groundwater can serve as substantial hotspots for NO3--N removal. However, denitrification rates at the other locations were low and may not substantially reduce NO3--N delivery to surface waters. Denitrification rates were negatively correlated with ambient dissolved oxygen (DO), redox potential (Eh), ks and NO3- (all p-values p<0.01) and positively correlated with SO42- (p<0.05). Higher mean N2O/(N2O+N2) ratios at arable (0.28) site than the grassland (0.10) revealed that arable site has higher potential to indirect N2O emissions. Identification of areas with high and low denitrification and related site parameters can be a tool to manage agricultural N to safeguard the environment.Department of Agriculture and Food, Ireland - Research Stimulus Fund Programme (Grant RSF 06383