Mouse obesity network reconstruction with a variational Bayes algorithm to employ aggressive false positive control

<p>Abstract</p> <p>Background</p> <p>We propose a novel variational Bayes network reconstruction algorithm to extract the most relevant disease factors from high-throughput genomic data-sets. Our algorithm is the only scalable method for regularized network recovery that employs Bayesian model averaging and that can internally estimate an appropriate level of sparsity to ensure few false positives enter the model without the need for cross-validation or a model selection criterion. We use our algorithm to characterize the effect of genetic markers and liver gene expression traits on mouse obesity related phenotypes, including weight, cholesterol, glucose, and free fatty acid levels, in an experiment previously used for discovery and validation of network connections: an F2 intercross between the C57BL/6 J and C3H/HeJ mouse strains, where apolipoprotein E is null on the background.</p> <p>Results</p> <p>We identified eleven genes, Gch1, Zfp69, Dlgap1, Gna14, Yy1, Gabarapl1, Folr2, Fdft1, Cnr2, Slc24a3, and Ccl19, and a quantitative trait locus directly connected to weight, glucose, cholesterol, or free fatty acid levels in our network. None of these genes were identified by other network analyses of this mouse intercross data-set, but all have been previously associated with obesity or related pathologies in independent studies. In addition, through both simulations and data analysis we demonstrate that our algorithm achieves superior performance in terms of power and type I error control than other network recovery algorithms that use the lasso and have bounds on type I error control.</p> <p>Conclusions</p> <p>Our final network contains 118 previously associated and novel genes affecting weight, cholesterol, glucose, and free fatty acid levels that are excellent obesity risk candidates.</p

A variational Bayes algorithm for fast and accurate multiple locus genome-wide association analysis

<p>Abstract</p> <p>Background</p> <p>The success achieved by genome-wide association (GWA) studies in the identification of candidate loci for complex diseases has been accompanied by an inability to explain the bulk of heritability. Here, we describe the algorithm V-Bay, a variational Bayes algorithm for multiple locus GWA analysis, which is designed to identify weaker associations that may contribute to this missing heritability.</p> <p>Results</p> <p>V-Bay provides a novel solution to the computational scaling constraints of most multiple locus methods and can complete a simultaneous analysis of a million genetic markers in a few hours, when using a desktop. Using a range of simulated genetic and GWA experimental scenarios, we demonstrate that V-Bay is highly accurate, and reliably identifies associations that are too weak to be discovered by single-marker testing approaches. V-Bay can also outperform a multiple locus analysis method based on the lasso, which has similar scaling properties for large numbers of genetic markers. For demonstration purposes, we also use V-Bay to confirm associations with gene expression in cell lines derived from the Phase II individuals of HapMap.</p> <p>Conclusions</p> <p>V-Bay is a versatile, fast, and accurate multiple locus GWA analysis tool for the practitioner interested in identifying weaker associations without high false positive rates.</p

Phosphorylation of CENP-A on serine 7 does not control centromere function

CENP-A is the histone H3 variant necessary to specify the location of all eukaryotic centromeres via its CENP-A targeting domain and either one of its terminal regions. In humans, several post-translational modifications occur on CENP-A, but their role in centromere function remains controversial. One of these modifications of CENP-A, phosphorylation on serine 7, has been proposed to control centromere assembly and function. Here, using gene targeting at both endogenous CENP-A alleles and gene replacement in human cells, we demonstrate that a CENP-A variant that cannot be phosphorylated at serine 7 maintains correct CENP-C recruitment, faithful chromosome segregation and long-term cell viability. Thus, we conclude that phosphorylation of CENP-A on serine 7 is dispensable to maintain correct centromere dynamics and function

Disruption of the Hippocampal and Hypothalamic Blood-Brain Barrier in a Diet-Induced Obese Model of Type II Diabetes: Prevention and Treatment by the Mitochondrial Carbonic Anhydrase Inhibitor, Topiramate

Background: Type II diabetes is a vascular risk factor for cognitive impairment and increased risk of dementia. Disruption of the blood–retinal barrier (BRB) and blood–brain barrier (BBB) are hallmarks of subsequent retinal edema and central nervous system dysfunction. However, the mechanisms by which diet or metabolic syndrome induces dysfunction are not understood. A proposed mechanism is an increase in reactive oxygen species (ROS) and oxidative stress. Inhibition of mitochondrial carbonic anhydrase (mCA) decreases ROS and oxidative stress. In this study, topiramate, a mCA inhibitor, was examined for its ability to protect the BRB and BBB in diet-induced obese type II diabetic mice. Methods: BBB and BRB permeability were assessed using 14C-sucrose and 99mTc-albumin in CD-1 mice fed a low-fat (control) or a high-fat diet. Topiramate administration was compared to saline controls in both preventative and efficacy arms examining BRB and BBB disruption. Body weight and blood glucose were measured weekly and body composition was assessed using EchoMRI. Metabolic activity was measured using a comprehensive laboratory animal monitoring system. Brain tissues collected from the mice were assessed for changes in oxidative stress and tight junction proteins. Results: High-fat feeding caused increased entry of 14C-sucrose and 99mTc-albumin into the brains of diet-induced obese type II diabetic mice. Increased permeability to 14C-sucrose was observed in the hypothalamus and hippocampus, and attenuated by topiramate treatment, while increased permeability to 99mTc-albumin occurred in the whole brain and was also attenuated by topiramate. Treatment with topiramate decreased measures of oxidative stress and increased expression of the tight junction proteins ZO-1 and claudin-12. In the retina, we observed increased entry of 99mTc-albumin simultaneously with increased entry into the whole brain during the preventative arm. This occurred prior to increased entry to the retina for 14C-sucrose which occurred during the efficacy arm. Treatment with topiramate had no effect on the retina. Conclusions: Blood–brain barrier and blood–retinal barrier dysfunction were examined in a mouse model of diet-induced obese type II diabetes. These studies demonstrate that there are spatial and temporal differences in 14C-sucrose and 99mTc-albumin permeability in the brain and retina of diet-induced obese type II diabetic mice. Topiramate, a mitochondrial carbonic anhydrase inhibitor, is efficacious at both preventing and treating BBB disruption in this diet-induced obese type II diabetic mouse model

People living with dementia and their family carers’ adherence to home-based Tai Chi practice

Objectives: The aim of this study was to understand what influenced people living with dementia and their family carers’ adherence to the home-based component of a Tai Chi exercise intervention. Method: Dyads, of people living with dementia and their family carers, who participated in the intervention arm of the TAi ChI for people living with demenTia (TACIT) trial, were invited to join weekly Tai Chi classes for 20 weeks and practice at home. Semi-structured dyadic home-interviews were conducted on average after 16 weeks of classes. The views of 15 dyads with a range of home practice adherence were sought in semi-structured interviews. The interviews were analysed using an inductive thematic approach. Results: Most participants found time to practise Tai Chi at home and practised for 17 hours on average. Amongst the barriers to adherence were participants’ competing commitments and a booklet not sufficiently conveying the Tai Chi movements. Hence, a video or DVD was requested by participants. Facilitators of their adherence to the home-based component of the intervention were their enjoyment of the practice and the development of a habit, which was supported by their commitment to the study and their willingness to benefit from Tai Chi. Conclusion: Enjoyment and perceived benefits had a great impact on participants living with dementia and their carers’ adherence to home-based Tai Chi practice. However, difficulties to perceive the Tai Chi movements through images might be hindering sustained participation and hence alternative aids such as videos and DVDs should be explored to facilitate adherence

Soil Moisture Sensing via Swept Frequency Based Microwave Sensors

There is a need for low-cost, high-accuracy measurement of water content in various materials. This study assesses the performance of a new microwave swept frequency domain instrument (SFI) that has promise to provide a low-cost, high-accuracy alternative to the traditional and more expensive time domain reflectometry (TDR). The technique obtains permittivity measurements of soils in the frequency domain utilizing a through transmission configuration, transmissometry, which provides a frequency domain transmissometry measurement (FDT). The measurement is comparable to time domain transmissometry (TDT) with the added advantage of also being able to separately quantify the real and imaginary portions of the complex permittivity so that the measured bulk permittivity is more accurate that the measurement TDR provides where the apparent permittivity is impacted by the signal loss, which can be significant in heavier soils. The experimental SFI was compared with a high-end 12 GHz TDR/TDT system across a range of soils at varying soil water contents and densities. As propagation delay is the fundamental measurement of interest to the well-established TDR or TDT technique; the first set of tests utilized precision propagation delay lines to test the accuracy of the SFI instrument’s ability to resolve propagation delays across the expected range of delays that a soil probe would present when subjected to the expected range of soil types and soil moisture typical to an agronomic cropping system. The results of the precision-delay line testing suggests the instrument is capable of predicting propagation delays with a RMSE of +/−105 ps across the range of delays ranging from 0 to 12,000 ps with a coefficient of determination of r2 = 0.998. The second phase of tests noted the rich history of TDR for prediction of soil moisture and leveraged this history by utilizing TDT measured with a high-end Hewlett Packard TDR/TDT instrument to directly benchmark the SFI instrument over a range of soil types, at varying levels of moisture. This testing protocol was developed to provide the best possible comparison between SFI to TDT than would otherwise be possible by using soil moisture as the bench mark, due to variations in soil density between soil water content levels which are known to impact the calibration between TDR’s estimate of soil water content from the measured propagation delay which is converted to an apparent permittivity measurement. This experimental decision, to compare propagation delay of TDT to FDT, effectively removes the errors due to variations in packing density from the evaluation and provides a direct comparison between the SFI instrument and the time domain technique of TDT. The tests utilized three soils (a sand, an Acuff loam and an Olton clay-loam) that were packed to varying bulk densities and prepared to provide a range of water contents and electrical conductivities by which to compare the performance of the SFI technology to TDT measurements of propagation delay. For each sample tested, the SFI instrument and the TDT both performed the measurements on the exact same probe, thereby both instruments were measuring the exact same soil/soil-probe response to ensure the most accurate means to compare the SFI instrument to a high-end TDT instrument. Test results provided an estimated instrumental accuracy for the SFI of +/−0.98% of full scale, RMSE basis, for the precision delay lines and +/−1.32% when the SFI was evaluated on loam and clay loam soils, in comparison to TDT as the bench-mark. Results from both experiments provide evidence that the low-cost SFI approach is a viable alternative to conventional TDR/TDT for high accuracy applications

Regional differences in the spatial and temporal heterogeneity of oceanographic habitat used by Steller sea lions

Over the past three decades, the decline and altered spatial distribution of the western stock of Steller sea lions (Eumetopias jubatus) in Alaska have been attributed to changes in the distribution or abundance of their prey due to the cumulative effects of fisheries and environmental perturbations. During this period, dietary prey occurrence and diet diversity were related to population decline within metapopulation regions of the western stock of Steller sea lions, suggesting that environmental conditions may be variable among regions. The objective of this study, therefore, was to examine regional differences in the spatial and temporal heterogeneity of oceanographic habitat used by Steller sea lions within the context of recent measures of diet diversity and population trajectories. Habitat use was assessed by deploying satellite-depth recorders and satellite relay data loggers on juvenile Steller sea lions (n = 45) over a five-year period (2000–2004) within four regions of the western stock, including the western, central, and eastern Aleutian Islands, and central Gulf of Alaska. Areas used by sea lions during summer months (June, July, and August) were demarcated using satellite telemetry data and characterized by environmental variables (sea surface temperature [SST] and chlorophyll a [chl a]), which possibly serve as proxies for environmental processes or prey. Spatial patterns of SST diversity and Steller sea lion population trends among regions were fairly consistent with trends reported for diet studies, possibly indicating a link between environmental diversity, prey diversity, and distribution or abundance of Steller sea lions. Overall, maximum spatial heterogeneity coupled with minimal temporal variability of SST appeared to be beneficial for Steller sea lions. In contrast, these patterns were not consistent for chl a, and there appeared to be an ecological threshold. Understanding how Steller sea lions respond to measures of environmental heterogeneity will ultimately be useful for implementing ecosystem management approaches and developing additional conservation strategies