A Genome-wide Screen Reveals that Reducing Mitochondrial DNA Polymerase Can Promote Elimination of Deleterious Mitochondrial Mutations.

A mutant mitochondrial genome arising amid the pool of mitochondrial genomes within a cell must compete with existing genomes to survive to the next generation. Even weak selective forces can bias transmission of one genome over another to affect the inheritance of mitochondrial diseases and guide the evolution of mitochondrial DNA (mtDNA). Studies in several systems suggested that purifying selection in the female germline reduces transmission of detrimental mitochondrial mutations [1-7]. In contrast, some selfish genomes can take over despite a cost to host fitness [8-13]. Within individuals, the outcome of competition is therefore influenced by multiple selective forces. The nuclear genome, which encodes most proteins within mitochondria, and all external regulators of mitochondrial biogenesis and dynamics can influence the competition between mitochondrial genomes [14-18], yet little is known about how this works. Previously, we established a Drosophila line transmitting two mitochondrial genomes in a stable ratio enforced by purifying selection benefiting one genome and a selfish advantage favoring the other [8]. Here, to find nuclear genes that impact mtDNA competition, we screened heterozygous deletions tiling ∼70% of the euchromatic regions and examined their influence on this ratio. This genome-wide screen detected many nuclear modifiers of this ratio and identified one as the catalytic subunit of mtDNA polymerase gene (POLG), tam. A reduced dose of tam drove elimination of defective mitochondrial genomes. This study suggests that our approach will uncover targets for interventions that would block propagation of pathogenic mitochondrial mutations

The effects of monetary policy on real estate investment in China: a regional perspective

Monetary policy on real estate investment in China has had varying impacts across the country due to regional differences. A supply-determined model is used to measure the policy effects on property investment volume based on a set of regional data from 2003 to 2010. This research yields several important findings contributing to an understanding of uneven policy effects on the unbalanced regional markets. Firstly, it is revealed that the eastern coastal provinces in China have a higher dependence on bank loans for housing investment than that of the other inland provinces. Secondly, this research has disentangled the specific transmission channels of monetary policy in the property market. Bank loan supply, instead of interest rates, would be a potentially effective policy tool for the government in making property market adjustment. Thirdly, the eastern coastal provinces are more sensitive in their responses to the changes of monetary stances than the other non-coastal central and western provinces. Therefore, the government must take note of the significant heterogeneity arising from the regional differences in estimating the policy impacts, although monetary policy is uniformly employed in the nation most of the time

Group descent algorithms for nonconvex penalized linear and logistic regression models with grouped predictors

Penalized regression is an attractive framework for variable selection problems. Often, variables possess a grouping structure, and the relevant selection problem is that of selecting groups, not individual variables. The group lasso has been proposed as a way of extending the ideas of the lasso to the problem of group selection. Nonconvex penalties such as SCAD and MCP have been proposed and shown to have several advantages over the lasso; these penalties may also be extended to the group selection problem, giving rise to group SCAD and group MCP methods. Here, we describe algorithms for fitting these models stably and efficiently. In addition, we present simulation results and real data examples comparing and contrasting the statistical properties of these methods

OLAM: A Wearable, Non-Contact Sensor for Continuous Heart-Rate and Activity Monitoring

A wearable, multi-modal sensor is presented that can non-invasively monitor a patient’s activity level and heart function concurrently for more than a week. The 4in² sensor incorporates both a non-contact heartrate sensor and a 5-axis inertial measurement unit (IMU), allowing simultaneous heart, respiration, and movement monitoring without requiring physical contact with the skin [1]. Hence, this Oregon State University Life and Activity Monitor (OLAM) provides the unique opportunity to combine motion data with heart-rate information, enabling assessment of actual physical activity beyond conventional movement sensors. OLAM also provides a unique platform for non-contact sensing, enabling the filtering of movement artifacts generated by the non-contact capacitive interface, using the IMU data as a movement noise channel. Intended to be used in clinical trials for weeks at a time with no physician intervention, the OLAM allows continuous noninvasive monitoring of patients, providing the opportunity for long-term observation into a patient’s physical activity and subtle longitudinal changes

Impact of functional studies on exome sequence variant interpretation in early-onset cardiac conduction system diseases

Aims The genetic cause of cardiac conduction system disease (CCSD) has not been fully elucidated. Whole-exome sequencing (WES) can detect various genetic variants; however, the identification of pathogenic variants remains a challenge. We aimed to identify pathogenic or likely pathogenic variants in CCSD patients by using WES and 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines as well as evaluating the usefulness of functional studies for determining them. Methods and Results We performed WES of 23 probands diagnosed with early-onset (<65 years) CCSD and analyzed 117 genes linked to arrhythmogenic diseases or cardiomyopathies. We focused on rare variants (minor allele frequency < 0.1%) that were absent from population databases. Five probands had protein truncating variants in EMD and LMNA which were classified as “pathogenic” by 2015 ACMG standards and guidelines. To evaluate the functional changes brought about by these variants, we generated a knock-out zebrafish with CRISPR-mediated insertions or deletions of the EMD or LMNA homologs in zebrafish. The mean heart rate and conduction velocities in the CRISPR/Cas9-injected embryos and F2 generation embryos with homozygous deletions were significantly decreased. Twenty-one variants of uncertain significance were identified in 11 probands. Cellular electrophysiological study and in vivo zebrafish cardiac assay showed that 2 variants in KCNH2 and SCN5A, 4 variants in SCN10A, and 1 variant in MYH6 damaged each gene, which resulted in the change of the clinical significance of them from “Uncertain significance” to “Likely pathogenic” in 6 probands. Conclusions Of 23 CCSD probands, we successfully identified pathogenic or likely pathogenic variants in 11 probands (48%). Functional analyses of a cellular electrophysiological study and in vivo zebrafish cardiac assay might be useful for determining the pathogenicity of rare variants in patients with CCSD. SCN10A may be one of the major genes responsible for CCSD. Translational Perspective Whole-exome sequencing (WES) may be helpful in determining the causes of cardiac conduction system disease (CCSD), however, the identification of pathogenic variants remains a challenge. We performed WES of 23 probands diagnosed with early-onset CCSD, and identified 12 pathogenic or likely pathogenic variants in 11 of these probands (48%) according to the 2015 ACMG standards and guidelines. In this context, functional analyses of a cellular electrophysiological study and in vivo zebrafish cardiac assay might be useful for determining the pathogenicity of rare variants, and SCN10A may be one of the major development factors in CCSD

AMiBA Wideband Analog Correlator

A wideband analog correlator has been constructed for the Yuan-Tseh Lee Array for Microwave Background Anisotropy. Lag correlators using analog multipliers provide large bandwidth and moderate frequency resolution. Broadband IF distribution, backend signal processing and control are described. Operating conditions for optimum sensitivity and linearity are discussed. From observations, a large effective bandwidth of around 10 GHz has been shown to provide sufficient sensitivity for detecting cosmic microwave background variations.Comment: 28 pages, 23 figures, ApJ in press

Mass and Hot Baryons in Massive Galaxy Clusters from Subaru Weak Lensing and AMiBA SZE Observations

We present a multiwavelength analysis of a sample of four hot (T_X>8keV) X-ray galaxy clusters (A1689, A2261, A2142, and A2390) using joint AMiBA Sunyaev-Zel'dovich effect (SZE) and Subaru weak lensing observations, combined with published X-ray temperatures, to examine the distribution of mass and the intracluster medium (ICM) in massive cluster environments. Our observations show that A2261 is very similar to A1689 in terms of lensing properties. Many tangential arcs are visible around A2261, with an effective Einstein radius \sim 40 arcsec (at z \sim 1.5), which when combined with our weak lensing measurements implies a mass profile well fitted by an NFW model with a high concentration c_{vir} \sim 10, similar to A1689 and to other massive clusters. The cluster A2142 shows complex mass substructure, and displays a shallower profile (c_{vir} \sim 5), consistent with detailed X-ray observations which imply recent interaction. The AMiBA map of A2142 exhibits an SZE feature associated with mass substructure lying ahead of the sharp north-west edge of the X-ray core suggesting a pressure increase in the ICM. For A2390 we obtain highly elliptical mass and ICM distributions at all radii, consistent with other X-ray and strong lensing work. Our cluster gas fraction measurements, free from the hydrostatic equilibrium assumption, are overall in good agreement with published X-ray and SZE observations, with the sample-averaged gas fraction of = 0.133 \pm 0.027, for our sample = (1.2 \pm 0.1) \times 10^{15} M_{sun} h^{-1}. When compared to the cosmic baryon fraction f_b = \Omega_b/\Omega_m constrained by the WMAP 5-year data, this indicates /f_b = 0.78 \pm 0.16, i.e., (22 \pm 16)% of the baryons are missing from the hot phase of clusters.Comment: accepted for publication in ApJ; high resolution figures available at http://www.asiaa.sinica.edu.tw/~keiichi/upfiles/AMiBA7/ms_highreso.pd

MicroRNAs in pulmonary arterial remodeling

Pulmonary arterial remodeling is a presently irreversible pathologic hallmark of pulmonary arterial hypertension (PAH). This complex disease involves pathogenic dysregulation of all cell types within the small pulmonary arteries contributing to vascular remodeling leading to intimal lesions, resulting in elevated pulmonary vascular resistance and right heart dysfunction. Mutations within the bone morphogenetic protein receptor 2 gene, leading to dysregulated proliferation of pulmonary artery smooth muscle cells, have been identified as being responsible for heritable PAH. Indeed, the disease is characterized by excessive cellular proliferation and resistance to apoptosis of smooth muscle and endothelial cells. Significant gene dysregulation at the transcriptional and signaling level has been identified. MicroRNAs are small non-coding RNA molecules that negatively regulate gene expression and have the ability to target numerous genes, therefore potentially controlling a host of gene regulatory and signaling pathways. The major role of miRNAs in pulmonary arterial remodeling is still relatively unknown although research data is emerging apace. Modulation of miRNAs represents a possible therapeutic target for altering the remodeling phenotype in the pulmonary vasculature. This review will focus on the role of miRNAs in regulating smooth muscle and endothelial cell phenotypes and their influence on pulmonary remodeling in the setting of PAH