SLOPE - Adaptive variable selection via convex optimization

We introduce a new estimator for the vector of coefficients $\beta$ in the linear model $y=X\beta+z$, where $X$ has dimensions $n\times p$ with $p$ possibly larger than $n$. SLOPE, short for Sorted L-One Penalized Estimation, is the solution to $$\min_{b\in\mathbb{R}^p}\frac{1}{2}\Vert y-Xb\Vert _{\ell_2}^2+\lambda_1\vert b\vert _{(1)}+\lambda_2\vert b\vert_{(2)}+\cdots+\lambda_p\vert b\vert_{(p)},$$ where $\lambda_1\ge\lambda_2\ge\cdots\ge\lambda_p\ge0$ and $\vert b\vert_{(1)}\ge\vert b\vert_{(2)}\ge\cdots\ge\vert b\vert_{(p)}$ are the decreasing absolute values of the entries of $b$. This is a convex program and we demonstrate a solution algorithm whose computational complexity is roughly comparable to that of classical $\ell_1$ procedures such as the Lasso. Here, the regularizer is a sorted $\ell_1$ norm, which penalizes the regression coefficients according to their rank: the higher the rank - that is, stronger the signal - the larger the penalty. This is similar to the Benjamini and Hochberg [J. Roy. Statist. Soc. Ser. B 57 (1995) 289-300] procedure (BH) which compares more significant $p$-values with more stringent thresholds. One notable choice of the sequence $\{\lambda_i\}$ is given by the BH critical values $\lambda_{\mathrm {BH}}(i)=z(1-i\cdot q/2p)$, where $q\in(0,1)$ and $z(\alpha)$ is the quantile of a standard normal distribution. SLOPE aims to provide finite sample guarantees on the selected model; of special interest is the false discovery rate (FDR), defined as the expected proportion of irrelevant regressors among all selected predictors. Under orthogonal designs, SLOPE with $\lambda_{\mathrm{BH}}$ provably controls FDR at level $q$. Moreover, it also appears to have appreciable inferential properties under more general designs $X$ while having substantial power, as demonstrated in a series of experiments running on both simulated and real data.Comment: Published at http://dx.doi.org/10.1214/15-AOAS842 in the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Population Biology and Interactions of Arbuscular Mycorrhizal Fungi and Their Benefits in Strawberry Cultivation

The diversity of arbuscular mycorrhizal fungi (AMF) and relative abundance among species may affect their ecological impact. Species-specific primers for qPCR quantification of Funneliformis geosporus and F.mosseae DNA were developed to quantify their relative abundance for use in studying mixed inocula in roots of strawberry under different conditions of water stress. Co-occupation of the same root by both species was shown to commonly occur but the relative abundance of the two species varied with water stress. Greater root colonisation was observed microscopically under water stress but this increased colonisation was often accompanied with decreased amounts of fungal DNA in the root. Funneliformis mosseae tended to become more abundant under water stress relative to F. geosporus. There was significant correlation in the fungal colonisation measurements from the microscopic and qPCR methods under some conditions, but the nature of this relationship varied greatly with AMF inoculum and abiotic conditions. Water stress experiments, undertaken with strawberry (Fragaria x ananassa) show a reduction of plant development when subjected to regulated deficit irrigation (RDI) conditions. The effect on growth of AMF colonisation and relative abundance of two co-occurring species of AMF, F. geosporus and F. mosseae, were determined in cultivated strawberry under conditions of water stress. Three AMF inoculation treatments (a single treatment either of F. mosseae BEG25, F. geosporus BEG11 or a 50:50 mixed inoculation treatment of both species) were compared to un-inoculated plants. This study demonstrated that in strawberry plants, under these experimental conditions, single species inoculation treatments gave similar benefits to the host as the mixed inoculation treatment regardless of irrigation regime, suggesting colonisation was of greater importance than mycorrhizal fungal species. The addition of AMF inocula to plants, subjected to reduced irrigation of up to 40%, restored plant growth to the same or higher values as the non-mycorrhizal, fully-watered plants. The water use efficiency of plants was greater under the RDI regime and in AMF-inoculated plants, but there were no significant differences between plants inoculated with the single or combined inoculum. The occurrence of multiple variant sequences within the rRNA genes of the AMF is now widely accepted; however the mechanisms for this are not currently clear. This work investigated the effect of different culture conditions (in vitro and in planta culture) on sequence diversity and relative abundance of a culture of Rhizophagus clarus. Next generation sequencing, using the Illumina platform, generated three major sequence variants that were the most common sequence variants in all conditions. All other sequences grouped phylogenetically about these three major sequence types along with an outgroup of less common sequence types. This study demonstrated that changes in the frequency of dominant sequence variants had occurred when AMF are maintained for two years under different culture conditions

Patterns and rates of viral evolution in HIV-1 subtype B infected females and males.

Biological sex differences affect the course of HIV infection, with untreated women having lower viral loads compared to their male counterparts but, for a given viral load, women have a higher rate of progression to AIDS. However, the vast majority of data on viral evolution, a process that is clearly impacted by host immunity and could be impacted by sex differences, has been derived from men. We conducted an intensive analysis of HIV-1 gag and env-gp120 evolution taken over the first 6-11 years of infection from 8 Women's Interagency HIV Study (WIHS) participants who had not received combination antiretroviral therapy (ART). This was compared to similar data previously collected from men, with both groups infected with HIV-1 subtype B. Early virus populations in men and women were generally homogenous with no differences in diversity between sexes. No differences in ensuing nucleotide substitution rates were found between the female and male cohorts studied herein. As previously reported for men, time to peak diversity in env-gp120 in women was positively associated with time to CD4+ cell count below 200 (P = 0.017), and the number of predicted N-linked glycosylation sites generally increased over time, followed by a plateau or decline, with the majority of changes localized to the V1-V2 region. These findings strongly suggest that the sex differences in HIV-1 disease progression attributed to immune system composition and sensitivities are not revealed by, nor do they impact, global patterns of viral evolution, the latter of which proceeds similarly in women and men

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

Dialects, Cultural Identity, and Economic Exchange

We investigate whether time-persistent cultural borders impede economic exchange across regions of the same country. To measure cultural differences we evaluate, for the first time in economics, linguistic micro-data about phonological and grammatical features of German dialects. These data are taken from a unique linguistic survey conducted between 1879 and 1888 in 45,000 schools. Matching this information to 439 current German regions, we construct a dialect similarity matrix. Using a gravity analysis, we show that current cross-regional migration is positively affected by historical dialect similarity. This suggests that cultural identities formed in the past still influence economic exchange today.gravity, internal migration, culture, language, dialects, Germany

Phosphorylation of protein kinase A (PKA) regulatory subunit RIα by protein kinase G (PKG) primes PKA for catalytic activity in cells.

cAMP-dependent protein kinase (PKAc) is a pivotal signaling protein in eukaryotic cells. PKAc has two well-characterized regulatory subunit proteins, RI and RII (each having α and β isoforms), which keep the PKAc catalytic subunit in a catalytically inactive state until activation by cAMP. Previous reports showed that the RIα regulatory subunit is phosphorylated by cGMP-dependent protein kinase (PKG) in vitro, whereupon phosphorylated RIα no longer inhibits PKAc at normal (1:1) stoichiometric ratios. However, the significance of this phosphorylation as a mechanism for activating type I PKA holoenzymes has not been fully explored, especially in cellular systems. In this study, we further examined the potential of RIα phosphorylation to regulate physiologically relevant "desensitization" of PKAc activity. First, the serine 101 site of RIα was validated as a target of PKGIα phosphorylation both in vitro and in cells. Analysis of a phosphomimetic substitution in RIα (S101E) showed that modification of this site increases PKAc activity in vitro and in cells, even without cAMP stimulation. Numerous techniques were used to show that although Ser101 variants of RIα can bind PKAc, the modified linker region of the S101E mutant has a significantly reduced affinity for the PKAc active site. These findings suggest that RIα phosphorylation may be a novel mechanism to circumvent the requirement of cAMP stimulus to activate type I PKA in cells. We have thus proposed a model to explain how PKG phosphorylation of RIα creates a "sensitized intermediate" state that is in effect primed to trigger PKAc activity

Many-to-Many Graph Matching: a Continuous Relaxation Approach

Graphs provide an efficient tool for object representation in various computer vision applications. Once graph-based representations are constructed, an important question is how to compare graphs. This problem is often formulated as a graph matching problem where one seeks a mapping between vertices of two graphs which optimally aligns their structure. In the classical formulation of graph matching, only one-to-one correspondences between vertices are considered. However, in many applications, graphs cannot be matched perfectly and it is more interesting to consider many-to-many correspondences where clusters of vertices in one graph are matched to clusters of vertices in the other graph. In this paper, we formulate the many-to-many graph matching problem as a discrete optimization problem and propose an approximate algorithm based on a continuous relaxation of the combinatorial problem. We compare our method with other existing methods on several benchmark computer vision datasets.Comment: 1

Dialects, Cultural Identity, and Economic Exchange

We investigate whether time-persistent cultural borders impede economic exchange across regions of the same country. To measure cultural differences we evaluate, for the first time in economics, linguistic micro-data about phonological and grammatical features of German dialects. These data are taken from a unique linguistic survey conducted between 1879 and 1888 in 45,000 schools. Matching this information to 439 current German regions, we construct a dialect similarity matrix. Using a gravity analysis, we show that current cross-regional migration is positively affected by historical dialect similarity. This suggests that cultural identities formed in the past still influence economic exchange today.dialects, language, culture, internal migration, gravity, Germany