Congruence of additive and non-additive effects on gene expression estimated from pedigree and SNP data

There is increasing evidence that heritable variation in gene expression underlies genetic variation in susceptibility to disease. Therefore, a comprehensive understanding of the similarity between relatives for transcript variation is warranted-in particular, dissection of phenotypic variation into additive and non-additive genetic factors and shared environmental effects. We conducted a gene expression study in blood samples of 862 individuals from 312 nuclear families containing MZ or DZ twin pairs using both pedigree and genotype information. From a pedigree analysis we show that the vast majority of genetic variation across 17,994 probes is additive, although non-additive genetic variation is identified for 960 transcripts. For 180 of the 960 transcripts with non-additive genetic variation, we identify expression quantitative trait loci (eQTL) with dominance effects in a sample of 339 unrelated individuals and replicate 31% of these associations in an independent sample of 139 unrelated individuals. Over-dominance was detected and replicated for a trans association between rs12313805 and ETV6, located 4MB apart on chromosome 12. Surprisingly, only 17 probes exhibit significant levels of common environmental effects, suggesting that environmental and lifestyle factors common to a family do not affect expression variation for most transcripts, at least those measured in blood. Consistent with the genetic architecture of common diseases, gene expression is predominantly additive, but a minority of transcripts display non-additive effects

Nonlinear Localization in Metamaterials

Metamaterials, i.e., artificially structured ("synthetic") media comprising weakly coupled discrete elements, exhibit extraordinary properties and they hold a great promise for novel applications including super-resolution imaging, cloaking, hyperlensing, and optical transformation. Nonlinearity adds a new degree of freedom for metamaterial design that allows for tuneability and multistability, properties that may offer altogether new functionalities and electromagnetic characteristics. The combination of discreteness and nonlinearity may lead to intrinsic localization of the type of discrete breather in metallic, SQUID-based, and ${\cal PT}-$symmetric metamaterials. We review recent results demonstrating the generic appearance of breather excitations in these systems resulting from power-balance between intrinsic losses and input power, either by proper initialization or by purely dynamical procedures. Breather properties peculiar to each particular system are identified and discussed. Recent progress in the fabrication of low-loss, active and superconducting metamaterials, makes the experimental observation of breathers in principle possible with the proposed dynamical procedures.Comment: 19 pages, 14 figures, Invited (Review) Chapte

The Effectiveness of Lower-Limb Wearable Technology for Improving Activity and Participation in Adult Stroke Survivors: A Systematic Review

Background: With advances in technology, the adoption of wearable devices has become a viable adjunct in poststroke rehabilitation. Regaining ambulation is a top priority for an increasing number of stroke survivors. However, despite an increase in research exploring these devices for lower limb rehabilitation, little is known of the effectiveness. Objective: This review aims to assess the effectiveness of lower limb wearable technology for improving activity and participation in adult stroke survivors. Methods: Randomized controlled trials (RCTs) of lower limb wearable technology for poststroke rehabilitation were included. Primary outcome measures were validated measures of activity and participation as defined by the International Classification of Functioning, Disability and Health. Databases searched were MEDLINE, Web of Science (Core collection), CINAHL, and the Cochrane Library. The Cochrane Risk of Bias Tool was used to assess the methodological quality of the RCTs. Results: In the review, we included 11 RCTs with collectively 550 participants at baseline and 474 participants at final follow-up including control groups and participants post stroke. Participants' stroke type and severity varied. Only one study found significant between-group differences for systems functioning and activity. Across the included RCTs, the lowest number of participants was 12 and the highest was 151 with a mean of 49 participants. The lowest number of participants to drop out of an RCT was zero in two of the studies and 19 in one study. Significant between-group differences were found across three of the 11 included trials. Out of the activity and participation measures alone, P values ranged from P=.87 to P≤.001. Conclusions: This review has highlighted a number of reasons for insignificant findings in this area including low sample sizes, appropriateness of the RCT methodology for complex interventions, a lack of appropriate analysis of outcome data, and participant stroke severity

The impact of point mutations in the human androgen receptor : classification of mutations on the basis of transcriptional activity

Peer reviewedPublisher PD

Finding needles in haystacks: linking scientific names, reference specimens and molecular data for Fungi

DNA phylogenetic comparisons have shown that morphology-based species recognition often underestimates fungal diversity. Therefore, the need for accurate DNA sequence data, tied to both correct taxonomic names and clearly annotated specimen data, has never been greater. Furthermore, the growing number of molecular ecology and microbiome projects using high-throughput sequencing require fast and effective methods for en masse species assignments. In this article, we focus on selecting and re-annotating a set of marker reference sequences that represent each currently accepted order of Fungi. The particular focus is on sequences from the internal transcribed spacer region in the nuclear ribosomal cistron, derived from type specimens and/or ex-type cultures. Re-annotated and verified sequences were deposited in a curated public database at the National Center for Biotechnology Information (NCBI), namely the RefSeq Targeted Loci (RTL) database, and will be visible during routine sequence similarity searches with NR_prefixed accession numbers. A set of standards and protocols is proposed to improve the data quality of new sequences, and we suggest how type and other reference sequences can be used to improve identification of Fungi

Trisomy of human chromosome 21 enhances amyloid-β deposition independently of an extra copy of APP

Down syndrome, caused by trisomy of chromosome 21, is the single most common risk factor for early-onset Alzheimer's disease. Worldwide approximately 6 million people have Down syndrome, and all these individuals will develop the hallmark amyloid plaques and neurofibrillary tangles of Alzheimer's disease by the age of 40 and the vast majority will go on to develop dementia. Triplication of APP, a gene on chromosome 21, is sufficient to cause early-onset Alzheimer's disease in the absence of Down syndrome. However, whether triplication of other chromosome 21 genes influences disease pathogenesis in the context of Down syndrome is unclear. Here we show, in a mouse model, that triplication of chromosome 21 genes other than APP increases amyloid-β aggregation, deposition of amyloid-β plaques and worsens associated cognitive deficits. This indicates that triplication of chromosome 21 genes other than APP is likely to have an important role to play in Alzheimer's disease pathogenesis in individuals who have Down syndrome. We go on to show that the effect of trisomy of chromosome 21 on amyloid-β aggregation correlates with an unexpected shift in soluble amyloid-β 40/42 ratio. This alteration in amyloid-β isoform ratio occurs independently of a change in the carboxypeptidase activity of the γ-secretase complex, which cleaves the peptide from APP, or the rate of extracellular clearance of amyloid-β. These new mechanistic insights into the role of triplication of genes on chromosome 21, other than APP, in the development of Alzheimer's disease in individuals who have Down syndrome may have implications for the treatment of this common cause of neurodegeneration

A cavity expansion–based solution for interpretation of CPTu data in soils under partially drained conditions

A cavity expansion–based solution is proposed in this paper for the interpretation of CPTu data under a partially drained condition. Variations of the normalized cone tip resistance, cone factor, and undrained‐drained resistance ratio are examined with different initial specific volume and overconsolidation ratio, based on the exact solutions of both undrained and drained cavity expansion in CASM, which is a unified state parameter model for clay and sand. A drainage index is proposed to represent the partially drained condition, and the critical state after expansion and stress paths of cavity expansion are therefore predicted by estimating a virtual plastic region and assuming a drainage‐index–based mapping technique. The stress paths and distributions of stresses and specific volume are investigated for different values of drainage index, which are also related to the penetration velocity with comparisons of experimental data and numerical results. The subsequent consolidation after penetration is thus predicted with the assumption of constant deviatoric stress during dissipation of the excess pore pressure. Both spherical and cylindrical consolidations are compared for dissipation around the cone tip and the probe shaft, respectively. The effects of overconsolidation ratio on the stress paths and the distributions of excess pore pressure and specific volume are then thoroughly investigated. The proposed solution and the findings would contribute to the interpretation of CPTu tests under a random drained condition, as well as the analysis of pile installation and the subsequent consolidation

Spatially oriented plasmonic ‘nanograter’ structures

One of the key motivations in producing 3D structures has always been the realization of metamaterials with effective constituent properties that can be tuned in all propagation directions at various frequencies. Here, we report the investigation of spatially oriented “Nanograter” structures with orientation-dependent responses over a wide spectrum by focused-ion-beam based patterning and folding of thin film nanostructures. Au nano units of different shapes, standing along specifically designated orientations, were fabricated. Experimental measurements and simulation results show that such structures offer an additional degree of freedom for adjusting optical properties with the angle of inclination, in additional to the size of the structures. The response frequency can be varied in a wide range (8 μm–14 μm) by the spatial orientation (0°–180°) of the structures, transforming the response from magnetic into electric coupling. This may open up prospects for the fabrication of 3D nanostructures as optical interconnects, focusing elements and logic elements, moving toward the realization of 3D optical circuits

Elevated antibody to D-alanyl lipoteichoic acid indicates caries experience associated with fluoride and gingival health

BACKGROUND: Acidogenic, acid-tolerant bacteria induce dental caries and require D-alanyl glycerol lipoteichoic acid (D-alanyl LTA) on their cell surface. Because fluoride inhibits acid-mediated enamel demineralization, an elevated antibody response to D-alanyl LTA may indicate subjects with more acidogenic bacteria and, therefore, an association of DMFT with fluoride exposure and gingival health not apparent in low responders. METHODS: Cluster analysis was used to identify low antibody content. Within low and high responders (control and test subjects), the number of teeth that were decayed missing and filled (DMFT), or decayed only (DT) were regressed against fluoride exposure in the water supply and from dentrifice use. The latter was determined from gingival health: prevalences of plaque (PL) and bleeding on probing (BOP), and mean pocket depth (PD). Age was measured as a possible confounding cofactor. RESULTS: In 35 high responders, DMFT associated with length of exposure to fluoridated water (F score), PL and BOP (R(2) = 0.51, p < 0.001), whereas in 67 low D-ala-IgG responders, DMFT associated with PL, age, and PD (R(2) = 0.26, p < 0.001). BOP correlated strongly with number of 7 7 decayed teeth (DT) in 54 high responders (R(2) = 0.57, p < 0.001), but poorly in 97 low responders (R(2) = 0.12, p < 0.001). The strength of the PD association with DMFT, or of BOP with DT, in high responders significantly differed from that in low responders (p < 0.05). CONCLUSION: Caries associates with gingival health and fluoridated water exposure in high D-alanyl LTA antibody responders