Test-retest reliability of graph theory measures of structural brain connectivity

The human connectome has recently become a popular research topic in neuroscience, and many new algorithms have been applied to analyze brain networks. In particular, network topology measures from graph theory have been adapted to analyze network efficiency and 'small-world' properties. While there has been a surge in the number of papers examining connectivity through graph theory, questions remain about its test-retest reliability (TRT). In particular, the reproducibility of structural connectivity measures has not been assessed. We examined the TRT of global connectivity measures generated from graph theory analyses of 17 young adults who underwent two high-angular resolution diffusion (HARDI) scans approximately 3 months apart. Of the measures assessed, modularity had the highest TRT, and it was stable across a range of sparsities (a thresholding parameter used to define which network edges are retained). These reliability measures underline the need to develop network descriptors that are robust to acquisition parameters.

Serum cholesterol and variant in cholesterol-related gene CETP predict white matter microstructure

Several common genetic variants influence cholesterol levels, which play a key role in overall health. Myelin synthesis and maintenance are highly sensitive to cholesterol concentrations, and abnormal cholesterol levels increase the risk for various brain diseases, including Alzheimer's disease. We report significant associations between higher serum cholesterol (CHOL) and high-density lipoprotein levels and higher fractional anisotropy in 403 young adults (23.8 ± 2.4years) scanned with diffusion imaging and anatomic magnetic resonance imaging at 4Tesla. By fitting a multi-locus genetic model within white matter areas associated with CHOL, we found that a set of 18 cholesterol-related, single-nucleotide polymorphisms implicated in Alzheimer's disease risk predicted fractional anisotropy. We focused on the single-nucleotide polymorphism with the largest individual effects, CETP (rs5882), and found that increased G-allele dosage was associated with higher fractional anisotropy and lower radial and mean diffusivities in voxel-wise analyses of the whole brain. A follow-up analysis detected white matter associations with rs5882 in the opposite direction in 78 older individuals (74.3 ± 7.3years). Cholesterol levels may influence white matter integrity, and cholesterol-related genes may exert age-dependent effects on the brain.

Identifying candidate gene effects by restricting search space in a multivariate genetic analysis of white matter microstructure

Several genetic variants are thought to influence white matter (WM) integrity, measured with diffusion tensor imaging (DTI). Voxel based methods can test genetic associations, but heavy multiple comparisons corrections are required to adjust for searching the whole brain and for all genetic variants analyzed. Thus, genetic associations are hard to detect even in large studies. Using a recently developed multi-SNP analysis, we examined the joint predictive power of a group of 18 cholesterol-related single nucleotide polymorphisms (SNPs) on WM integrity, measured by fractional anisotropy. To boost power, we limited the analysis to brain voxels that showed significant associations with total serum cholesterol levels. From this space, we identified two genes with effects that replicated in individual voxel-wise analyses of the whole brain. Multivariate analyses of genetic variants on a reduced anatomical search space may help to identify SNPs with strongest effects on the brain from a broad panel of genes.

Strain- and host species-specific inflammasome activation, IL-1β release, and cell death in macrophages infected with uropathogenic Escherichia coli

Uropathogenic Escherichia coli (UPEC) is the main etiological agent of urinary tract infections (UTIs). Little is known about interactions between UPEC and the inflammasome, a key innate immune pathway. Here we show that UPEC strains CFT073 and UTI89 trigger inflammasome activation and lytic cell death in human macrophages. Several other UPEC strains, including two multidrug-resistant ST131 isolates, did not kill macrophages. In mouse macrophages, UTI89 triggered cell death only at a high multiplicity of infection, and CFT073-mediated inflammasome responses were completely NLRP3-dependent. Surprisingly, CFT073- and UTI89-mediated responses only partially depended on NLRP3 in human macrophages. In these cells, NLRP3 was required for interleukin-1β (IL-1β) maturation, but contributed only marginally to cell death. Similarly, caspase-1 inhibition did not block cell death in human macrophages. In keeping with such differences, the pore-forming toxin α-hemolysin mediated a substantial proportion of CFT073-triggered IL-1β secretion in mouse but not human macrophages. There was also a more substantial α-hemolysin-independent cell death response in human vs. mouse macrophages. Thus, in mouse macrophages, CFT073-triggered inflammasome responses are completely NLRP3-dependent, and largely α-hemolysin-dependent. In contrast, UPEC activates an NLRP3-independent cell death pathway and an α-hemolysin-independent IL-1β secretion pathway in human macrophages. This has important implications for understanding UTI in humans.

Provisioning a 3.3 MW PhotoVoltaic generation system onto a distribution authority’s 11 kV rural feeder

This paper describes part of an engineering study that was undertaken to demonstrate that a multi-megawatt Photovoltaic (PV) generation system could be connected to a rural 11 kV feeder without creating power quality issues for other consumers. The paper concentrates solely on the voltage regulation aspect of the study as this was the most innovative part of the study. The study was carried out using the time-domain software package, PSCAD/EMTDC. The software model included real time data input of actual measured load and scaled PV generation data, along with real-time substation voltage regulator and PV inverter reactive power control. The outputs from the model plot real-time voltage, current and power variations throughout the daily load and PV generation variations. Other aspects of the study not described in the paper include the analysis of harmonics, voltage flicker, power factor, voltage unbalance and system losses.

Adoption of alternative habitats by a threatened, "obligate" forest-dwelling bat in a fragmented landscape

While they are among the most ecologically important animals within forest ecosystems, little is known about how bats respond to habitat loss and fragmentation. The threatened lesser short-tailed bat (Mystacina tuberculata), considered to be an obligate deep-forest species, is one of only 2 extant land mammals endemic to New Zealand; it plays a number of important roles within native forests, including pollination and seed dispersal, and rarely occurs in modified forests. We used radiotelemetry to study the movements, roosting behavior, and habitat use of M. tuberculata within a fragmented landscape comprised of 3 main habitat types: open space (harvested forest and pastoral land), native forests, and exotic pine plantations. We found that the bats had smaller home-range areas and travelled shorter nightly distances than populations investigated previously from contiguous native forest. Furthermore, M. tuberculata occupied all 3 habitat types, with native forest being preferred overall. However, individual variation in habitat selection was high, with some bats preferring exotic plantation and open space over native forest. Roosting patterns were similar to those previously observed in contiguous forest; individual bats often switched between communal and solitary roosts. Our findings indicate that M. tuberculata exhibit some degree of behavioral plasticity that allows them to adapt to different landscape mosaics and exploit alternative habitats. To our knowledge, this is the first such documentation of plasticity in habitat use for a bat species believed to be an obligate forest-dweller.

Females as mobile resources: communal roosts promote the adoption of lek breeding in a temperate bat

Males of lek-breeding species defend clustered territories from which they display to visiting females. However, the mechanisms leading to the adoption of clustered male display sites are often unknown. In this study, we examined the possibility of a resource-based lek in New Zealand’s lesser short-tailed bat (Mystacina tuberculata) (Mammalia: Chiroptera), by assessing the placement of “singing roosts” used by males in relation to communal roosting sites used by females. The “resource-based lek” model posits that males settle near resources required by females to increase female encounter rates. For most bat species, where females are highly mobile and widely dispersed across landscapes while foraging, communal daytime roosts dominated by females may represent such a resource. Through use of video footage, spatial analyses of singing-roost locations, and passive-integrated transponder tags we confirmed that M. tuberculata employs a lek mating system. We found that male singing roosts were significantly clustered in space, were defended by resident individuals, and were visited by females (who did not receive resources from males) for mating purposes. Transponder records also indicated that some singing roosts were shared between multiple males. Spatial logistic regression indicated that singing-roost locations were associated with communal roosting sites. Communal roosts are selected based on criteria independent of the locations of singing roosts, suggesting that males responded to the location of communal roosts and not the reverse. Mystacina tuberculata thus provides evidence of a resource-based lek, and is only the second bat species worldwide confirmed to use a lek-mating system.

Effect of different surface profile on wear of rail steel (AS1085.1) used in Australian heavy-haul railways

The extreme diversity of conditions acting on railways necessitates a variety of experimental approaches to study the critical wear mechanisms that present themselves at the contact interface. This work investigates the effects of contact pressure and geometry in rolling-contact wear tests by using discs with different radii of curvature to simulate the varying contact conditions that may be typically found in the field. It is commonly adapted to line contact interface as it has constant contact pressure. But practical scenario of the rail wheel interface, the contact area increase and contact pressure change as tracks worn off. The tests were conducted without any significant amount of traction, but micro slip was still observed due to contact deformation. Moreover, variation of contact pressure was observed due to contact patch elongation and diameter reduction. Rolling contact fatigue, adhesive and sliding wear were observed on the curved contact interface. The development of different wear regimes and material removal phenomena were analysed using microscopic images in order to broaden the understanding of the wear mechanisms occurring in the rail-wheel contact.

Stone baby: An exploration of trembling and its potential for visual art

Informed by Kristeva's formulation of affect and Winnicott's Holding Environment, this practice-led visual art project is an exploration into how sensitivity to the physical sensation of trembling can sustain a creative practice. Building upon this is a further enquiry into what the significance of the affective experience of trembling is for an ethics of affect in contemporary art. I have done this through object and video-based installations informed by my own experience of trembling. This has been further informed by the work of artists like Louise Bourgeois, Dennis Del Favero and Willie Doherty. The creative outcomes contribute to the discourse around ethical responses to affect by extending and developing on the works of these artists.

A "Candidate-Interactome" Aggregate Analysis of Genome-Wide Association Data in Multiple Sclerosis

Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a "candidate interactome" (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms. © 2013 Mechelli et al.

Correction: Genome-wide association studies of asthma in population-based cohorts confirm known and suggested loci and identify an additional association near HLA

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Genome-Wide Association Studies of Asthma in Population-Based Cohorts Confirm Known and Suggested Loci and Identify an Additional Association near HLA

Rationale: Asthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies. Objectives: To test if population-based cohorts with self-reported physician-diagnosed asthma and genome-wide association (GWA) data could be used to validate known associations with asthma and identify novel associations. Methods: The APCAT (Analysis in Population-based Cohorts of Asthma Traits) consortium consists of 1,716 individuals with asthma and 16,888 healthy controls from six European-descent population-based cohorts. We examined associations in APCAT of thirteen variants previously reported as genome-wide significant (P<5x10-8) and three variants reported as suggestive (P<5×10-7). We also searched for novel associations in APCAT (Stage 1) and followed-up the most promising variants in 4,035 asthmatics and 11,251 healthy controls (Stage 2). Finally, we conducted the first genome-wide screen for interactions with smoking or hay fever. Main Results: We observed association in the same direction for all thirteen previously reported variants and nominally replicated ten of them. One variant that was previously suggestive, rs11071559 in RORA, now reaches genome-wide significance when combined with our data (P = 2.4×10-9). We also identified two genome-wide significant associations: rs13408661 near IL1RL1/IL18R1 (PStage1+Stage2 = 1.1x10-9), which is correlated with a variant recently shown to be associated with asthma (rs3771180), and rs9268516 in the HLA region (PStage1+Stage2 = 1.1x10-8), which appears to be independent of previously reported associations in this locus. Finally, we found no strong evidence for gene-environment interactions with smoking or hay fever status. Conclusions: Population-based cohorts with simple asthma phenotypes represent a valuable and largely untapped resource for genetic studies of asthma. © 2012 Ramasamy et al.

Acute inflammatory response to low-, moderate- and high-load resistance exercise in women with breast cancer-related lymphoedema

Background Resistance exercise is emerging as a potential adjunct therapy to aid in the management of breast cancer-related lymphedema (BCRL). However, the mechanisms underlying the relationships between the acute and long-term benefits of resistance exercise on BCRL are not well understood. Purpose. To examine the acute inflammatory response to upper-body resistance exercise in women with BCRL and to compare these effects between resistance exercises involving low-, moderate- and high-loads. The impact on lymphoedema status and associated symptoms was also compared. Methods Twenty-one women aged 62 ± 10 years with mild to severe BCRL participated in the study. Participants completed a low-load (15-20 repetition maximum), moderate-load (10-12 repetition maximum) and high-load (6-8 repetition maximum) exercise sessions consisting of three sets of six upper-body resistance exercises. Sessions were completed in a randomized order separated by a seven to 10 day wash-out period. Venous blood samples were obtained to assess markers of exercise-induced muscle damage and inflammation (creatine kinase [CK], C-reactive protein [CRP], interleukin-6 [IL-6] and tumour necrosis factor-alpha [TNF-α]). Lymphoedema status was assessed using bioimpedance spectroscopy and arm circumferences, and associated symptoms were assessed using visual analogue scales (VAS) for pain, heaviness and tightness. Measurements were conducted before and 24 hours after the exercise sessions. Results No significant changes in CK, CRP, IL-6 and TNF-α were observed following the low-, moderate- or high-load resistance exercise sessions. There were no significant changes in arm swelling or symptom severity scores across the three resistance exercise conditions. Conclusions The magnitude of acute exercise-induced inflammation following upper-body resistance exercise in women with BCRL does not vary between resistance exercise loads. Given these observations, moderate- to high-load resistance training is recommended for this patient population as these loads prompt superior physiological and functional benefits.

Multicentric carpotarsal osteolysis is caused by mutations clustering in the amino-terminal transcriptional activation domain of MAFB

Multicentric carpotarsal osteolysis (MCTO) is a rare skeletal dysplasia characterized by aggressive osteolysis, particularly affecting the carpal and tarsal bones, and is frequently associated with progressive renal failure. Using exome capture and next-generation sequencing in five unrelated simplex cases of MCTO, we identified previously unreported missense mutations clustering within a 51 base pair region of the single exon of MAFB, validated by Sanger sequencing. A further six unrelated simplex cases with MCTO were also heterozygous for previously unreported mutations within this same region, as were affected members of two families with autosomal-dominant MCTO. MAFB encodes a transcription factor that negatively regulates RANKL-induced osteoclastogenesis and is essential for normal renal development. Identification of this gene paves the way for development of novel therapeutic approaches for this crippling disease and provides insight into normal bone and kidney development.