Perceptually smooth timbral guides by state-space analysis of phase-vocoder parameters

Sculptor is a phase-vocoder-based package of programs that allows users to explore timbral manipulation of sound in real time. It is the product of a research program seeking ultimately to perform gestural capture by analysis of the sound a performer makes using a conventional instrument. Since the phase-vocoder output is of high dimensionality — typically more than 1,000 channels per analysis frame—mapping phase-vocoder output to appropriate input parameters for a synthesizer is only feasible in theory

Estimation of the atmospheric flux of nutrients and trace metals to the Eastern Tropical North Atlantic Ocean

Atmospheric deposition contributes potentially significant amounts of the nutrients iron, nitrogen and phosphorus (via mineral dust and anthropogenic aerosols) to the oligotrophic tropical North Atlantic Ocean. Transport pathways, deposition processes and source strengths contributing to this atmospheric flux are all highly variable in space and time. Atmospheric sampling was conducted during 28 research cruises through the Eastern Tropical North Atlantic (ETNA) over a 12 year period and a substantial dataset of measured concentrations of nutrients and trace metals in aerosol and rainfall over the region was acquired. This database was used to quantify (on a spatial- and seasonal-basis) the atmospheric input of ammonium, nitrate, soluble phosphorus and soluble and total iron, aluminium and manganese to the ETNA. The magnitude of atmospheric input varies strongly across the region, with high rainfall rates associated with the Inter-tropical Convergence Zone contributing to high wet deposition fluxes in the south, particularly for soluble species. Dry deposition fluxes of species associated with mineral dust exhibited strong seasonality, with highest fluxes associated with winter-time low-level transport of Saharan dust. Overall (wet plus dry) atmospheric inputs of soluble and total trace metals were used to estimate their soluble fractions. These also varied with season and were generally lower in the dry north than in the wet south. The ratio of ammonium plus nitrate to soluble iron in deposition to the ETNA was lower than the N:Fe requirement for algal growth in all cases, indicating the importance of the atmosphere as a source of excess iron

Multiple interactions between the alpha2C- and beta1-adrenergic receptors influence heart failure survival

<p>Abstract</p> <p>Background</p> <p>Persistent stimulation of cardiac β₁-adrenergic receptors by endogenous norepinephrine promotes heart failure progression. Polymorphisms of this gene are known to alter receptor function or expression, as are polymorphisms of the α_2C-adrenergic receptor, which regulates norepinephrine release from cardiac presynaptic nerves. The purpose of this study was to investigate possible synergistic effects of polymorphisms of these two intronless genes (<it>ADRB1 </it>and <it>ADRA2C</it>, respectively) on the risk of death/transplant in heart failure patients.</p> <p>Methods</p> <p>Sixteen sequence variations in <it>ADRA2C </it>and 17 sequence variations in <it>ADRB1 </it>were genotyped in a longitudinal study of 655 white heart failure patients. Eleven sequence variations in each gene were polymorphic in the heart failure cohort. Cox proportional hazards modeling was used to identify polymorphisms and potential intra- or intergenic interactions that influenced risk of death or cardiac transplant. A leave-one-out cross-validation method was utilized for internal validation.</p> <p>Results</p> <p>Three polymorphisms in <it>ADRA2C </it>and five polymorphisms in <it>ADRB1 </it>were involved in eight cross-validated epistatic interactions identifying several two-locus genotype classes with significant relative risks ranging from 3.02 to 9.23. There was no evidence of intragenic epistasis. Combining high risk genotype classes across epistatic pairs to take into account linkage disequilibrium, the relative risk of death or transplant was 3.35 (1.82, 6.18) relative to all other genotype classes.</p> <p>Conclusion</p> <p>Multiple polymorphisms act synergistically between the <it>ADRA2C </it>and <it>ADRB1 </it>genes to increase risk of death or cardiac transplant in heart failure patients.</p

Analysis of variants in DNA damage signalling genes in bladder cancer

<p>Abstract</p> <p>Background</p> <p>Chemicals from occupational exposure and components of cigarette smoke can cause DNA damage in bladder urothelium. Failure to repair DNA damage by DNA repair proteins may result in mutations leading to genetic instability and the development of bladder cancer. Immunohistochemistry studies have shown DNA damage signal activation in precancerous bladder lesions which is lost on progression, suggesting that the damage signalling mechanism acts as a brake to further tumorigenesis. Single nucleotide polymorphisms (SNPs) in DSB signalling genes may alter protein function. We hypothesized that SNPs in DSB signalling genes may modulate predisposition to bladder cancer and influence the effects of environmental exposures.</p> <p>Methods</p> <p>We recruited 771 cases and 800 controls (573 hospital-based and 227 population-based from a previous case-control study) and interviewed them regarding their smoking habits and occupational history. DNA was extracted from a peripheral blood sample and genotyping of 24 SNPs in <it>MRE11, NBS1, RAD50, H2AX </it>and <it>ATM </it>was undertaken using an allelic discrimination method (Taqman).</p> <p>Results</p> <p>Smoking and occupational dye exposure were strongly associated with bladder cancer risk. Using logistic regression adjusting for age, sex, smoking and occupational dye exposure, there was a marginal increase in risk of bladder cancer for an <it>MRE11 </it>3'UTR SNP (rs2155209, adjusted odds ratio 1.54 95% CI (1.13–2.08, p = 0.01) for individuals homozygous for the rare allele compared to those carrying the common homozygous or heterozygous genotype). However, in the hospital-based controls, the genotype distribution for this SNP deviated from Hardy-Weinberg equilibrium. None of the other SNPs showed an association with bladder cancer and we did not find any significant interaction between any of these polymorphisms and exposure to smoking or dye exposure.</p> <p>Conclusion</p> <p>Apart from a possible effect for one MRE11 3'UTR SNP, our study does not support the hypothesis that SNPs in DSB signaling genes modulate predisposition to bladder cancer.</p

Short-term treatment with multi-drug regimens combining BRAF/MEK-targeted therapy and immunotherapy results in durable responses in Braf-mutated melanoma

Targeted and immunotherapy regimens have revolutionized the treatment of advanced melanoma patients. Despite this, only a subset of patients respond durably. Recently, combination strategies of BRAF/MEK inhibitors with immune checkpoint inhibitor monotherapy (α-CTLA-4 or α-PD-1) have increased the rate of durable responses. Based on evidence from our group and others, these therapies appear synergistic, but at the cost of significant toxicity. We know from other treatment paradigms (e.g. hematologic malignancies) that combination strategies with multi-drug regimens (\u3e4 drugs) are associated with more durable disease control. To better understand the mechanism of these improved outcomes, and to identify and prioritize new strategies for testing, we studied several multi-drug regimens combining BRAF/MEK targeted therapy and immunotherapy combinations in a Braf-mutant murine melanoma model (BrafV600E/Pten−/−). Short-term treatment with α-PD-1 and α-CTLA-4 monotherapies were relatively ineffective, while treatment with α-OX40 demonstrated some efficacy [17% of mice with no evidence of disease, (NED), at 60-days]. Outcomes were improved in the combined α-OX40/α-PD-1 group (42% NED). Short-term treatment with quadruplet therapy of immunotherapy doublets in combination with targeted therapy [dabrafenib and trametinib (DT)] was associated with excellent tumor control, with 100% of mice having NED after combined DT/α-CTLA-4/α-PD-1 or DT/α-OX40/α-PD-1. Notably, tumors from mice in these groups demonstrated a high proportion of effector memory T cells, and immunologic memory was maintained with tumor re-challenge. Together, these data provide important evidence regarding the potential utility of multi-drug therapy in treating advanced melanoma and suggest these models can be used to guide and prioritize combinatorial treatment strategies

Architectural Paint Research and the Archaeology of Buildings

Architectural Paint Research (APR) is the archaeological study of interior and exterior applied decoration. Over time, applied layers of paint and other decorative finishes build-up on the surface of a built structure, encapsulating microscopic deposits of material evidence. This evidence can be used to inform the phase dating of a structure, or illuminate the historic function of a space. It can challenge preconceived ideas of how specific areas were decorated, and track the changes in aesthetics over time. It can identify when architects’ ideologies have been balanced by practical considerations. It can provide an insight into the intangible and ephemeral atmosphere that decoration gives to a room. Finally, it can examine the dirt trapped between layers of decoration and thus categorize the physical environmental conditions that surrounded a building at varying points in its history. Although used in the commercial heritage and conservation sectors, Architectural Paint Research is almost completely unknown to building archaeologists. This article aims to introduce APR to a new audience, and argues that is an invaluable tool in the archaeological interpretation of buildings

Paxillin and Hic-5 Interaction with Vinculin Is Differentially Regulated by Rac1 and RhoA

Cell migration is of paramount importance to organism development and maintenance as well as multiple pathological processes, including cancer metastasis. The RhoGTPases Rac1 and RhoA are indispensable for cell migration as they regulate cell protrusion, cell-extracellular matrix (ECM) interactions and force transduction. However, the consequences of their activity at a molecular level within the cell remain undetermined. Using a combination of FRET, FRAP and biochemical analyses we show that the interactions between the focal adhesion proteins vinculin and paxillin, as well as the closely related family member Hic-5 are spatially and reciprocally regulated by the activity of Rac1 and RhoA. Vinculin in its active conformation interacts with either paxillin or Hic-5 in adhesions in response to Rac1 and RhoA activation respectively, while inactive vinculin interacts with paxillin in the membrane following Rac1 inhibition. Additionally, Rac1 specifically regulates the dynamics of paxillin as well as its binding partner and F-actin interacting protein actopaxin (α-parvin) in adhesions. Furthermore, FRET analysis of protein:protein interactions within cell adhesions formed in 3D matrices revealed that, in contrast to 2D systems vinculin interacts preferentially with Hic-5. This study provides new insight into the complexity of cell-ECM adhesions in both 2D and 3D matrices by providing the first description of RhoGTPase-coordinated protein:protein interactions in a cellular microenvironment. These data identify discrete roles for paxillin and Hic-5 in Rac1 and RhoA-dependent cell adhesion formation and maturation; processes essential for productive cell migration

Is bisexuality invisible? A review of sexualities scholarship 1970–2015

This article provides a review of sexualities scholarship within the social sciences between 1970 and 2015. It takes an innovative approach by focusing on the way in which bisexuality is addressed in this body of literature. The article reveals the marginalisation, under-representation and invisibility of bisexuality within and across the social sciences in relation to both bisexual experience and identity. Reasons for this varied across the different eras, including the heterosexist nature of the literature, the impact of gay and lesbian-focused identity politics, and queer deconstructionism. In addition, patterns of bisexual erasure and invisibility were uneven, with some scholarship taking inclusive approaches or criticising prejudice against bisexuality. The initial findings of the review were enriched by critical commentary from key relevant sociologists and political scientists. The article concludes that future sexualities scholarship could be enhanced by greater consideration of bisexuality

A Cis-Regulatory Map of the Drosophila Genome

Systematic annotation of gene regulatory elements is a major challenge in genome science. Direct mapping of chromatin modification marks and transcriptional factor binding sites genome-wide1, 2 has successfully identified specific subtypes of regulatory elements3. In Drosophila several pioneering studies have provided genome-wide identification of Polycomb response elements4, chromatin states5, transcription factor binding sites6, 7, 8, 9, RNA polymerase II regulation8 and insulator elements10; however, comprehensive annotation of the regulatory genome remains a significant challenge. Here we describe results from the modENCODE cis-regulatory annotation project. We produced a map of the Drosophila melanogaster regulatory genome on the basis of more than 300 chromatin immunoprecipitation data sets for eight chromatin features, five histone deacetylases and thirty-eight site-specific transcription factors at different stages of development. Using these data we inferred more than 20,000 candidate regulatory elements and validated a subset of predictions for promoters, enhancers and insulators in vivo. We identified also nearly 2,000 genomic regions of dense transcription factor binding associated with chromatin activity and accessibility. We discovered hundreds of new transcription factor co-binding relationships and defined a transcription factor network with over 800 potential regulatory relationships

A re-evaluation of the magnitude and impacts of anthropogenic atmospheric nitrogen inputs on the ocean

We report a new synthesis of best estimates of the inputs of fixed nitrogen to the world ocean via atmospheric deposition, and compare this to fluvial inputs and di-nitrogen fixation. We evaluate the scale of human perturbation of these fluxes. Fluvial inputs dominate inputs to the continental shelf, and we estimate about 75% of this fluvial nitrogen escapes from the shelf to the open ocean. Biological di-nitrogen fixation is the main external source of nitrogen to the open ocean, i.e. beyond the continental shelf. Atmospheric deposition is the primary mechanism by which land based nitrogen inputs, and hence human perturbations of the nitrogen cycle, reach the open ocean. We estimate that anthropogenic inputs are currently leading to an increase in overall ocean carbon sequestration of ~0.4% (equivalent to an uptake of 0.15 Pg C yr-1 and less than the Duce et al., 2008 estimate). The resulting reduction in climate change forcing from this ocean CO2 uptake is offset to a small extent by an increase in ocean N2O emissions. We identify four important feedbacks in the ocean atmosphere nitrogen system that need to be better quantified to improve our understanding of the perturbation of ocean biogeochemistry by atmospheric nitrogen inputs. These feedbacks are recycling of (1) ammonia and (2) organic nitrogen from the ocean to the atmosphere and back, (3) the suppression of nitrogen fixation by increased nitrogen concentrations in surface waters from atmospheric deposition, and (4) increased loss of nitrogen from the ocean by denitrification due to increased productivity stimulated by atmospheric inputs