Lattice matched GaN/InAlN waveguides at λ = 1.55 μm grown by metalorganic vapor phase epitaxy

We report on the demonstration of low-loss, single-mode GaN-InAlN ridge waveguides (WGs) at fiber-optics telecommunication wavelengths. The structure grown by metal-organic vapor phase epitaxy contains AlInN cladding layers lattice-matched to GaN. For slab-like WGs propagation losses are below 3 dB/mm and independent of light polarization. For 2.6-μm-wide WGs the propagation losses in the 1.5- to 1.58-μm spectral region are as low as 1.8 and 4.9 dB/mm for transverse-electric- and transverse-magnetic-polarization, respectively. The losses are attributed to the sidewall roughness and can be further reduced by the optimization of the etching process

Biomarkers in drug hypersensitivity

Biomarkers, especially those based on pharmacogenomics testing, have proved to be extremely useful for type A adverse drug reactions. Clinical practice guidelines based on biomarker testing are presently being developed and updated for type A adverse drug reactions. In contrast, little attention has been paid to the potential use of biomarkers in type B adverse reactions, characterized by the occurrence of reactions not directly related to the pharmacological properties of the drug. Drug-induced hypersensitivity belongs to those type B reactions. Drug-induced hypersensitivity reactions involve complex mechanisms that include, among others, the metabolic activation and haptenization of drug metabolites. Hence, factors that influence the pharmacokinetics of drug and metabolites may contribute to the development of some drug-induced hypersensitivity reactions. This implies that processes such as ADME (absorption, distribution, metabolism and excretion) that are typically involved in type A adverse drug reactions, may have a role in hypersensitivity reactions too. In addition to metabolic activation, several signal transduction pathways participate and modulate the development and the clinical presentation of drug hypersensitivity. The diverse mechanisms underlying such drug-hypersensitivity reactions lead to four major groups of reactions according to the Gell and Coombs classification: immediate, cytotoxic, immune complex and delayed. The enormous complexity of drug-hypersensitivity reactions is a consequence of the variety of mechanisms involved, which may be related, among others, to drug metabolism, generation of antigenic signals, stimulation and maturation of dendritic cells, presentation of haptens and mechanisms of cytotoxicity. In addition, a plethora of possible clinical presentations exists, including urticaria, angioedema, anaphylaxis, cytopenias, nephritis, serum sickness, vasculitis, contact dermatitis, drug rash, eosinophilia and systemic symptoms, Stevens–Johnson syndrome, toxic epidermal necrolysis and acute generalized exanthematous pustulosis. The rapid progress in the field in recent years indicates that the combination of several disciplines is essential to understand the mechanisms involved in this particular, and not completely understood, type of adverse drug reactions. The objective of this Research Topic is to present insights obtained from both basic and clinical scientists, which may include studies related to the identification, validation, refinement and clinical implementation of biomarkers for drug-induced hypersensitivity. The Topic aims to include recent findings related, but not limited to, potential phenomic, genomic, proteomic, metabolomic and signal transduction biomarkers. These biomarkers could eventually be used in clinical practice and/or these might contribute, as a proof of concept, to our understanding of the complex events leading to drug hypersensitivity reactions. In addition the Topic will cover recent developments and methodological advances in the diagnosis, prevention and therapeutic management of drug-induced hypersensitivity

Genetic determinants of steatosis and fibrosis progression in paediatric non‐alcoholic fatty liver disease

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and adolescents today. In comparison with adult disease, paediatric NAFLD may show a periportal localization, which is associated with advanced fibrosis. This study aimed to assess the role of genetic risk variants for histological disease pattern and severity in childhood NAFLD. METHODS: We studied 14 single nucleotide polymorphisms (SNP) in a cohort of 70 adolescents with biopsy-proven NAFLD. Genotype was compared to an adult control cohort (n = 200) and analysed in relation to histological disease severity and liver tissue proteomics. RESULTS: Three of the 14 SNPs were significantly associated with paediatric NAFLD after FDR adjustment, rs738409 (PNPLA3, P = 2.80 × 10-06 ), rs1044498 (ENPP1, P = 0.0091) and rs780094 (GCKR, P = 0.0281). The severity of steatosis was critically associated with rs738409 (OR=3.25; 95% CI: 1.72-6.52, FDR-adjusted P = 0.0070). The strongest variants associated with severity of fibrosis were rs1260326, rs780094 (both GCKR) and rs659366 (UCP2). PNPLA3 was associated with a portal pattern of steatosis, inflammation and fibrosis. Proteome profiling revealed decreasing levels of GCKR protein with increasing carriage of the rs1260326/rs780094 minor alleles and downregulation of the retinol pathway in rs738409 G/G carriers. Computational metabolic modelling highlighted functional relevance of PNPLA3, GCKR and UCP2 for NAFLD development. CONCLUSIONS: This study provides evidence for the role of PNPLA3 as a determinant of portal NAFLD localization and severity of portal fibrosis in children and adolescents, the risk variant being associated with an impaired hepatic retinol metabolism

Comparison of scores for bimodality of gene expression distributions and genome-wide evaluation of the prognostic relevance of high-scoring genes

<p>Abstract</p> <p>Background</p> <p>A major goal of the analysis of high-dimensional RNA expression data from tumor tissue is to identify prognostic signatures for discriminating patient subgroups. For this purpose genome-wide identification of bimodally expressed genes from gene array data is relevant because distinguishability of high and low expression groups is easier compared to genes with unimodal expression distributions.</p> <p>Recently, several methods for the identification of genes with bimodal distributions have been introduced. A straightforward approach is to cluster the expression values and score the distance between the two distributions. Other scores directly measure properties of the distribution. The kurtosis, e.g., measures divergence from a normal distribution. An alternative is the outlier-sum statistic that identifies genes with extremely high or low expression values in a subset of the samples.</p> <p>Results</p> <p>We compare and discuss scores for bimodality for expression data. For the genome-wide identification of bimodal genes we apply all scores to expression data from 194 patients with node-negative breast cancer. Further, we present the first comprehensive genome-wide evaluation of the prognostic relevance of bimodal genes. We first rank genes according to bimodality scores and define two patient subgroups based on expression values. Then we assess the prognostic significance of the top ranking bimodal genes by comparing the survival functions of the two patient subgroups. We also evaluate the global association between the bimodal shape of expression distributions and survival times with an enrichment type analysis.</p> <p>Various cluster-based methods lead to a significant overrepresentation of prognostic genes. A striking result is obtained with the outlier-sum statistic (<it>p </it>< 10^-12). Many genes with heavy tails generate subgroups of patients with different prognosis.</p> <p>Conclusions</p> <p>Genes with high bimodality scores are promising candidates for defining prognostic patient subgroups from expression data. We discuss advantages and disadvantages of the different scores for prognostic purposes. The outlier-sum statistic may be particularly valuable for the identification of genes to be included in prognostic signatures. Among the genes identified as bimodal in the breast cancer data set several have not yet previously been recognized to be prognostic and bimodally expressed in breast cancer.</p

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

Using derivative logic to speculate on the future of the social investment market

This article pries open the black box of the social impact bond (SIB), the novel financial instrument at the heart of social investment. We discover that concrete information is currently limited and our method is thus more speculative. We address the obfuscation of the nomenclature of the instrument and explore the mechanics of SIBs to suggest that they are not simple bonds but rather also bear properties akin to those associated with derivative contracts. We speculate on possible developments of the market in these bonds by considering the history of some previous financial innovations, namely, collateralized debt obligations (CDOs) underpinned by microfinance loans and the short-lived policy analysis market. Our discussion leads us to reevaluate Goodhart’s law and the ways in which it operates in relation to SIBs. We conclude by suggesting that SIBs' inherent indifference to the underlying state of the world renders them ultimately unlikely to delivery improvements in public services