Molecular signatures define alopecia areata subtypes and transcriptional biomarkers

AbstractAlopecia areata (AA) is an autoimmune disease typified by nonscarring hair loss with a variable clinical course. In this study, we conducted whole genome gene expression analysis of 96 human scalp skin biopsy specimens from AA or normal control subjects. Based on gene expression profiling, samples formed distinct clusters based on the presence or absence of disease as well as disease phenotype (patchy disease compared with alopecia totalis or universalis). Differential gene expression analysis allowed us to robustly demonstrate graded immune activity in samples of increasing phenotypic severity and generate a quantitative gene expression scoring system that classified samples based on interferon and cytotoxic T lymphocyte immune signatures critical for disease pathogenesis

Kappa Opioid receptor-induced aversion requires p38 MAPK activation in VTA dopamine neurons

The endogenous dynorphin-κ opioid receptor (KOR) system encodes the dysphoric component of the stress response and controls the risk of depression-like and addiction behaviors; however, the molecular and neural circuit mechanisms are not understood. In this study, we report that KOR activation of p38α MAPK in ventral tegmental (VTA) dopaminergic neurons was required for conditioned place aversion (CPA) in mice. Conditional genetic deletion of floxed KOR or floxed p38α MAPK by Cre recombinase expression in dopaminergic neurons blocked place aversion to the KOR agonist U50,488. Selective viral rescue by wild-type KOR expression in dopaminergic neurons of KOR(−/−) mice restored U50,488-CPA, whereas expression of a mutated form of KOR that could not initiate p38α MAPK activation did not. Surprisingly, while p38α MAPK inactivation blocked U50,488-CPA, p38α MAPK was not required for KOR inhibition of evoked dopamine release measured by fast scan cyclic voltammetry in the nucleus accumbens. In contrast, KOR activation acutely inhibited VTA dopaminergic neuron firing, and repeated exposure attenuated the opioid response. This adaptation to repeated exposure was blocked by conditional deletion of p38α MAPK, which also blocked KOR-induced tyrosine phosphorylation of the inwardly rectifying potassium channel (GIRK) subunit Kir3.1 in VTA dopaminergic neurons. Consistent with the reduced response, GIRK phosphorylation at this amino terminal tyrosine residue (Y12) enhances channel deactivation. Thus, contrary to prevailing expectations, these results suggest that κ opioid-induced aversion requires regulation of VTA dopaminergic neuron somatic excitability through a p38α MAPK effect on GIRK deactivation kinetics rather than by presynaptically inhibiting dopamine release. SIGNIFICANCE STATEMENT Kappa opioid receptor (KOR) agonists have the potential to be effective, nonaddictive analgesics, but their therapeutic utility is greatly limited by adverse effects on mood. Understanding how KOR activation produces dysphoria is key to the development of better analgesics and to defining how the endogenous dynorphin opioids produce their depression-like effects. Results in this study show that the aversive effects of κ receptor activation required arrestin-dependent p38α MAPK activation in dopamine neurons but did not require inhibition of dopamine release in the nucleus accumbens. Thus, contrary to the prevailing view, inhibition of mesolimbic dopamine release does not mediate the aversive effects of KOR activation and functionally selective κ opioids that do not activate arrestin signaling may be effective analgesics lacking dysphoric effects

Principal components ancestry adjustment for Genetic Analysis Workshop 17 data

Statistical tests on rare variant data may well have type I error rates that differ from their nominal levels. Here, we use the Genetic Analysis Workshop 17 data to estimate type I error rates and powers of three models for identifying rare variants associated with a phenotype: (1) by using the number of minor alleles, age, and smoking status as predictor variables; (2) by using the number of minor alleles, age, smoking status, and the identity of the population of the subject as predictor variables; and (3) by using the number of minor alleles, age, smoking status, and ancestry adjustment using 10 principal component scores. We studied both quantitative phenotype and a dichotomized phenotype. The model with principal component adjustment has type I error rates that are closer to the nominal level of significance of 0.05 for single-nucleotide polymorphisms (SNPs) in noncausal genes for the selected phenotype than the model directly adjusting for population. The principal component adjustment model type I error rates are also closer to the nominal level of 0.05 for noncausal SNPs located in causal genes for the phenotype. The power for causal SNPs with the principal component adjustment model is comparable to the power of the other methods. The power using the underlying quantitative phenotype is greater than the power using the dichotomized phenotype

Envisioning more equitable and just futures: feminist organizational communication in theory and praxis

In this forum, we engage in a reflexive intergenerational conversation regarding the contributions of feminist scholars to organizational communication scholarship, as well as the potentials of feminist organizational communication theory and praxis to address urgent challenges facing our institutions and communities. We also offer critique of this body of work and grapple with its, and in some cases our own, shortcomings. In this article, we highlight four major themes from our conversations including (a) navigating between the center and the margins in feminist organizational communication, (b) making time for intersectionality, (c) reenvisioning academic work based on our feminist values, and (d) imagining feminist futures. We hope this forum will inspire others to join us in exploring innovative ways to advance feminist organizational communication theory, praxis, and pedagogy

Overview : Integrative and Comprehensive Understanding on Polar Environments (iCUPE) - concept and initial results

The role of polar regions is increasing in terms of megatrends such as globalization, new transport routes, demography, and the use of natural resources with consequent effects on regional and transported pollutant concentrations. We set up the ERA-PLANET Strand 4 project "iCUPE - integrative and Comprehensive Understanding on Polar Environments" to provide novel insights and observational data on global grand challenges with an Arctic focus. We utilize an integrated approach combining in situ observations, satellite remote sensing Earth observations (EOs), and multi-scale modeling to synthesize data from comprehensive long-term measurements, intensive campaigns, and satellites to deliver data products, metrics, and indicators to stakeholders concerning the environmental status, availability, and extraction of natural resources in the polar areas. The iCUPE work consists of thematic state-of-the-art research and the provision of novel data in atmospheric pollution, local sources and transboundary transport, the characterization of arctic surfaces and their changes, an assessment of the concentrations and impacts of heavy metals and persistent organic pollutants and their cycling, the quantification of emissions from natural resource extraction, and the validation and optimization of satellite Earth observation (EO) data streams. In this paper we introduce the iCUPE project and summarize initial results arising out of the integration of comprehensive in situ observations, satellite remote sensing, and multi-scale modeling in the Arctic context.Peer reviewe

Overview: Integrative and Comprehensive Understanding on Polar Environments (iCUPE) – concept and initial results

The role of polar regions is increasing in terms of megatrends such as globalization, new transport routes, demography, and the use of natural resources with consequent effects on regional and transported pollutant concentrations. We set up the ERA-PLANET Strand 4 project “iCUPE – integrative and Comprehensive Understanding on Polar Environments” to provide novel insights and observational data on global grand challenges with an Arctic focus. We utilize an integrated approach combining in situ observations, satellite remote sensing Earth observations (EOs), and multi-scale modeling to synthesize data from comprehensive long-term measurements, intensive campaigns, and satellites to deliver data products, metrics, and indicators to stakeholders concerning the environmental status, availability, and extraction of natural resources in the polar areas. The iCUPE work consists of thematic state-of-the-art research and the provision of novel data in atmospheric pollution, local sources and transboundary transport, the characterization of arctic surfaces and their changes, an assessment of the concentrations and impacts of heavy metals and persistent organic pollutants and their cycling, the quantification of emissions from natural resource extraction, and the validation and optimization of satellite Earth observation (EO) data streams. In this paper we introduce the iCUPE project and summarize initial results arising out of the integration of comprehensive in situ observations, satellite remote sensing, and multi-scale modeling in the Arctic context

Chapter 4. Breaks with the traditional city: the colonial and collectivist eras

Up until the colonial era, the integration of villages into the city had taken place in keeping with the Chinese model, namely that the administration had integrated within the city limits a hundred or so villages, comprising the craft green belt that supplied the capital. In contrast, during the colonial era (1873-1945), then during the collectivist era (1954-1986), the urban model promoted at that time was a clear separation between what was defined as urban and as rural, with development p..