RESUMO
Sweet's syndrome is a poorly understood inflammatory skin disease characterized by neutrophil infiltration to the dermis. Single-nucleus and bulk transcriptomics of archival clinical samples of Sweet's syndrome revealed a prominent interferon signature in Sweet's syndrome skin that was reduced in tissue from other neutrophilic dermatoses. This signature was observed in different subsets of cells, including fibroblasts that expressed interferon-induced genes. Functionally, this response was supported by analysis of cultured primary human dermal fibroblasts that were observed to highly express neutrophil chemokines in response to activation by type I interferon. Furthermore, single-molecule resolution spatial transcriptomics of skin in Sweet's syndrome identified positionally distinct immune acting fibroblasts that included a CXCL1+ subset proximal to neutrophils and a CXCL12+ subset distal to the neutrophilic infiltrate. This study defines the cellular landscape of neutrophilic dermatoses and suggests dermal immune acting fibroblasts play a role in the pathogenesis of Sweet's syndrome through recognition of type I interferons.
RESUMO
BACKGROUND: Obsessive-compulsive disorder (OCD), a severe mental disease manifested in time-consuming repetition of behaviors, affects 1 to 3% of the human population. While highly heritable, complex genetics has hampered attempts to elucidate OCD etiology. Dogs suffer from naturally occurring compulsive disorders that closely model human OCD, manifested as an excessive repetition of normal canine behaviors that only partially responds to drug therapy. The limited diversity within dog breeds makes identifying underlying genetic factors easier. RESULTS: We use genome-wide association of 87 Doberman Pinscher cases and 63 controls to identify genomic loci associated with OCD and sequence these regions in 8 affected dogs from high-risk breeds and 8 breed-matched controls. We find 119 variants in evolutionarily conserved sites that are specific to dogs with OCD. These case-only variants are significantly more common in high OCD risk breeds compared to breeds with no known psychiatric problems. Four genes, all with synaptic function, have the most case-only variation: neuronal cadherin (CDH2), catenin alpha2 (CTNNA2), ataxin-1 (ATXN1), and plasma glutamate carboxypeptidase (PGCP). In the 2 Mb gene desert between the cadherin genes CDH2 and DSC3, we find two different variants found only in dogs with OCD that disrupt the same highly conserved regulatory element. These variants cause significant changes in gene expression in a human neuroblastoma cell line, likely due to disrupted transcription factor binding. CONCLUSIONS: The limited genetic diversity of dog breeds facilitates identification of genes, functional variants and regulatory pathways underlying complex psychiatric disorders that are mechanistically similar in dogs and humans.
Assuntos
Carboxipeptidases/genética , Cateninas/genética , Desmocolinas/genética , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Transtorno Obsessivo-Compulsivo/genética , Sequências Reguladoras de Ácido Nucleico/genética , Animais , Animais Endogâmicos , Ataxina-1 , Ataxinas , Cães , Estudo de Associação Genômica AmplaRESUMO
This was an exploratory study of sex and relationship seeking on the Internet, based on a survey of 15,246 respondents in the United States Seventy-five percent of men and 41% of women had intentionally viewed or downloaded porn. Men and gays/lesbians were more likely to access porn or engage in other sex-seeking behaviors online compared with straights or women. A symmetrical relationship was revealed between men and women as a result of viewing pornography, with women reporting more negative consequences, including lowered body image, partner critical of their body, increased pressure to perform acts seen in pornographic films, and less actual sex, while men reported being more critical of their partners' body and less interested in actual sex. Married and divorced were more likely than singles to go online seeking a serious relationship. Only 2% of users met the threshold of compulsive use established by previous studies.
