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Protein degradation by the ubiquitin-proteasome system is critical for

Factors that underlie the clustering of metabolic syndrome traits are

Sequencing of DNA extracted from environmental samples can provide key

Heterozygous in-frame mutations in coding regions of human STAT3

The establishment of latent infection and poorly characterized viral

Studies of vertebrate immunity have traditionally focused on professional cells, including circulating and tissue-resident leukocytes. Evidence that non-professional cells are also intrinsically essential (i.e. not via their effect on leukocytes) for protective immunity in natural conditions of infection has emerged from three lines of research in human genetics. First, studies of Mendelian resistance to infection have revealed an essential role of DARC-expressing erythrocytes in protection against Plasmodium vivax infection, and an essential role of FUT2-expressing intestinal epithelial cells for protection against norovirus and rotavirus infections. Second, studies of inborn errors of non-hematopoietic cell-extrinsic immunity have shown that APOL1 and complement cascade components secreted by hepatocytes are essential for protective immunity to trypanosome and pyogenic bacteria, respectively. Third, studies of inborn errors of non-hematopoietic cell-intrinsic immunity have suggested that keratinocytes, pulmonary epithelial cells, and cortical neurons are essential for tissue-specific protective immunity to human papillomaviruses, influenza virus, and herpes simplex virus, respectively. Various other types of genetic resistance or predisposition to infection in human populations are not readily explained by inborn variants of genes operating in leukocytes and may, therefore, involve defects in other cells. The probing of this unchartered territory by human genetics is reshaping immunology, by scaling immunity to infection up from the immune system to the whole organism.

Aim To assess progressive learning of root canal shaping in order to

The 3rd Annual Symposium on Hidradenitis Suppurativa Advances (SHSA) took place on 12-14 October 2018 at the Women's College Hospital in Toronto, Ontario, Canada. This symposium was a joint meeting of the Hidradenitis Suppurativa Foundation (HSF) founded in the USA and the Canadian Hidradenitis Suppurativa Foundation (CHSF). This cross-disciplinary meeting with experts from around the world was an opportunity to discuss the most recent advances in the study of hidradenitis suppurativa pathogenesis, epidemiology, classification, scoring systems, radiologic diagnosis, treatment approaches and psychologic assessment. Two special sessions this year were HS as a systemic disease and HS management guidelines. There were focused workshops on wound healing and ultrasound. There were two sessions primarily for patients and their families in the HS School programme: One workshop focused on mindfulness, and the second involved discussion among clinicians and patients about various disease aspects and the latest management. To facilitate networking between clinical and research experts and those early in their career, a mentoring breakfast was held.

Genomic analyses of patients with congenital heart disease (CHD) have identified significant contribution from mutations affecting cilia genes and chromatin remodeling genes; however, the mechanism(s) connecting chromatin remodeling to CHD is unknown. Histone H2B monoubiquitination (H2Bub1) is catalyzed by the RNF20 complex consisting of RNF20, RNF40, and UBE2B. Here, we show significant enrichment of loss-of-function mutations affecting H2Bub1 in CHD patients (enrichment 6.01, P = 1.67 x 10(-03)), some of whom had abnormal laterality associated with ciliary dysfunction. In Xenopus, knockdown of rnf20 and rnf40 results in abnormal heart looping, defective development of left-right (LR) asymmetry, and impaired cilia motility. Rnf20, Rnf40, and Ube2b affect LR patterning and cilia synergistically. Examination of global H2Bub1 level in Xenopus embryos shows that H2Bub1 is developmentally regulated and requires Rnf20. To examine gene-specific H2Bub1, we performed ChlP-seq of mouse ciliated and nonciliated tissues and showed tissue-specific H2Bub1 marks significantly enriched at cilia genes including the transcription factor Rfx3. Rnf20 knockdown results in decreased levels of rfx3 mRNA in Xenopus, and exogenous rfx3 can rescue the Rnf20 depletion phenotype. These data suggest that Rnf20 functions at the Rfx3 locus regulating cilia motility and cardiac situs and identify H2Bub1 as an upstream transcriptional regulator controlling tissue-specific expression of cilia genes. Our findings mechanistically link the two functional gene ontologies that have been implicated in human CHD: chromatin remodeling and cilia function.