Divergence of the Yeast Transcription Factor FZF1 Affects Sulfite Resistance

Changes in gene expression are commonly observed during evolution. However, the phenotypic consequences of expression divergence are frequently unknown and difficult to measure. Transcriptional regulators provide a mechanism by which phenotypic divergence can occur through multiple, coordinated changes in gene expression during development or in response to environmental changes. Yet, some changes in transcriptional regulators may be constrained by their pleiotropic effects on gene expression. Here, we use a genome-wide screen for promoters that are likely to have diverged in function and identify a yeast transcription factor, FZF1, that has evolved substantial differences in its ability to confer resistance to sulfites. Chimeric alleles from four Saccharomyces species show that divergence in FZF1 activity is due to changes in both its coding and upstream noncoding sequence. Between the two closest species, noncoding changes affect the expression of FZF1, whereas coding changes affect the expression of SSU1, a sulfite efflux pump activated by FZF1. Both coding and noncoding changes also affect the expression of many other genes. Our results show how divergence in the coding and promoter region of a transcription factor alters the response to an environmental stress

MicroRNA profiles discriminate among colon cancer metastasis

MicroRNAs are being exploited for diagnosis, prognosis and monitoring of cancer and other diseases. Their high tissue specificity and critical role in oncogenesis provide new biomarkers for the diagnosis and classification of cancer as well as predicting patients' outcomes. MicroRNAs signatures have been identified for many human tumors, including colorectal cancer (CRC). In most cases, metastatic disease is difficult to predict and to prevent with adequate therapies. The aim of our study was to identify a microRNA signature for metastatic CRC that could predict and differentiate metastatic target organ localization. Normal and cancer tissues of three different groups of CRC patients were analyzed. RNA microarray and TaqMan Array analysis were performed on 66 Italian patients with or without lymph nodes and/or liver recurrences. Data obtained with the two assays were analyzed separately and then intersected to identify a primary CRC metastatic signature. Five differentially expressed microRNAs (hsa-miR-21, -103, -93, -31 and -566) were validated by qRT-PCR on a second group of 16 American metastatic patients. In situ hybridization was performed on the 16 American patients as well as on three distinct commercial tissues microarray (TMA) containing normal adjacent colon, the primary adenocarcinoma, normal and metastatic lymph nodes and liver. Hsa-miRNA-21, -93, and -103 upregulation together with hsa-miR-566 downregulation defined the CRC metastatic signature, while in situ hybridization data identified a lymphonodal invasion profile. We provided the first microRNAs signature that could discriminate between colorectal recurrences to lymph nodes and liver and between colorectal liver metastasis and primary hepatic tumor

Cell-surface ZnT8 antibody prevents and reverses autoimmune diabetes in mice

Type 1 diabetes (T1D) is an autoimmune disease where pathogenic lymphocytes target autoantigens expressed in the pancreatic islets, leading to the destruction of insulin-producing β-cells. Zinc transporter 8 (ZnT8) is a major autoantigen abundantly present on the β-cell surface. This unique molecular target offers the potential to shield β-cells against autoimmune attacks in T1D. Our previous work showed that a monoclonal antibody (mAb43) against cell-surface ZnT8 can home in on the pancreatic islets and prevent autoantibodies from recognizing β-cells. This study demonstrates that mAb43 binds to exocytotic sites on the β-cell surface, masking the antigenic exposure of ZnT8 and insulin following glucose-stimulated insulin secretion. In vivo administration of mAb43 to nonobese diabetic (NOD) mice selectively increased the proportion of regulatory T-cells (Tregs) in the islet, resulting in complete and sustained protection against T1D onset as well as reversal of new-onset diabetes. The mAb43-induced self-tolerance was reversible after treatment cessation and exhibited no adverse effects during long-term monitoring. Our findings suggest that mAb43 masking of the antigenic exposure of β-cells suppresses the immunological cascade from B-cell antigen presentation to T-cell mediated β-cell destruction, providing a novel islet-targeted and antigen-specific immunotherapy to prevent and reverse clinical T1D.</p

Social Skill-Based Treatment for Social Anxiety Disorder in Adolescents

Adolescents with social anxiety disorder (SAD) experience significant social anxiety and frequently avoid social situations. Additionally, many adolescents with SAD have social skill deficits, which could suggest that interventions solely targeting reductions in social anxiety may not result in enhanced social functioning. Thus, improving social skill is an important target in treatment protocols for adolescent SAD. Social skills training (SST) involves the use of various behavioral methods to establish, modify, and improve social skill in this group. Many successful interventions for adolescents with SAD incorporate a SST component. In this chapter, we discuss social skill-based interventions for SAD, including Cognitive-Behavioral Group Therapy for Adolescents and Social Effectiveness Therapy for Children. These interventions have demonstrated efficacy in reducing social anxiety and improving social skill in socially anxious adolescents. We also discuss important caveats that are present in current SST paradigms that limit their success and utility both in and outside of the university setting. Finally, future directions for social skill-based treatments are discussed