Selective Induction of DNA Repair Pathways in Human B Cells Activated by CD4+ T Cells

Greater than 75% of all hematologic malignancies derive from germinal center (GC) or post-GC B cells, suggesting that the GC reaction predisposes B cells to tumorigenesis. Because GC B cells acquire expression of the highly mutagenic enzyme activation-induced cytidine deaminase (AID), GC B cells may require additional DNA repair capacity. The goal of this study was to investigate whether normal human B cells acquire enhanced expression of DNA repair factors upon AID induction. We first demonstrated that several DNA mismatch repair, homologous recombination, base excision repair, and ATR signaling genes were overexpressed in GC B cells relative to naïve and memory B cells, reflecting activation of a process we have termed somatic hyperrepair (SHR). Using an in vitro system, we next characterized activation signals required to induce AID expression and SHR. Although AID expression was induced by a variety of polyclonal activators, SHR induction strictly required signals provided by contact with activated CD4+ T cells, and B cells activated in this manner displayed reduced levels of DNA damage-induced apoptosis. We further show the induction of SHR is independent of AID expression, as GC B cells from AID -/- mice retained heightened expression of SHR proteins. In consideration of the critical role that CD4+ T cells play in inducing the SHR process, our data suggest a novel role for CD4+ T cells in the tumor suppression of GC/post-GC B cells

Adaptation and Convergent Evolution within the Jamesonia-Eriosorus Complex in High-Elevation Biodiverse Andean Hotspots

The recent uplift of the tropical Andes (since the late Pliocene or early Pleistocene) provided extensive ecological opportunity for evolutionary radiations. We test for phylogenetic and morphological evidence of adaptive radiation and convergent evolution to novel habitats (exposed, high-altitude páramo habitats) in the Andean fern genera Jamesonia and Eriosorus. We construct time-calibrated phylogenies for the Jamesonia-Eriosorus clade. We then use recent phylogenetic comparative methods to test for evolutionary transitions among habitats, associations between habitat and leaf morphology, and ecologically driven variation in the rate of morphological evolution. Páramo species (Jamesonia) display morphological adaptations consistent with convergent evolution in response to the demands of a highly exposed environment but these adaptations are associated with microhabitat use rather than the páramo per se. Species that are associated with exposed microhabitats (including Jamesonia and Eriorsorus) are characterized by many but short pinnae per frond whereas species occupying sheltered microhabitats (primarily Eriosorus) have few but long pinnae per frond. Pinnae length declines more rapidly with altitude in sheltered species. Rates of speciation are significantly higher among páramo than non-páramo lineages supporting the hypothesis of adaptation and divergence in the unique Páramo biodiversity hotspot

Cell cycle-specific UNG2 phosphorylations regulate protein turnover, activity and association with RPA

Human UNG2 is a multifunctional glycosylase that removes uracil near replication forks and in non-replicating DNA, and is important for affinity maturation of antibodies in B cells. How these diverse functions are regulated remains obscure. Here, we report three new phosphoforms of the non-catalytic domain that confer distinct functional properties to UNG2. These are apparently generated by cyclin-dependent kinases through stepwise phosphorylation of S23, T60 and S64 in the cell cycle. Phosphorylation of S23 in late G1/early S confers increased association with replication protein A (RPA) and replicating chromatin and markedly increases the catalytic turnover of UNG2. Conversely, progressive phosphorylation of T60 and S64 throughout S phase mediates reduced binding to RPA and flag UNG2 for breakdown in G2 by forming a cyclin E/c-myc-like phosphodegron. The enhanced catalytic turnover of UNG2 p-S23 likely optimises the protein to excise uracil along with rapidly moving replication forks. Our findings may aid further studies of how UNG2 initiates mutagenic rather than repair processing of activation-induced deaminase-generated uracil at Ig loci in B cells

Long-term outcome and prognosis of dissociative disorder with onset in childhood or adolescence

<p>Abstract</p> <p>Background</p> <p>In the majority of cases short-term treatment outcome of juvenile dissociative disorder is rather favourable. In contrast, the long-term course seems to be less positive, but meaningful results are still fragmentary. The aim of this follow-up study is to bridge this gap to some extent describing the long-term outcome of juvenile dissociative disorder in a clinical sample. To our knowledge there is no comparable other long-term follow-up study which is based on a case definition according to actual classification systems using standardized interviews for individual assessment of the patients at the time of follow-up.</p> <p>Methods</p> <p>The total study group was made up of all patients treated for dissociative disorder at our department for child and adolescent psychiatry between 1983 and 1992 (<it>N </it>= 62). Two of these former patients committed suicide during the follow-up period (3%). We got information on the clinical course of 27 former patients (44%). 17 out of these 27 former patients were female (63%). The mean age of onset of dissociative disorder was11.7 years and the mean follow-up time was 12.4 years. Most of the patients were reassessed personally (n = 23) at a mean age of 24.8 years using structured interviews covering dissociative disorders, other Axis I disorders and personality disorders (Heidelberg Dissociation Inventory HDI; Expert System for Diagnosing Mental Disorders, DIA-X; Structured Clinical Interview for DSM-IV, SCID-II). Social adjustment was assessed by a semi-structured interview and by patient self report (Social Adjustment Scale – Self Report, SAS-SR). Psychosocial outcome variables were additionally assessed in 36 healthy controls (67% female, mean age = 22.9 years).</p> <p>Results</p> <p>At the time of follow-up investigation 82.6% of the patients met the criteria for some form of psychiatric disorder, while 26.1% were still suffering from dissociative disorder. A total of 56.5% presented with an Axis I disorder (especially anxiety, dissociative and somatoform disorders). Personality disorders were seen in 47.8% (especially borderline, obsessive-compulsive and negativistic personality disorders). More dissociative symptoms and inpatient treatment in childhood or adolescence were significantly related to a lower level of psychosocial adjustment in adulthood.</p> <p>Conclusion</p> <p>Treatment strategies have to consider that in a significant portion of young patients initial recovery may not be stable over time. Limitations of the study refer to the small sample size and the low rate of former patients taking part in the follow-up investigation.</p