Somatic Hypermutation Is Limited by CRM1-dependent Nuclear Export of Activation-induced Deaminase

Somatic hypermutation (SHM) and class switch recombination (CSR) are initiated in activated B lymphocytes by activation-induced deaminase (AID). AID is thought to make lesions in DNA by deaminating cytidine residues in single-stranded DNA exposed by RNA polymerase during transcription. Although this must occur in the nucleus, AID is found primarily in the cytoplasm. Here we show that AID is actively excluded from the nucleus by an exportin CRM1-dependent pathway. The AID nuclear export signal (NES) is found at the carboxyl terminus of AID in a region that overlaps a sequence required for CSR but not SHM. We find that AID lacking a functional NES causes more hypermutation of a nonphysiologic target gene in transfected fibroblasts. However, the NES does not impact on the rate of mutation of immunoglobulin genes in B lymphocytes, suggesting that the AID NES does not limit AID activity in these cells

LOWER LEG MORPHOLOGY AND STRETCH-SHORTENING CYCLE PERFORMANCE IN YOUNG AND ELDERLY MALES

The purpose of this investigation was to examine bone and muscle characteristics of the lower leg and stretch-shortening cycle capabilities of the ankle in young (22.3 ± 1.3 yrs) and elderly (67.5 ± 3.3 yrs) males. Peripheral quantitiative computed tomography (pQCT) was utilized to assess bone stress-strain index, bone ultimate fracture load, muscle density, muscle cross-sectional area (CSA), fat CSA and muscle+bone CSA. Maximal voluntary isometric plantarflexion (MVIP) force and force-velocity measurments during a countermovement hop (CMH) and drop hops from 20, 30 and 40 cm (DH20, DH30, DH40) were also measured. Bone stress-strain index was significantly higher in young males as well as muscle density, muscle CSA and muscle+bone CSA in comparison to elderly males. MVIP peak force and rate of force development was significantly higher in young males in comparsion to elderly males as well. An analysis of the force-velocity curves indicated that young males had significanlty higher levels of force and velocity in both the eccentric and concentric phase during the CMH, DH20, DH30 and DH40 in comparsion to elderly males. The data from this investigation indicate that aging potentially negatively influences lower leg bone and muscle strength and this may be reflected in lower stretch-shortening cycle capabilities of the ankle

Regulation of class switch recombination and somatic mutation by AID phosphorylation

Activation-induced cytidine deaminase (AID) is a mutator enzyme that initiates somatic mutation and class switch recombination in B lymphocytes by introducing uracil:guanine mismatches into DNA. Repair pathways process these mismatches to produce point mutations in the Ig variable region or double-stranded DNA breaks in the switch region DNA. However, AID can also produce off-target DNA damage, including mutations in oncogenes. Therefore, stringent regulation of AID is required for maintaining genomic stability during maturation of the antibody response. It has been proposed that AID phosphorylation at serine 38 (S38) regulates its activity, but this has not been tested in vivo. Using a combination of mass spectrometry and immunochemical approaches, we found that in addition to S38, AID is also phosphorylated at position threonine 140 (T140). Mutation of either S38 or T140 to alanine does not impact catalytic activity, but interferes with class switching and somatic hypermutation in vivo. This effect is particularly pronounced in haploinsufficient mice where AID levels are limited. Although S38 is equally important for both processes, T140 phosphorylation preferentially affects somatic mutation, suggesting that posttranslational modification might contribute to the choice between hypermutation and class switching

Austerity: Neoliberal dreams come true?

The 2008 global economic crisis paved the way for the construction of a new, elitedriven, capitalcentric, shrunken welfare state project founded on ideology disguised as pragmatism and objective ‘truths’. Today, welfare states exist in a context in which a new politics of austerity sets the parameters of the debate. Austerity incorporates the neoliberal desire to shrink the (social welfare) state, deregulate labour markets and emphasise private markets as the drivers of growth, enabling a reconfiguration of the interests of capital, the needs of people and the role of the state. The new politics of austerity looks like a ‘dream come true’ for neoliberals. Or is it? There is also a powerful counternarrative that suggests that the global crisis exposed the fundamental weaknesses and limitations of neoliberalism and forced policy makers to question core principles and change direction. Focusing on the International Monetary Fund (IMF), perhaps the preeminent global neoliberal interlocutor, and using quantitative textual analysis, the article locates some evidence of movement, but little to suggest that the fundamental assumptions of neoliberalism have been displaced

Wwox Deletion in Mouse B Cells Leads to Genomic Instability, Neoplastic Transformation, and Monoclonal Gammopathies

WWOX (WW domain containing oxidoreductase) expression loss is common in various cancers and characteristic of poor prognosis. Deletions, translocations, and loss of expression affecting the WWOX gene are a common feature of various B cell neoplasms such as certain B cell lymphomas and multiple myeloma. However, the role of this common abnormality in B cell tumor initiation and/or progression has not been defined. In this study, we conditionally deleted Wwox early in B cell development by means of breeding Cd19-Cre transgenic mice crossed to Wwox floxed mice (Cd19 Wwox KO). We observed a significant reduced survival in Cd19 Wwox KO mice and the development of B cell neoplasms including B cell lymphomas, plasma cell neoplasias characterized by increased numbers of CD138+ populations as well as monoclonal gammopathies detected by serum protein electrophoresis. To investigate whether Wwox loss could play a role in genomic instability, we analyzed DNA repair functions during immunoglobulin class switch joining between DNA segments in antibody genes. While class switch recombination (CSR) was only slightly impaired, Wwox deficiency resulted in a dramatic shift of double strand break (DSB) repair from normal classical-NHEJ toward the microhomology-mediated alternative-NHEJ pathway, a pathway associated with chromosome translocations and genome instability. Consistent with this, Wwox deficiency resulted in a marked increase of spontaneous translocations during CSR. This work defines for the first time a role for Wwox for maintaining B cell genome stability during a process that can promote neoplastic transformation and monoclonal gammopathies.Facultad de Ciencias MédicasCentro de Investigaciones Inmunológicas Básicas y Aplicada

Cognitive skills and literacy performance of Chinese adolescents with and without dyslexia

The present study sought to identify cognitive abilities that might distinguish Hong Kong Chinese adolescents with dyslexia and to assess how these abilities were associated with Chinese word reading, word dictation, and reading comprehension. The cognitive skills of interest were morphological awareness, visual-orthographic knowledge, rapid naming, and verbal working memory. A total of 90 junior secondary school students, 30 dyslexic, 30 chronological age controls, and 30 reading level controls was tested on a range of cognitive and literacy tasks. Dyslexic students were less competent than the control students in all cognitive and literacy measures. The regression analyses also showed that verbal working memory, rapid naming, morphological awareness, and visual-orthographic knowledge were significantly associated with literacy performance. Findings underscore the importance of these cognitive skills for Chinese literacy acquisition. Overall, this study highlights the persistent difficulties of Chinese dyslexic adolescents who seem to have multiple causes for reading and spelling difficulties

Manual / Issue 12 / On Further Review

Manual, a journal about art and its making. On Further Review. This issue uncovers narratives once central to objects’ histories but that now have been systematically obscured, inadvertently overlooked, or otherwise lost. Softcover, 96 pages. Published 2019 by the RISD Museum.(On Further Review) contributors include Anita N. Bateman, Laurie Anne Brewer, Becci Davis, Jamie Gabbarelli, Bethany Johns, Elon Cook Lee, Kevin McBride, Walker Mettling, Jessica Rosner, Suzanne Scanlan, Nell Painter, Allison Pappas, Pamela A. Parmal, Shiyanthi Thavapalan, and Nick White.https://digitalcommons.risd.edu/risdmuseum_journals/1038/thumbnail.jp

Maize Cultivar Performance under Diverse Organic Production Systems

Maize (Zea mays L.) performance can vary widely between different production systems. The need for high-performing hybrids for organic systems with wide adaptation to various macroenvironments is becoming increasingly important. The goal of this study was to characterize inbred lines developed by distinct breeding programs for their combining ability and hybrid yield performance across diverse organic environments. Parent lines were selected from five different breeding programs to give a sample of publically available germplasm with potential for use in organic production systems with expired plant variety protection (Ex-PVP) and current commercial inbreds as benchmarks. A North Carolina Design II mating design was used to produce all possible cross combinations between seven lines designated as males and seven lines designated as females. A significantly positive general combining ability for the female inbred UHF134 suggests that it performs well in hybrid combination. Significant general combining ability was not observed for any male inbred line in this study. Several significantly positive specific combining abilities suggest that nonadditive genetic effects play an important role in determining yield in this germplasm. Further analysis revealed that hybrids containing either an Ex-PVP line or a commercial inbred line were on average superior to hybrids containing only inbreds developed by the cooperators of this study. This demonstrates the utility of testing inbreds from diverse sources when developing hybrids for organic production systems

Prognostic and Predictive Biomarkers in Patients With Coronavirus Disease 2019 Treated With Tocilizumab in a Randomized Controlled Trial

OBJECTIVES: To explore candidate prognostic and predictive biomarkers identified in retrospective observational studies (interleukin-6, C-reactive protein, lactate dehydrogenase, ferritin, lymphocytes, monocytes, neutrophils, d-dimer, and platelets) in patients with coronavirus disease 2019 pneumonia after treatment with tocilizumab, an anti-interleukin-6 receptor antibody, using data from the COVACTA trial in patients hospitalized with severe coronavirus disease 2019 pneumonia. DESIGN: Exploratory analysis from a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. SETTING: Hospitals in North America and Europe. PATIENTS: Adults hospitalized with severe coronavirus disease 2019 pneumonia receiving standard care. INTERVENTION: Randomly assigned 2:1 to IV tocilizumab 8 mg/kg or placebo. MEASUREMENTS AND MAIN RESULTS: Candidate biomarkers were measured in 295 patients in the tocilizumab arm and 142 patients in the placebo arm. Efficacy outcomes assessed were clinical status on a seven-category ordinal scale (1, discharge; 7, death), mortality, time to hospital discharge, and mechanical ventilation (if not receiving it at randomization) through day 28. Prognostic and predictive biomarkers were evaluated continuously with proportional odds, binomial or Fine-Gray models, and additional sensitivity analyses. Modeling in the placebo arm showed all candidate biomarkers except lactate dehydrogenase and d-dimer were strongly prognostic for day 28 clinical outcomes of mortality, mechanical ventilation, clinical status, and time to hospital discharge. Modeling in the tocilizumab arm showed a predictive value of ferritin for day 28 clinical outcomes of mortality (predictive interaction, p = 0.03), mechanical ventilation (predictive interaction, p = 0.01), and clinical status (predictive interaction, p = 0.02) compared with placebo. CONCLUSIONS: Multiple biomarkers prognostic for clinical outcomes were confirmed in COVACTA. Ferritin was identified as a predictive biomarker for the effects of tocilizumab in the COVACTA patient population; high ferritin levels were associated with better clinical outcomes for tocilizumab compared with placebo at day 28

Galaxy Zoo: The Environmental Dependence of Bars and Bulges in Disc Galaxies

We present an analysis of the environmental dependence of bars and bulges in disc galaxies, using a volume-limited catalogue of 15810 galaxies at z<0.06 from the Sloan Digital Sky Survey with visual morphologies from the Galaxy Zoo 2 project. We find that the likelihood of having a bar, or bulge, in disc galaxies increases when the galaxies have redder (optical) colours and larger stellar masses, and observe a transition in the bar and bulge likelihoods, such that massive disc galaxies are more likely to host bars and bulges. We use galaxy clustering methods to demonstrate statistically significant environmental correlations of barred, and bulge-dominated, galaxies, from projected separations of 150 kpc/h to 3 Mpc/h. These environmental correlations appear to be independent of each other: i.e., bulge-dominated disc galaxies exhibit a significant bar-environment correlation, and barred disc galaxies show a bulge-environment correlation. We demonstrate that approximately half (50 +/- 10%) of the bar-environment correlation can be explained by the fact that more massive dark matter haloes host redder disc galaxies, which are then more likely to have bars. Likewise, we show that the environmental dependence of stellar mass can only explain a small fraction (25 +/- 10%) of the bar-environment correlation. Therefore, a significant fraction of our observed environmental dependence of barred galaxies is not due to colour or stellar mass dependences, and hence could be due to another galaxy property. Finally, by analyzing the projected clustering of barred and unbarred disc galaxies with halo occupation models, we argue that barred galaxies are in slightly higher-mass haloes than unbarred ones, and some of them (approximately 25%) are satellite galaxies in groups. We also discuss implications about the effects of minor mergers and interactions on bar formation.Comment: 20 pages, 18 figures; references updated; published in MNRA