Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies.

CAPRISA, 2014.Antibodies capable of neutralizing HIV-1 often target variable regions 1 and 2 (V1V2) of the HIV-1 envelope, but the mechanism of their elicitation has been unclear. Here we define the developmental pathway by which such antibodies are generated and acquire the requisite molecular characteristics for neutralization. Twelve somatically related neutralizing antibodies (CAP256-VRC26.01-12) were isolated from donor CAP256 (from the Centre for the AIDS Programme of Research in South Africa (CAPRISA)); each antibody contained the protruding tyrosine-sulphated, anionic antigen-binding loop (complementarity-determining region (CDR) H3) characteristic of this category of antibodies. Their unmutated ancestor emerged between weeks 30-38 post-infection with a 35-residue CDR H3, and neutralized the virus that superinfected this individual 15 weeks after initial infection. Improved neutralization breadth and potency occurred by week 59 with modest affinity maturation, and was preceded by extensive diversification of the virus population. HIV-1 V1V2-directed neutralizing antibodies can thus develop relatively rapidly through initial selection of B cells with a long CDR H3, and limited subsequent somatic hypermutation. These data provide important insights relevant to HIV-1 vaccine development

A first-generation linkage disequilibrium map of human chromosome 22

A collection of DNA sequence variants across the genome may be used to test specific genes or regions of the human genome for association with a variety of phenotypes such as disease risk or variable drug response. Detecting association relies on the non-random correlation (“linkage disequilibrium”, LD) of one of the marker alleles with a trait-related variant. We have measured LD along the complete sequence of human chromosome 22. Duplicate genotyping and analysis of 1,504 markers in CEPH reference families at a median spacing of 15kb reveals a highly variable pattern of LD along the chromosome, in which extensive regions of virtually complete LD up to 758 kb in length are interspersed with regions of little or no detectable LD. The LD patterns are replicated in 1,286 overlapping markers genotyped on a panel of unrelated U.K. Caucasians. There is a strong correlation between high LD and low recombination frequency in the extant genetic map, reflecting patterns of historic recombination between ancestral chromosomes that yield conserved blocks of LD in present-day chromosomes. This study demonstrates the feasibility for developing genome-wide maps of LD

Physician-scientist or basic scientist? Exploring the nature of clinicians\u27 research engagement

Theoretical understanding of what motivates clinician researchers has met with some success in launching research careers, but it does not account for professional identification as a factor determining sustained research engagement over the long-term. Deeper understanding of clinicians\u27 research-related motivation may better foster their sustained research engagement post-training and, by extension, the advancement of medicine and health outcomes. This study used an integrated theoretical framework (Social Cognitive Career Theory and Professional Identity Formation) and appreciative inquiry to explore the interplay of professional identification and research context in shaping post-training research success narratives. To foreground professional identification, 19 research-active clinicians and 17 basic scientists served as interviewees. A multi-institutional, multi-national design was used to explore how contextual factors shape external valuation of research success. The findings suggest that research-active clinicians do not identify as the career scientists implied by the modern physician-scientist construct and the goal of many clinician research-training programs. Their primary identification as care providers shapes their definition of research success around extending their clinical impact; institutional expectations and prevailing healthcare concerns that value this aim facilitate their sustained research engagement. Integrated developmental and organizational interventions adaptive to research context and conducive to a wider range of medical inquiry may better leverage clinicians\u27 direct involvement in patient care and advance progress toward human health and well-being

TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum

Ciliary dysfunction leads to a broad range of overlapping phenotypes, termed collectively as ciliopathies. This grouping is underscored by genetic overlap, where causal genes can also contribute modifying alleles to clinically distinct disorders. Here we show that mutations in TTC21B/IFT139, encoding a retrograde intraflagellar transport (IFT) protein, cause both isolated nephronophthisis (NPHP) and syndromic Jeune Asphyxiating Thoracic Dystrophy (JATD). Moreover, although systematic medical resequencing of a large, clinically diverse ciliopathy cohort and matched controls showed a similar frequency of rare changes, in vivo and in vitro evaluations unmasked a significant enrichment of pathogenic alleles in cases, suggesting that TTC21B contributes pathogenic alleles to ∼5% of ciliopathy patients. Our data illustrate how genetic lesions can be both causally associated with diverse ciliopathies, as well as interact in trans with other disease-causing genes, and highlight how saturated resequencing followed by functional analysis of all variants informs the genetic architecture of disorders