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

Ordovician ash geochemistry and the establishment of land plants

<p>Abstract</p> <p>The colonization of the terrestrial environment by land plants transformed the planetary surface and its biota, and shifted the balance of Earth’s biomass from the subsurface towards the surface. However there was a long delay between the formation of palaeosols (soils) on the land surface and the key stage of plant colonization. The record of palaeosols, and their colonization by fungi and lichens extends well back into the Precambrian. While these early soils provided a potential substrate, they were generally leached of nutrients as part of the weathering process. In contrast, volcanic ash falls provide a geochemically favourable substrate that is both nutrient-rich and has high water retention, making them good hosts to land plants. An anomalously extensive system of volcanic arcs generated unprecedented volumes of lava and volcanic ash (tuff) during the Ordovician. The earliest, mid-Ordovician, records of plant spores coincide with these widespread volcanic deposits, suggesting the possibility of a genetic relationship. The ash constituted a global environment of nutrient-laden, water-saturated soil that could be exploited to maximum advantage by the evolving anchoring systems of land plants. The rapid and pervasive inoculation of modern volcanic ash by plant spores, and symbiotic nitrogen-fixing fungi, suggests that the Ordovician ash must have received a substantial load of the earliest spores and their chemistry favoured plant development. In particular, high phosphorus levels in ash were favourable to plant growth. This may have allowed photosynthesizers to diversify and enlarge, and transform the surface of the planet.</p

Near-atomic resolution visualization of human transcription promoter opening

In eukaryotic transcription initiation, a large multi-subunit pre-initiation complex (PIC) that assembles at the core promoter is required for the opening of the duplex DNA and identification of the start site for transcription by RNA polymerase II. Here we use cryo-electron microscropy (cryo-EM) to determine near-atomic resolution structures of the human PIC in a closed state (engaged with duplex DNA), an open state (engaged with a transcription bubble), and an initially transcribing complex (containing six base pairs of DNA–RNA hybrid). Our studies provide structures for previously uncharacterized components of the PIC, such as TFIIE and TFIIH, and segments of TFIIA, TFIIB and TFIIF. Comparison of the different structures reveals the sequential conformational changes that accompany the transition from each state to the next throughout the transcription initiation process. This analysis illustrates the key role of TFIIB in transcription bubble stabilization and provides strong structural support for a translocase activity of XPB