HIV Evolution in Early Infection: Selection Pressures, Patterns of Insertion and Deletion, and the Impact of APOBEC

The pattern of viral diversification in newly infected individuals provides information about the host environment and immune responses typically experienced by the newly transmitted virus. For example, sites that tend to evolve rapidly across multiple early-infection patients could be involved in enabling escape from common early immune responses, could represent adaptation for rapid growth in a newly infected host, or could represent reversion from less fit forms of the virus that were selected for immune escape in previous hosts. Here we investigated the diversification of HIV-1 env coding sequences in 81 very early B subtype infections previously shown to have resulted from transmission or expansion of single viruses (n = 78) or two closely related viruses (n = 3). In these cases, the sequence of the infecting virus can be estimated accurately, enabling inference of both the direction of substitutions as well as distinction between insertion and deletion events. By integrating information across multiple acutely infected hosts, we find evidence of adaptive evolution of HIV-1 env and identify a subset of codon sites that diversified more rapidly than can be explained by a model of neutral evolution. Of 24 such rapidly diversifying sites, 14 were either i) clustered and embedded in CTL epitopes that were verified experimentally or predicted based on the individual's HLA or ii) in a nucleotide context indicative of APOBEC-mediated G-to-A substitutions, despite having excluded heavily hypermutated sequences prior to the analysis. In several cases, a rapidly evolving site was embedded both in an APOBEC motif and in a CTL epitope, suggesting that APOBEC may facilitate early immune escape. Ten rapidly diversifying sites could not be explained by CTL escape or APOBEC hypermutation, including the most frequently mutated site, in the fusion peptide of gp41. We also examined the distribution, extent, and sequence context of insertions and deletions, and we provide evidence that the length variation seen in hypervariable loop regions of the envelope glycoprotein is a consequence of selection and not of mutational hotspots. Our results provide a detailed view of the process of diversification of HIV-1 following transmission, highlighting the role of CTL escape and hypermutation in shaping viral evolution during the establishment of new infections

Epithelial to mesenchymal transition and breast cancer

Epithelial-mesenchymal plasticity in breast carcinoma encompasses the phenotypic spectrum whereby epithelial carcinoma cells within a primary tumor acquire mesenchymal features and re-epithelialize to form a cohesive secondary mass at a metastatic site. Such plasticity has implications in progression of breast carcinoma to metastasis, and will likely influence response to therapy. The transcriptional and epigenetic regulation of molecular and cellular processes that underlie breast cancer and result in characteristic changes in cell behavior can be monitored using an increasing array of marker proteins. Amongst these markers exists the potential for emergent prognostic, predictive and therapeutic targeting

Incidence of Aphelenchoides Besseyi in rice in Louisiana and host status of the most widely planted cultivars

Aphelenchoides besseyi, the causal agent of white tip disease of rice, has been considered a minor pest of rice during the past 50 years in the United States. Recently, this nematode has been found in a number of quarantine samples in Louisiana and Arkansas. The objectives of this research were to determine incidence of this nematode in commercial seed sold to producers in Louisiana and to determine the host status of major rice cultivars currently produced in the state. During 2015-2016, a total of 216 seed samples, representing 3 medium grain, 18 long grain, and 4 long grain hybrid rice cultivars, were examined for A. besseyi. The nematode was detected in 12% of the samples, and the highest incidence occurred on long grain hybrids with 30% of the 63 samples infested. Nineteen-week-duration greenhouse studies were conducted to evaluate reproduction of the nematode and pathogenicity to three medium, three long grain, and three long grain hybrid rice cultivars currently popular in Louisiana. Reproductive values of the nematode ranged from 11.9 to 2.9 for medium grain cultivar Jupiter and long grain hybrid XL 753, respectively. Grain weights of Jupiter, CL 111, and XL 753 rice plants inoculated with A. besseyi were reduced below those of non-inoculated controls (P<0.01). The nematode reduced plant height of all cultivars (P<0.01). Plant weights of Jupiter, CL 111, CL 152, XL 745, and XL 753 were reduced when inoculated with A. besseyi. Germination and seedling growth studies conducted in the laboratory and greenhouse indicated that A. besseyi reduced medium grain Jupiter seed germination by 27% with a decrease in the germination index on 6 of the 9 cultivars evaluated

Chimeric Vitronectin : Insulin-like Growth Factor Proteins Enhance Cell Growth and Migration through Co-Activation of Receptors

Complexes comprised of IGF-I, IGF-binding proteins and the ECM protein vitronectin (VN) stimulate cell migration and growth and can replace the requirement for serum for the ex vivo expansion of cells, as well as promote wound healing in vivo. Moreover, the activity of the complexes is dependent on co-activation of the IGF-I receptor and VN-binding integrins. In view of this we sought to develop chimeric proteins able to recapitulate the action of the multiprotein complex within a single molecular species. We report here the production of two recombinant chimeric proteins, incorporating domains of VN linked to IGF-I, which mimic the functions of the complex. Further, the activity of the chimeric proteins is dependent on co-activation of the IGF-I- and VN-binding cell surface receptors. Clearly the use of chimeras that mimic the activity of growth factor:ECM complexes, such as these, offer manufacturing advantages that ultimately will facilitate translation to cost-effective therapies