The early UL3 gene of equine herpesvirus-1 encodes a tegument protein not essential for replication or virulence in the mouse

AbstractThe UL3 gene of equine herpesvirus-1 (EHV-1) is retained in the genome of defective interfering particles and encodes a ~33kDa myristylated protein. Further characterization showed that the UL3 gene is trans-activated only by the sole immediate early (IE) protein and encodes an early protein that is dispensable for EHV-1 replication and localizes in the tegument of purified virions. UL3-deleted EHV-1 (vL11ΔUL3) exhibits properties of host cell tropism, plaque size, and growth kinetics similar to those of the parental virus. Expression levels of EHV-1 proteins representative of all three gene classes in vL11ΔUL3-infected cells were identical to those in cells infected with parental virus. Mice intranasally infected with vL11ΔUL3 and parental virus showed no significant difference in mortality or virus lung titers. These findings suggest that the UL3 protein does not play a major role in the biology of EHV-1 in cell culture or virulence in the mouse

Performance of two formal tests based on martingales residuals to check the proportional hazard assumption and the functional form of the prognostic factors in flexible parametric excess hazard models.

: Net survival, the one that would be observed if the disease under study was the only cause of death, is an important, useful, and increasingly used indicator in public health, especially in population-based studies. Estimates of net survival and effects of prognostic factor can be obtained by excess hazard regression modeling. Whereas various diagnostic tools were developed for overall survival analysis, few methods are available to check the assumptions of excess hazard models. We propose here two formal tests to check the proportional hazard assumption and the validity of the functional form of the covariate effects in the context of flexible parametric excess hazard modeling. These tests were adapted from martingale residual-based tests for parametric modeling of overall survival to allow adding to the model a necessary element for net survival analysis: the population mortality hazard. We studied the size and the power of these tests through an extensive simulation study based on complex but realistic data. The new tests showed sizes close to the nominal values and satisfactory powers. The power of the proportionality test was similar or greater than that of other tests already available in the field of net survival. We illustrate the use of these tests with real data from French cancer registries.<br/

A Systemically-Administered Small Molecule Antagonist of CCR9 Acts as a Tissue-Selective Inhibitor of Lymphocyte Trafficking

A goal for developers of immunomodulatory drugs has long been a systemically administered small molecule that can selectively inhibit inflammation in specific tissues. The chemokine receptor CCR9 is an attractive target for this approach, as entry of T cells into the small intestine from blood requires interaction between CCR9 and its ligand CCL25. We have tested the ability of a small molecule CCR9 antagonist, CCX8037, to inhibit antigen-mediated T cell accumulation in the intestine. This compound prevented accumulation of gut-imprinted antigen-specific CD8 T cells within epithelium of the small intestine. Interestingly, the antagonist did not affect the robust generation of gut-imprinted CD8 T cells within mesenteric lymph nodes. To distinguish “gut-selective” from “general” T cell inhibition, we tested the drug’s ability to influence accumulation of T cells within skin, a tissue in which CCR9 plays no known role, and we found no appreciable effect. This study demonstrates the feasibility of creating systemically-administered pharmaceuticals capable of tissue-selective immune modulation. This proof of concept is of utmost importance for designing effective treatments against various autoimmune disorders localized to a specific tissue

Access to Archived Astronaut Data for Human Research Program Researchers: Update on Progress and Process Improvements

No abstract availabl

Access to Archived Astronaut Data for Human Research Program Researchers: Update on Progress and Process Improvements

Since the 2010 NASA directive to make the Life Sciences Data Archive (LSDA) and Lifetime Surveillance of Astronaut Health (LSAH) data archives more accessible by the research and operational communities, demand for astronaut medical data has increased greatly. LSAH and LSDA personnel are working with Human Research Program on many fronts to improve data access and decrease lead time for release of data. Some examples include the following: Feasibility reviews for NASA Research Announcement (NRA) data mining proposals; Improved communication, support for researchers, and process improvements for retrospective Institutional Review Board (IRB) protocols; Supplemental data sharing for flight investigators versus purely retrospective studies; Work with the Multilateral Human Research Panel for Exploration (MHRPE) to develop acceptable data sharing and crew consent processes and to organize inter-agency data coordinators to facilitate requests for international crewmember data. Current metrics on data requests crew consenting will be presented, along with limitations on contacting crew to obtain consent. Categories of medical monitoring data available for request will be presented as well as flow diagrams detailing data request processing and approval steps

Intimate partner violence as a predictor of marital disruption in rural Rakai, Uganda: a longitudinal study.

ObjectivesWe assessed the association between intimate partner violence (IPV) and union disruption (divorce or separation) in the rural Ugandan setting of Rakai District.MethodsWe analyzed longitudinal data collected from April 1999 to June 2006, from 6834 women (15-49 years) living in 50 communities in Rakai. Participants were either officially married, traditionally married or in a consensual union during one or more surveys and completed at least one follow-up survey. The primary outcome was union disruption through divorce or separation from the primary sexual partner.ResultsPast year IPV ranged from 6.49 % (severe physical abuse) to 31.99 % (emotional abuse). Severe physical IPV was significantly associated with divorce/separation, after adjusting for other covariates (aOR = 1.80, 95 % CI 1.01-3.22). Another predictor of union disruption was a woman having two or more sexual partners in the past year (aOR = 8.42, 95 % CI 5.97-11.89). Factors protecting against divorce/separation included an increasing number of co-resident biological children and longer duration of union.ConclusionsIPV, particularly severe physical abuse, is an important risk factor for union disruption. Marital counseling, health education and interventions should address the role of IPV on the wellbeing of women and the stability of couples in Uganda

Somatostatin subtype-2 receptor-targeted metal-based anticancer complexes

Conjugates of a dicarba analogue of octreotide, a potent somatostatin agonist whose receptors are overexpressed on tumor cells, with [PtCl 2(dap)] (dap = 1-(carboxylic acid)-1,2-diaminoethane) (3), [(η 6-bip)Os(4-CO 2-pico)Cl] (bip = biphenyl, pico = picolinate) (4), [(η 6-p-cym)RuCl(dap)] + (p-cym = p-cymene) (5), and [(η 6-p-cym)RuCl(imidazole-CO 2H)(PPh 3)] + (6), were synthesized by using a solid-phase approach. Conjugates 3-5 readily underwent hydrolysis and DNA binding, whereas conjugate 6 was inert to ligand substitution. NMR spectroscopy and molecular dynamics calculations showed that conjugate formation does not perturb the overall peptide structure. Only 6 exhibited antiproliferative activity in human tumor cells (IC 50 = 63 ± 2 μ in MCF-7 cells and IC 50 = 26 ± 3 μ in DU-145 cells) with active participation of somatostatin receptors in cellular uptake. Similar cytotoxic activity was found in a normal cell line (IC 50 = 45 ± 2.6 μ in CHO cells), which can be attributed to a similar level of expression of somatostatin subtype-2 receptor. These studies provide new insights into the effect of receptor-binding peptide conjugation on the activity of metal-based anticancer drugs, and demonstrate the potential of such hybrid compounds to target tumor cells specifically. © 2012 American Chemical Society