HIV Shedding from Male Circumcision Wounds in HIV-Infected Men: A Prospective Cohort Study

BackgroundA randomized trial of voluntary medical male circumcision (MC) of HIV—infected men reported increased HIV transmission to female partners among men who resumed sexual intercourse prior to wound healing. We conducted a prospective observational study to assess penile HIV shedding after MC.ConclusionPenile HIV shedding is significantly reduced after healing of MC wounds. Lower plasma VL is associated with decreased frequency and quantity of HIV shedding from MC wounds. Starting ART prior to MC should be considered to reduce male-to-female HIV transmission risk. Research is needed to assess the time on ART required to decrease shedding, and the acceptability and feasibility of initiating ART at the time of MC.     

Effective Treatment of Established GL261 Murine Gliomas through Picornavirus Vaccination-Enhanced Tumor Antigen-Specific CD8+ T Cell Responses

Glioblastoma (GBM) is among the most invasive and lethal of cancers, frequently infiltrating surrounding healthy tissue and giving rise to rapid recurrence. It is therefore critical to establish experimental model systems and develop therapeutic approaches that enhance anti-tumor immunity. In the current study, we have employed a newly developed murine glioma model to assess the efficacy of a novel picornavirus vaccination approach for the treatment of established tumors. The GL261-Quad system is a variation of the GL261 syngeneic glioma that has been engineered to expresses model T cell epitopes including OVA_257–264. MRI revealed that both GL261 and GL261-Quad tumors display characteristic features of human gliomas such as heterogeneous gadolinium leakage and larger T2 weighted volumes. Analysis of brain-infiltrating immune cells demonstrated that GL261-Quad gliomas generate detectable CD8+ T cell responses toward the tumor-specific K^b:OVA_257–264 antigen. Enhancing this response via a single intracranial or peripheral vaccination with picornavirus expressing the OVA_257–264 antigen increased anti-tumor CD8+ T cells infiltrating the brain, attenuated progression of established tumors, and extended survival of treated mice. Importantly, the efficacy of the picornavirus vaccination is dependent on functional cytotoxic activity of CD8+ T cells, as the beneficial response was completely abrogated in mice lacking perforin expression. Therefore, we have developed a novel system for evaluating mechanisms of anti-tumor immunity in vivo, incorporating the GL261-Quad model, 3D volumetric MRI, and picornavirus vaccination to enhance tumor-specific cytotoxic CD8+ T cell responses and track their effectiveness at eradicating established gliomas in vivo.     

Protein Dynamics Associated with Failed and Rescued Learning in the Ts65Dn Mouse Model of Down Syndrome

Down syndrome (DS) is caused by an extra copy of human chromosome 21 (Hsa21). Although it is the most common genetic cause of intellectual disability (ID), there are, as yet, no effective pharmacotherapies. The Ts65Dn mouse model of DS is trisomic for orthologs of ∼55% of Hsa21 classical protein coding genes. These mice display many features relevant to those seen in DS, including deficits in learning and memory (L/M) tasks requiring a functional hippocampus. Recently, the N-methyl-D-aspartate (NMDA) receptor antagonist, memantine, was shown to rescue performance of the Ts65Dn in several L/M tasks. These studies, however, have not been accompanied by molecular analyses. In previous work, we described changes in protein expression induced in hippocampus and cortex in control mice after exposure to context fear conditioning (CFC), with and without memantine treatment. Here, we extend this analysis to Ts65Dn mice, measuring levels of 85 proteins/protein modifications, including components of MAP kinase and MTOR pathways, and subunits of NMDA receptors, in cortex and hippocampus of Ts65Dn mice after failed learning in CFC and after learning was rescued by memantine. We show that, compared with wild type littermate controls, (i) of the dynamic responses seen in control mice in normal learning, >40% also occur in Ts65Dn in failed learning or are compensated by baseline abnormalities, and thus are considered necessary but not sufficient for successful learning, and (ii) treatment with memantine does not in general normalize the initial protein levels but instead induces direct and indirect responses in approximately half the proteins measured and results in normalization of the endpoint protein levels. Together, these datasets provide a first view of the complexities associated with pharmacological rescue of learning in the Ts65Dn. Extending such studies to additional drugs and mouse models of DS will aid in identifying pharmacotherapies for effective clinical trials.     

Do Parents Meet Adolescents’ Monitoring Standards? Examination of the Impact on Teen Risk Disclosure and Behaviors if They Don’t

In this study, we examined how adolescents compare monitoring efforts by their parents to those of a "good parent" standard and assessed the impact of these comparisons on adolescent self-disclosure and risk behavior and their perceptions of their parents'' monitoring knowledge. Survey responses from 519 adolescents (12–17 years) at baseline of a larger, longitudinal study examining parental monitoring and adolescent risk were examined. Adolescents’ “good parent comparisons” differed greatly by monitoring areas (e.g., telephone use, health, money); however, between 5.5% and 25.8% of adolescents believed their parents needed to monitor their activities more than they currently were monitoring. Alternatively, between 8.5% and 23.8% of adolescents believed their parents needed to monitor their activities less often. These perceptions significantly distinguished adolescents in terms of their level of disclosure, perceived monitoring knowledge, and risk involvement. Adolescents who viewed their parents as needing to monitor more were less likely to disclose information to their parents (p<.001), less likely to perceive their parents as having greater monitoring knowledge (p<.001), and more likely to be involved in a risk behaviors (p<.001) than adolescents who perceived their parents needed no change. Adolescent disclosure to a parent is a powerful predictor of adolescent risk and poor health outcomes. These findings demonstrate that adolescents'' comparisons of their parents'' monitoring efforts can predict differences in adolescent disclosure and future risk. Obtaining adolescent "good parent" comparisons may successfully identify intervention opportunities with the adolescent and parent by noting the areas of need and direction of monitoring improvement.     

An Agent-Based Model of Private Woodland Owner Management Behavior Using Social Interactions,Information Flow,and Peer-To-Peer Networks

Privately owned woodlands are an important source of timber and ecosystem services in North America and worldwide. Impacts of management on these ecosystems and timber supply from these woodlands are difficult to estimate because complex behavioral theory informs the owner’s management decisions. The decision-making environment consists of exogenous market factors, internal cognitive processes, and social interactions with fellow landowners, foresters, and other rural community members. This study seeks to understand how social interactions, information flow, and peer-to-peer networks influence timber harvesting behavior using an agent-based model. This theoretical model includes forested polygons in various states of ‘harvest readiness’ and three types of agents: forest landowners, foresters, and peer leaders (individuals trained in conservation who use peer-to-peer networking). Agent rules, interactions, and characteristics were parameterized with values from existing literature and an empirical survey of forest landowner attitudes, intentions, and demographics. The model demonstrates that as trust in foresters and peer leaders increases, the percentage of the forest that is harvested sustainably increases. Furthermore, peer leaders can serve to increase landowner trust in foresters. Model output and equations will inform forest policy and extension/outreach efforts. The model also serves as an important testing ground for new theories of landowner decision making and behavior.     

The B Cell Adaptor Molecule Bam32 Is Critically Important for Optimal Antibody Response and Resistance to Trypanosoma congolense Infection in Mice

Background

Bam32, a 32 kDa adaptor molecule, plays important role in B cell receptor signalling, T cell receptor signalling and antibody affinity maturation in germinal centres. Since antibodies against trypanosome variant surface glycoproteins (VSG) are critically important for control of parasitemia, we hypothesized that Bam32 deficient (Bam32-/-) mice would be susceptible to T. congolense infection.

Methodology/Principal Findings

We found that T. congolense-infected Bam32^-/- mice successfully control the first wave of parasitemia but then fail to control subsequent waves and ultimately succumb to their infection unlike wild type (WT) C57BL6 mice which are relatively resistant. Although infected Bam32^-/- mice had significantly higher hepatomegaly and splenomegaly, their serum AST and ALT levels were not different, suggesting that increased liver pathology may not be responsible for the increased susceptibility of Bam32^-/- mice to T. congolense. Using direct ex vivo flow cytometry and ELISA, we show that CD4+ T cells from infected Bam32^-/- mice produced significantly increased amounts of disease-exacerbating proinflammatory cytokines (including IFN-γ, TNF-α and IL-6). However, the percentages of regulatory T cells and IL-10-producing CD4+ cells were similar in infected WT and Bam32^-/- mice. While serum levels of parasite-specific IgM antibodies were normal, the levels of parasite-specific IgG, (particularly IgG1 and IgG2a) were significantly lower in Bam32^-/- mice throughout infection. This was associated with impaired germinal centre response in Bam32^-/- mice despite increased numbers of T follicular helper (Tfh) cells. Adoptive transfer studies indicate that intrinsic B cell defect was responsible for the enhanced susceptibility of Bam32^-/- mice to T. congolense infection.

Conclusions/Significance

Collectively, our data show that Bam32 is important for optimal anti-trypanosome IgG antibody response and suppression of disease-promoting proinflammatory cytokines and its deficiency leads to inability to control T. congolense infection in mice.     

Maize Stover and Cob Cell Wall Composition and Ethanol Potential as Affected by Nitrogen Fertilization

Maize (Zea mays L.) stover and cobs are potential feedstock sources for cellulosic ethanol production. Nitrogen (N) fertilization is an important management decision that influences cellulosic biomass and grain production, but its effect on cell wall composition and subsequent cellulosic ethanol production is not known. The objectives of this study were to quantify the responses of maize stover (leaves, stalks, husks, and tassel) and cob cell wall composition and theoretical ethanol yield potential to N fertilization across a range of sites. Field experiments were conducted at rainfed and irrigated sites in Minnesota, USA, over a 2-year period. Stover cell wall polysaccharides, pentose sugar concentration, and theoretical ethanol yield decreased as N fertilization increased. Stover Klason lignin increased with N fertilization at all sites. Cob cell wall composition was less sensitive to N fertilization, as only pentose and Klason lignin decreased with N fertilization at two and one site(s), respectively, and hexose increased with N fertilization at one of eight sites. Cob theoretical ethanol yield was not affected by N fertilization at any site. These results indicate variation in stover cellulosic ethanol production is possible as a result of N management. This study also demonstrated that cell wall composition and subsequent theoretical ethanol yield of maize cobs are generally more stable than those with stover because of overall less sensitivity to N management.