The Innate Anti-HIV-1 Activity of Human Seminal Plasma

Human immunodeficiency virus (HIV) has become a global pandemic over the past few decades, with new infections and related deaths in the millions each year. There is no cure in sight for HIV-1 infection, and there has been little progress in developing an efficacious vaccine. Heterosexual transmission of HIV-1 remains the principal mode of transmission throughout the world and thus measures, such as topical vaginal microbicides, to prevent infection of the female reproductive tract are actively being explored. Recent trials of topical vaginal microbicides have shown that their interaction with the mucosal surfaces of the female reproductive tract as well as semen can hinder microbicide effectiveness against HIV-1 infection. Therefore, understanding the role these fluids play in HIV transmission would be critical towards developing effective antiviral prophylaxes. A recent study from our group demonstrated that human cervicovaginal secretions contained numerous cationic antimicrobial peptides and proteins, which collectively inhibited HIV-1 infection of target cells and tissues. To ascertain if human seminal plasma (SP), the main vector responsible for transmitting HIV-1, exhibited antiviral activity we utilized several antiHIV assays in the presence or absence of minimally manipulated SP. The majority of the intrinsic anti-HIV-1 activity of SP resided in the cationic polypeptide fraction. Antiviral assays utilizing luciferase reporter cells and lymphocytic cells revealed the ability of whole SP to prevent HIV-1 infection, even when SP was diluted 3200-fold. Subsequent fractionation by continuous flow acid-urea (AU)-PAGE and antiviral testing revealed that cationic polypeptides within SP were responsible for the majority of anti-HIV-1 activity. A proteomic approach was utilized to resolve and identify 52 individual cationic polypeptides that contribute to the aggregate anti-HIV-1 activity of SP. One peptide fragment of semenogelin I, termed SG-1, was purified from SP by a multi-step chromatographic approach, protein sequenced, and determined to exhibit anti-HIV-1 activity against HIV-1. Anti-HIV-1 activity was transient, as whole SP incubated for prolonged time intervals exhibited a proportional decrease in anti-HIV-1 activity that was directly attributed to the degradation of semenogelin I peptides. Collectively, these results indicate that the cationic polypeptide fraction of SP is active against HIV-1, and that semenogelin-derived peptides contribute to the intrinsic anti-HIV-1 activity of SP. Conversely, naturally occurring peptidic fragments from the SP-derived prostatic acid phosphatase (PAP) have been reported to form amyloid fibrils called SEVI capable of enhancing HIV-1 infection in vitro. In order to understand the biological consequence of this proviral effect, we extended these studies in the presence of human SP. PAP-derived peptides were agitated to form SEVI and incubated in the presence or absence of SP. While PAP-derived peptides and SEVI alone were proviral, the presence of 1% SP ablated their proviral activity in several different anti-HIV-1 assays. The anti-HIV-1 activity of SP was concentration dependent and was reduced following filtration. Supraphysiological concentrations of PAP peptides and SEVI incubated with diluted SP were degraded within hours, with SP exhibiting proteolytic activity at dilutions as high as 1:200. Sub-physiological concentrations of two prominent proteases of SP, prostate-specific antigen (PSA) and matriptase, could degrade physiological and supraphysiological concentrations of PAP peptides and SEVI. While human SP is a complex biological fluid, containing both antiviral and proviral factors, our results suggest that PAP peptides and SEVI may be subject to naturally occurring proteolytic components capable of reducing their proviral activity. Our studies demonstrate the overall antiviral activity of human SP, but there is still a critical need for effective topical vaginal microbicides that can prevent HIV-1 transmission. The synthetic human retrocyclins are cyclic antimicrobial peptides that are remarkably active against HIV-1, and are being developed as topical vaginal microbicides. Herein, we assessed whether the putative proviral SEVI was able to adversely affect the anti-HIV-1 activity of the retrocyclin analog RC-101. While SEVI alone enhanced viral infection, this effect was completely negated in the presence of RC-101. Retrocyclins such as RC-101 are inhibitors of HIV-1 entry, by preventing gp41-mediated viral fusion. Interestingly, using an HIV-1 reverse transcriptase (RT) specific assay, we also determined that RC-101 directly inhibited the activity of RT in a dose dependent manner, suggesting a secondary mechanism of viral inhibition. Our group has determined that RC-101 induces only a modest level of resistance in HIV, which may be due in part to RC-101\u27s dual mechanisms of viral inhibition

Let’s Talk! Facilitating a Faculty Learning Community Using a Critical Friends Group Approach

This article focuses on the complex process of facilitating a Critical Friends Group as a form of a professional learning community by teacher education faculty. During a three-year initiative, seven faculty members created a forum for collegial conversations regarding pedagogical dilemmas in efforts of improving teaching practice and student achievement. Critical Friends Groups use protocol guides to actively engage its members in learning, thinking, reading and discussing dilemmas from interdisciplinary perspectives. This article reviews the literature of Critical Friends Groups, the work of this particular Critical Friends Group and concludes by providing a rationale for sustainability of Critical Friends Groups in Institutions of Higher Education

FOOD SAFETY INNOVATION IN THE UNITED STATES: EVIDENCE FROM THE MEAT INDUSTRY

Recent industry innovations improving the safety of the Nation's meat supply range from new pathogen tests, high-tech equipment, and supply chain management systems, to new surveillance networks. Despite these and other improvements, the market incentives that motivate private firms to invest in innovation seem to be fairly weak. Results from an ERS survey of U.S. meat and poultry slaughter and processing plants and two case studies of innovation in the U.S. beef industry reveal that the industry has developed a number of mechanisms to overcome that weakness and to stimulate investment in food safety innovation. Industry experience suggests that government policy can increase food safety innovation by reducing informational asymmetries and strengthening the ability of innovating firms to appropriate the benefits of their investments.Food safety, innovation, meat, asymmetric information, Beef Steam Pasteurization System, Bacterial Pathogen Sampling and Testing Program, Food Consumption/Nutrition/Food Safety, Livestock Production/Industries,

Cell Attachment and Osteoinductive Properties of Tissue Engineered, Demineralized Bone Fibers for Bone Void Filling Applications

Demineralized bone matrices (DBMs) have been used in a wide variety of clinical applications involving bone repair. Ideally, DBMs should provide osteoinductive and osteoconductive properties, while offering versatile handling capabilities. With this, a novel fiber technology, LifeNet Health-Moldable Demineralized Fibers (L-MDF), was recently developed. Human cortical bone was milled and demineralized to produce L-MDF. Subsequently, the fibers were lyophilized and terminally sterilized using low-dose and low-temperature gamma irradiation. Using L929 mouse fibroblasts, L-MDF underwent cytotoxicity testing to confirm lack of a cytotoxic response. An alamarBlue assay and scanning electron microscopy demonstrated L-MDF supported the cellular function and attachment of bone-marrow mesenchymal stem cells (BM-MSCs). Using an enzyme-linked immunosorbent assay, L-MDF demonstrated BMP-2 and 7 levels similar to those reported in the literature. In vivo data from an athymic mouse model implanted with L-MDF demonstrated the formation of new bone elements and blood vessels. This study showed that L-MDF have the necessary characteristics of a bone void filler to treat osseous defects

Targeted muscle reinnervation for the management of pain in the setting of major limb amputation

The life altering nature of major limb amputations may be further complicated by neuroma formation in up to 60% of the estimated 2 million major limb amputees in the United States. This can be a source of pain and functional limitation of the residual limb. Pain associated with neuromas may limit prosthetic limb use, require reoperation, lead to opioid dependence, and dramatically reduce quality of life. A number of management options have been described including excision alone, excision with repair, excision with transposition, and targeted muscle reinnervation. Targeted muscle reinnervation has been shown to reduce phantom limb and neuroma pain for patients with upper and lower extremity amputations. It may be performed at the time of initial amputation to prevent pain development or secondarily for the treatment of established pain. Encouraging outcomes have been reported, and targeted muscle reinnervation is emerging as a leading surgical technique for pain prevention in patients undergoing major limb amputations and pain management in patients with pre-existing amputations

The VWFA Is the Home of Orthographic Learning When Houses Are Used as Letters

Learning to read specializes a portion of the left mid-fusiform cortex for printed word recognition, the putative visual word form area (VWFA). This study examined whether a VWFA specialized for English is sufficiently malleable to support learning a perceptually atypical second writing system. The study utilized an artificial orthography, HouseFont, in which house images represent English phonemes. House images elicit category-biased activation in a spatially distinct brain region, the so-called parahippocampal place area (PPA). Using house images as letters made it possible to test whether the capacity for learning a second writing system involves neural territory that supports reading in the first writing system, or neural territory tuned for the visual features of the new orthography. Twelve human adults completed two weeks of training to establish basic HouseFont reading proficiency and underwent functional neuroimaging pre and post-training. Analysis of three functionally defined regions of interest (ROIs), the VWFA, and left and right PPA, found significant pre-training versus post-training increases in response to HouseFont words only in the VWFA. Analysis of the relationship between the behavioral and neural data found that activation changes from pre-training to post-training within the VWFA predicted HouseFont reading speed. These results demonstrate that learning a new orthography utilizes neural territory previously specialized by the acquisition of a native writing system. Further, they suggest VWFA engagement is driven by orthographic functionality and not the visual characteristics of graphemes, which informs the broader debate about the nature of category-specialized areas in visual association cortex

Shelf Edge Tide Correlated Eddies Along the Southeastern United States

High frequency radar observations in the Southeastern United States have revealed sequences of small short‐lived cyclonic eddies along the shoreward edge of the Gulf Stream, that spin up as the local tide turns alongshelf antiparallel to the Stream. Eddies propagate equatorward along the shelf edge, sometimes progressing shoreward before dissipating one to three hours later. They are distinctly different from Gulf Stream meander eddies, which propagate poleward. In this article, radar and mooring data are used to establish three important aspects of these neweddies: they represent an instability process operating at a previously unidentified frequency, scale, and cross‐Stream position; they contribute to shoreward momentum fluxes,defining a link between Gulf Stream and outer shelf subtidal variability and illustrating a mechanism to justify locally large horizontal eddy viscosity estimates; and they transport properties across the shelf edge, importing nutrients onto the shelf and transferring heat between the Gulf Stream and the coastal ocean

Timing of Moderate Level Prenatal Alcohol Exposure Influences Gene Expression of Sensory Processing Behavior in Rhesus Monkeys

Sensory processing disorder, characterized by over- or under-responsivity to non-noxious environmental stimuli, is a common but poorly understood disorder. We examined the role of prenatal alcohol exposure, serotonin transporter gene polymorphic region variation (rh5-HTTLPR), and striatal dopamine (DA) function on behavioral measures of sensory responsivity to repeated non-noxious sensory stimuli in macaque monkeys. Results indicated that early gestation alcohol exposure induced behavioral under-responsivity to environmental stimuli in monkeys carrying the short (s) rh5-HTTLPR allele compared to both early-exposed monkeys homozygous for the long (l) allele and monkeys from middle-to-late exposed pregnancies and controls, regardless of genotype. Moreover, prenatal timing of alcohol exposure altered the relationship between sensory scores and DA D2R availability. In early-exposed monkeys, a positive relationship was shown between sensory scores and DA D2R availability, with low or blunted DA function associated with under-responsive sensory function. The opposite pattern was found for the middle-to-late gestation alcohol-exposed group. These findings raise questions about how the timing of prenatal perturbation and genotype contributes to effects on neural processing and possibly alters neural connections