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1.  Small molecule-mediated refolding and activation of myosin motor function 
eLife  2014;3:e01603.
The small molecule EMD 57033 has been shown to stimulate the actomyosin ATPase activity and contractility of myofilaments. Here, we show that EMD 57033 binds to an allosteric pocket in the myosin motor domain. EMD 57033-binding protects myosin against heat stress and thermal denaturation. In the presence of EMD 57033, ATP hydrolysis, coupling between actin and nucleotide binding sites, and actin affinity in the presence of ATP are increased more than 10-fold. Addition of EMD 57033 to heat-inactivated β-cardiac myosin is followed by refolding and reactivation of ATPase and motile activities. In heat-stressed cardiomyocytes expression of the stress-marker atrial natriuretic peptide is suppressed by EMD 57033. Thus, EMD 57033 displays a much wider spectrum of activities than those previously associated with small, drug-like compounds. Allosteric effectors that mediate refolding and enhance enzymatic function have the potential to improve the treatment of heart failure, myopathies, and protein misfolding diseases.
eLife digest
Our muscles contain large numbers of ‘motor proteins’ called myosins. To contract a muscle, many myosin molecules expend energy to ‘walk’ along a filament made from another molecule, called actin, and generate a pulling force. Like other proteins, myosins must fold into the correct shape to work, but high temperatures or other types of stress can disrupt their ability to adopt or maintain the correct shape. Misfolding of myosins, for example, can result in muscular diseases, including those that affect the heart; so there is an ongoing effort to find compounds that can stabilize protein folding and treat these diseases.
The small molecule EMD 57033 was discovered over 20 years ago, and its ability to increase the strength of muscle contractions suggested that it could be used to treat chronic heart failure, but the risk of side effects limited its clinical use. The effectiveness of other compounds that improve cardiac muscle function is still routinely compared to EMD 57033, however the exact mechanism responsible for its effect on muscle tissue remained unknown.
Now Radke, Taft et al. have identified the part of the myosin protein that EMD 57033 binds to, and shown how this activates muscle contraction. The experiments also, unexpectedly, revealed that EMD 57033 is able to convert misfolded myosin back into the fully functional form. By revealing this refolding effect, the findings of Radtke, Taft et al. suggest that similar small molecules could be used as drugs for the treatment of protein misfolding diseases, muscular diseases, and heart failure.
PMCID: PMC3920478  PMID: 24520162
myosin; protein folding; allostery; pharmacological chaperone; Dictyostelium; human; rat
2.  Ecological Energetics of an Abundant Aerial Insectivore, the Purple Martin 
PLoS ONE  2013;8(9):e76616.
The atmospheric boundary layer and lower free atmosphere, or aerosphere, is increasingly important for human transportation, communication, environmental monitoring, and energy production. The impacts of anthropogenic encroachment into aerial habitats are not well understood. Insectivorous birds and bats are inherently valuable components of biodiversity and play an integral role in aerial trophic dynamics. Many of these insectivores are experiencing range-wide population declines. As a first step toward gaging the potential impacts of these declines on the aerosphere’s trophic system, estimates of the biomass and energy consumed by aerial insectivores are needed. We developed a suite of energetics models for one of the largest and most common avian aerial insectivores in North America, the Purple Martin (Prognesubis). The base model estimated that Purple Martins consumed 412 (± 104) billion insects*y-1 with a biomass of 115,860 (± 29,192) metric tonnes*y-1. During the breeding season Purple Martins consume 10.3 (+ 3.0) kg of prey biomass per km3 of aerial habitat, equal to about 36,000 individual insects*km-3. Based on these calculations, the cumulative seasonal consumption of insects*km-3 is greater in North America during the breeding season than during other phases of the annual cycle, however the maximum daily insect consumption*km-3 occurs during fall migration. This analysis provides the first range-wide quantitative estimate of the magnitude of the trophic impact of this large and common aerial insectivore. Future studies could use a similar modeling approach to estimate impacts of the entire guild of aerial insectivores at a variety of temporal and spatial scales. These analyses would inform our understanding of the impact of population declines among aerial insectivores on the aerosphere’s trophic dynamics.
PMCID: PMC3783489  PMID: 24086755
3.  Psychiatric Risk Factors for HIV Disease Progression: The Role of Inconsistent Patterns of Anti-Retroviral Therapy Utilization 
In the era of anti-retroviral therapy (ART), depression and substance use predict hastened HIV disease progression but the underlying biological or behavioral mechanisms that explain these effects are not fully understood.
Using outcome data from 603 participants enrolled in a randomized controlled trial of a behavioral intervention, binary logistic and linear regression were employed to examine whether inconsistent patterns of ART utilization partially mediated the effects of depression and substance use on higher HIV viral load over a 25-month follow-up.
Elevated affective symptoms of depression independently predicted ART discontinuation (Adjusted OR [AOR] = 1.39, 95% CI = 1.08 – 1.78), and use of stimulants at least weekly independently predicted intermittent ART utilization (AOR = 2.62, 95% CI = 1.45 – 4.73). After controlling for the average self-reported percentage of ART doses taken and baseline T-helper (CD4+) count, elevated depressive symptoms predicted a 50% higher mean viral load, and weekly stimulant use predicted a 137% higher mean viral load. These effects became non-significant after accounting for inconsistent patterns of ART utilization, providing evidence of partial mediation.
Inconsistent patterns of ART utilization may partially explain the effects of depression and stimulant use on hastened HIV disease progression.
PMCID: PMC3494991  PMID: 21116186
Access; Adherence; Antiretroviral; Cocaine; Depression; Disease Progression; Highly Active; HIV/AIDS; HIV Viral Load; Methamphetamine; Substance Use; Utilization
5.  Climate and Weather Impact Timing of Emergence of Bats 
PLoS ONE  2012;7(8):e42737.
Interest in forecasting impacts of climate change have heightened attention in recent decades to how animals respond to variation in climate and weather patterns. One difficulty in determining animal response to climate variation is lack of long-term datasets that record animal behaviors over decadal scales. We used radar observations from the national NEXRAD network of Doppler weather radars to measure how group behavior in a colonially-roosting bat species responded to annual variation in climate and daily variation in weather over the past 11 years. Brazilian free-tailed bats (Tadarida brasiliensis) form dense aggregations in cave roosts in Texas. These bats emerge from caves daily to forage at high altitudes, which makes them detectable with Doppler weather radars. Timing of emergence in bats is often viewed as an adaptive trade-off between emerging early and risking predation or increased competition and emerging late which restricts foraging opportunities. We used timing of emergence from five maternity colonies of Brazilian free-tailed bats in south-central Texas during the peak lactation period (15 June–15 July) to determine whether emergence behavior was associated with summer drought conditions and daily temperatures. Bats emerged significantly earlier during years with extreme drought conditions than during moist years. Bats emerged later on days with high surface temperatures in both dry and moist years, but there was no relationship between surface temperatures and timing of emergence in summers with normal moisture levels. We conclude that emergence behavior is a flexible animal response to climate and weather conditions and may be a useful indicator for monitoring animal response to long-term shifts in climate.
PMCID: PMC3411708  PMID: 22876331
7.  Radar aeroecology: exploring the movements of aerial fauna through radio-wave remote sensing 
Biology Letters  2012;8(5):698-701.
An international and interdisciplinary Radar Aeroecology Workshop was held at the National Weather Center on 5–6 March 2012 on the University of Oklahoma campus in Norman, OK, USA. The workshop brought together biologists, meteorologists, radar engineers and computer scientists from 22 institutions and four countries. A central motivation behind the Radar Aeroecology Workshop was to foster better communication and cross-disciplinary collaboration among a diverse spectrum of researchers, and promote a better understanding of the ecology of animals that move within and use the Earth's lower atmosphere (aerosphere).
PMCID: PMC3440989  PMID: 22628093
radar; aeroecology; phenology; migration
8.  Reactions of Heterosexual African-American Men to Women’s Condom Negotiation Strategies 
Journal of sex research  2010;47(6):539-551.
This study describes responses of 172 single heterosexual African American men, ages 18–35, to condom negotiation attempts. Strategies used included reward, coercive, legitimate, expert, referent, and informational strategies, based on Raven’s (1992) influence model. The purpose was: 1) to identify strategies influencing participant acquiescence to request, and 2) to identify predictors of participant compliance/refusal to comply with negotiation attempts. Participants viewed six videotape segments showing an actress, portrayed in silhouette, speaking to the viewer as a ‘steady partner’. After each segment, participants completed measures of: request compliance, positive and negative affect, and attributions concerning the model and themselves. No significant differences were found in men’s ratings across all vignettes. However, differences in response existed across subgroups of individuals, suggesting that while the strategy used had little impact on participant response, the act of suggesting condom use produced responses that differed across participant subgroups. Subgroups differed on levels of AIDS risk knowledge, STD history, and experience with sexual coercion. Also, the “least-willing-to-use” subgroup was highest in anger/rejection and least likely to make attributions of caring for partner. Effective negotiation of condom use with a male sexual partner may not be determined as much by specific strategy used as by partner characteristics.
PMCID: PMC2888974  PMID: 19760529
9.  Cerebral Blood Flow Heterogeneity in Preterm Sheep: Lack of Physiological Support for Vascular Boundary Zones in Fetal Cerebral White Matter 
Periventricular white matter (PVWM) injury is the leading cause of chronic neurological disability in survivors of prematurity. To address the role of cerebral ischemia in the pathogenesis of this injury, we tested the hypothesis that immaturity of spatially distal vascular “end” or “border” zones predisposes the PVWM to be more susceptible to falls in cerebral blood flow (CBF) than more proximal regions, such as the cerebral cortex. We used fluorescently-labeled microspheres to quantify regional CBF in situ in the 0.65 gestation fetal sheep in histopathologically-defined 3-dimensional regions by means of post hoc digital dissection and co-registration algorithms.
Basal flow in PVWM was significantly lower than gyral white matter and cerebral cortex, but was equivalent in superficial, middle and deep PVWM. Absolute and relative CBF (expressed as percentage of basal) CBF did not differ during ischemia or reperfusion between the PVWM and more superficial gyral white matter or cortex. Moreover, CBF during ischemia and reperfusion was equivalent at three distinct levels of the PVWM. Absolute and relative CBF during ischemia and reperfusion was not predictive of the severity of PVWM injury, as defined by TUNEL staining. However, the magnitude of ischemia to the cerebral cortex directly correlated with lesion severity (r= −0.48, p<.05). Hence, the PVWM did not display unique CBF disturbances that accounted for the distribution of injury. These results suggest that previously-defined cellular-maturational factors have a greater influence on the vulnerability of PVWM to ischemic injury than the presence of immature vascular-boundary zones.
PMCID: PMC3139427  PMID: 18091757
10.  Lessons Learned about Behavioral Science and Acute/Early HIV Infection. The NIMH Multisite Acute HIV Infection Study: V 
AIDS and behavior  2009;13(6):1068-1074.
Acute/early HIV infection is a period of heightened HIV transmission and a window of opportunity for intervention to prevent onward disease transmission. The NIMH Multisite Acute HIV Infection (AHI) Study was an exploratory initiative aimed at determining the feasibility of recruiting persons with AHI into research, assessing their psychosocial and behavioral characteristics, and examining short-term changes in these characteristics. This paper reports on lessons learned in the study, including: (1) the need to establish the cost-effectiveness of AHI testing; (2) challenges to identifying persons with AHI; (3) the need to increase awareness of acute-phase HIV transmission risks; (4) determining the goals of behavioral interventions following AHI diagnosis; and (5) the need for “rapid response” public health systems that can move quickly enough to intervene while persons are still in the AHI stage. There are untapped opportunities for behavioral and medical science collaborations in these areas that could reduce the incidence of HIV infection.
PMCID: PMC2787956  PMID: 19504179
Acute HIV infection; HIV prevention; Public health
11.  HSP72 Protects Cells from ER Stress-induced Apoptosis via Enhancement of IRE1α-XBP1 Signaling through a Physical Interaction 
PLoS Biology  2010;8(7):e1000410.
The cytosolic chaperone Hsp72 directly modulates stress sensing in response to the accumulation of unfolded proteins in the endoplasmic reticulum and promotes cell survival.
Endoplasmic reticulum (ER) stress is a feature of secretory cells and of many diseases including cancer, neurodegeneration, and diabetes. Adaptation to ER stress depends on the activation of a signal transduction pathway known as the unfolded protein response (UPR). Enhanced expression of Hsp72 has been shown to reduce tissue injury in response to stress stimuli and improve cell survival in experimental models of stroke, sepsis, renal failure, and myocardial ischemia. Hsp72 inhibits several features of the intrinsic apoptotic pathway. However, the molecular mechanisms by which Hsp72 expression inhibits ER stress-induced apoptosis are not clearly understood. Here we show that Hsp72 enhances cell survival under ER stress conditions. The UPR signals through the sensor IRE1α, which controls the splicing of the mRNA encoding the transcription factor XBP1. We show that Hsp72 enhances XBP1 mRNA splicing and expression of its target genes, associated with attenuated apoptosis under ER stress conditions. Inhibition of XBP1 mRNA splicing either by dominant negative IRE1α or by knocking down XBP1 specifically abrogated the inhibition of ER stress-induced apoptosis by Hsp72. Regulation of the UPR was associated with the formation of a stable protein complex between Hsp72 and the cytosolic domain of IRE1α. Finally, Hsp72 enhanced the RNase activity of recombinant IRE1α in vitro, suggesting a direct regulation. Our data show that binding of Hsp72 to IRE1α enhances IRE1α/XBP1 signaling at the ER and inhibits ER stress-induced apoptosis. These results provide a physical connection between cytosolic chaperones and the ER stress response.
Author Summary
The endoplasmic reticulum (ER) is responsible for production and folding of secreted proteins. When the protein folding machinery cannot keep up with demand, misfolded proteins accumulate, leading to a state of ER stress that contributes to diseases such as cancer, neurodegeneration, diabetes, and myocardial infarct. The unfolded protein response (UPR) is an intracellular signaling network activated in response to ER stress. It initially tries to restore normal ER homeostasis, but if the damage is too severe cell death pathways mediated by cytosolic and mitochondrial proteins are activated. The molecular mechanisms involved in the transition of the UPR from a protective to an apoptotic phase are unclear. IRE1α is an ER membrane protein that acts as a sensor of ER stress. A number of proteins can interact with IRE1α to regulate its function, which includes an RNase activity responsible for inducing the unconventional splicing of the transcript for a downstream signaling protein called XBP-1. Here, we report that Hsp72, a stress-inducible cytosolic molecular chaperone, can bind to and enhance the RNase activity of IRE1α, providing an important molecular link between the heat shock response and the ER stress response. Importantly, increased production of active XBP-1 was necessary for Hsp72 to exert its prosurvival effect under conditions of ER stress. Our results suggest a mechanism whereby Hsp72 overexpression helps cells adapt to long-term ER stress in vivo by enhancing the pro-survival effects of the IRE1α/XBP1 branch of the UPR.
PMCID: PMC2897763  PMID: 20625543
12.  BiP Binding to the ER-Stress Sensor Ire1 Tunes the Homeostatic Behavior of the Unfolded Protein Response 
PLoS Biology  2010;8(7):e1000415.
Computational modeling and experimentation in the unfolded protein response reveals a role for the ER-resident chaperone protein BiP in fine-tuning the system's response dynamics.
The unfolded protein response (UPR) is an intracellular signaling pathway that counteracts variable stresses that impair protein folding in the endoplasmic reticulum (ER). As such, the UPR is thought to be a homeostat that finely tunes ER protein folding capacity and ER abundance according to need. The mechanism by which the ER stress sensor Ire1 is activated by unfolded proteins and the role that the ER chaperone protein BiP plays in Ire1 regulation have remained unclear. Here we show that the UPR matches its output to the magnitude of the stress by regulating the duration of Ire1 signaling. BiP binding to Ire1 serves to desensitize Ire1 to low levels of stress and promotes its deactivation when favorable folding conditions are restored to the ER. We propose that, mechanistically, BiP achieves these functions by sequestering inactive Ire1 molecules, thereby providing a barrier to oligomerization and activation, and a stabilizing interaction that facilitates de-oligomerization and deactivation. Thus BiP binding to or release from Ire1 is not instrumental for switching the UPR on and off as previously posed. By contrast, BiP provides a buffer for inactive Ire1 molecules that ensures an appropriate response to restore protein folding homeostasis to the ER by modulating the sensitivity and dynamics of Ire1 activity.
Author Summary
Secreted and membrane-spanning proteins constitute one of every three proteins produced by a eukaryotic cell. Many of these proteins initially fold and assemble in the endoplasmic reticulum (ER). A variety of physiological and environmental conditions can increase the demands on the ER, overwhelming the ER protein folding machinery. To restore homeostasis in response to ER stress, cells activate an intracellular signaling pathway called the unfolded protein response (UPR) that adjusts the folding capacity of the ER according to need. Its failure impairs cell viability and has been implicated in numerous disease states. In this study, we quantitatively interrogate the homeostatic capacity of the UPR. We arrive at a mechanistic model for how the ER stress sensor Ire1 cooperates with its binding partner BiP, a highly redundant ER chaperone, to fine-tune UPR activity. Moving between a predictive computational model and experiments, we show that BiP release from Ire1 is not the switch that activates Ire1; rather, BiP modulates Ire1 activation and deactivation dynamics. BiP binding to Ire1 and its dissociation in an ER stress-dependent manner buffers the system against mild stresses. Furthermore, BiP binding accelerates Ire1 deactivation when stress is removed. We conclude that BiP binding to Ire1 serves to fine-tune the dynamic behavior of the UPR by modulating its sensitivity and shutoff kinetics. This function of the interaction between Ire1 and BiP may be a general paradigm for other systems in which oligomer formation and disassembly must be finely regulated.
PMCID: PMC2897766  PMID: 20625545
This study recruited four sociocentric networks (n = 156) of men who have sex with men in Budapest, Hungary, and St. Petersburg, Russia. The sampling approach was based on identifying an initial “seed” in the community for each network, and then recruiting three successive friendship group waves out from the seed. HIV prevalence in the networks was 9%, and the composite rate of other sexually transmitted diseases was 6%. 57% of participants reported both main and casual male partners, and two thirds reported unprotected anal intercourse in the past 3 months. Fifty-five percent of men’s most recent anal intercourse acts were with nonexclusive partners, and 56% of most recent anal intercourse acts were unprotected. Sexual risk predictors were generally consistent with behavioral science theory. In addition, risk was associated with more often talking with friends about AIDS, higher ecstasy use, and less often drinking. Sociocentric social network sampling approaches are feasible and constitute a modality for reaching hidden high-risk populations inaccessible through conventional methods.
PMCID: PMC2802572  PMID: 19519240
14.  HIV Testing Rates, Testing Locations, and Healthcare Utilization among Urban African-American Men 
African-American men bear a disproportionate burden of HIV infection in the United States. HIV testing is essential to ensure that HIV-infected persons are aware of their HIV-positive serostatus, can benefit from early initiation of antiretroviral therapy, and can reduce their risk of transmitting the virus to sex partners. This cross-sectional study assessed HIV testing history and healthcare utilization among 352 young African-American men recruited in urban neighborhoods in a Midwestern city. The self-administered survey measured sexual risk behaviors, factors associated with HIV testing, and barriers to testing. The acceptability of community venues for HIV testing was also assessed. Of the respondents, 76% had been tested for HIV at some time in their lives, 52% during the prior 12 months. Of the participants, 70% had unprotected intercourse during the prior 12 months, 26% with two or more partners. Nearly three-quarters (72%) of participants had seen a healthcare provider during the prior year. In univariate analyses, those who had at least one healthcare provider visit during the prior 12 months and those who had a primary doctor were more likely to have been tested in the prior 12 months. In multivariate analyses, having a regular doctor who recommended HIV testing was the strongest predictor of having been tested [OR = 7.38 (3.55, 15.34)]. Having been diagnosed or treated for a sexually transmitted disease also was associated with HIV testing [OR = 1.83 (1.04, 3.21)]. The most commonly preferred testing locations were medical settings. However, community venues were acceptable alternatives. Having a primary doctor recommend testing was strongly associated with HIV testing and most HIV testing occurred at doctors’ offices. But, a substantial proportion of persons were not tested for HIV, even if seen by a doctor. These results suggest that HIV testing could be increased within the healthcare system by increasing the number of recommendations made by physicians to patients. The use of community venues for HIV testing sites could further increase the number of persons tested for HIV.
PMCID: PMC2629519  PMID: 19067176
HIV; HIV testing; Healthcare utilization; Healthcare access; Community-based HIV testing; African American; Urban; Inner city
15.  Condom Use Negotiation in Heterosexual African-American Adults: Responses to Types of Social Power-Based Strategies 
Journal of sex research  2008;45(2):150-163.
Little research has been performed on how people respond to different strategies to negotiate condom use in sexual situations, and whether certain strategies tend to be perceived as more or less effective in condom use negotiation. This study examined gender differences and preferences in the use of and response to six different styles of condom use negotiation with a hypothetical sexual partner of the opposite gender. Participants were 51 heterosexually-active African-American men and women between the ages of 18 and 35, attending an inner-city community center. Study participants completed a semi-structured qualitative interview in which they were presented with six negotiation strategies —coercive, reward, legitimate, expert, referent, and informational--based on Raven’s 1992 Power/Interaction Model of Interpersonal Influence. Results showed that women participants responded best to referent, reward, and legitimate strategies, and worst to informational tactics. Men participants responded best to reward strategies, and worst to coercion to use condoms. Further, responses given by a subset of both women—and, to a greater extent, men--indicated that use of negotiation tactics involving coercion to use condoms may result in negative or angry reactions. Finally, response to strategies may vary with the value of the relationship as viewed by the target of negotiation. Implications for HIV prevention programs and media campaigns are discussed.
PMCID: PMC2753393  PMID: 18569536
16.  Influence of Coping, Social Support, and Depression on Subjective Health Status Among HIV-Positive Adults With Different Sexual Identities 
The authors examined associations between psychosocial variables (coping self-efficacy, social support, and cognitive depression) and subjective health status among a large national sample (N = 3,670) of human immunodeficiency virus (HIV)-positive persons with different sexual identities. After controlling for ethnicity, heterosexual men reported fewer symptoms than did either bisexual or gay men and heterosexual women reported fewer symptoms than did bisexual women. Heterosexual and bisexual women reported greater symptom intrusiveness than did heterosexual or gay men. Coping self-efficacy and cognitive depression independently explained symptom reports and symptom intrusiveness for heterosexual, gay, and bisexual men. Coping self-efficacy and cognitive depression explained symptom intrusiveness among heterosexual women. Cognitive depression significantly contributed to the number of symptom reports for heterosexual and bisexual women and to symptom intrusiveness for lesbian and bisexual women. Individuals likely experience HIV differently on the basis of sociocultural realities associated with sexual identity. Further, symptom intrusiveness may be a more sensitive measure of subjective health status for these groups.
PMCID: PMC2653049  PMID: 19064372
coping; depression; HIV; sexual identity; symptoms; social support
17.  A Behavioral Intervention Reduces HIV Transmission Risk by Promoting Sustained Serosorting Practices Among HIV-Infected Men Who Have Sex with Men 
To examine factors that explain the effect of a cognitive-behavioral intervention on reductions in HIV transmission risk among HIV-infected men who have sex with men (MSM).
Of the 1,910 HIV-infected MSM screened, 616 participants considered to be at risk of transmitting HIV were randomized to a 15-session, individually delivered cognitive-behavioral intervention (n = 301) or a wait-list control (n = 315).
Consistent with previous intent-to-treat findings, there was an overall reduction in transmission risk acts among MSM in both intervention and control arms, with significant intervention effects observed at the 5, 10, 15, and 20 month assessments (Risk Ratios = .78, .62, .48, and .38, respectively). These intervention-related decreases in HIV transmission risk acts appeared to be partially due to sustained serosorting practices. MSM in the intervention condition reported a significantly greater proportion of sexual partners who were HIV-infected at the 5 and 10 month assessments (Risk Ratio = 1.14 and 1.18).
The Healthy Living Project, a cognitive-behavioral intervention, is efficacious in reducing transmission risk acts among MSM. This appears to have been due in large part to the fact that MSM in the intervention condition reported sustained serosorting practices.
PMCID: PMC2659703  PMID: 18989221
Men Who Have Sex with Men; Prevention with Positives; Randomized Controlled Trial; Prevention Case Management
18.  Severely Mentally Ill Women’s HIV Risk: The Influence of Social Support, Substance Use, and Contextual Risk Factors 
In structured interviews with 96 women with severe mental illness, nearly two-thirds had not used condoms during sexual intercourse in the past 3 months, more than two-thirds had sex with multiple partners, and almost one-third had been treated for a sexually transmitted infection (STI) in the past year. Women who reported fewer sexual risk context factors, such as having sex with someone the participant did not know or transactional sex, had fewer sexual partners. Larger social support networks were associated with less frequent sex after drug use. In turn, women who less often had sex after using drugs had unprotected intercourse less frequently.
PMCID: PMC2410084  PMID: 17143730
sexual risk behavior; HIV/AIDS; serious mental illness; women’s health
19.  Defining, Designing, Implementing, and Evaluating Phase 4 HIV Prevention Effectiveness Trials for Vulnerable Populations 
The efficacy of behavioral HIV prevention interventions has been convincingly demonstrated in a large number of randomized controlled phase 3 research outcome trials. Little research attention has been directed toward studying the effectiveness of the same interventions when delivered by providers to their own clients or community members, however. This article argues for the need to conduct phase 4 effectiveness trials of HIV prevention interventions that have been found efficacious in the research arena. Such trials can provide important information concerning the impact of interventions when applied in heterogeneous “real-world” circumstances. This article raises design issues and methodologic questions that need to be addressed in the conduct of phase 4 trials of behavioral interventions. These issues include the selection and training of service providers engaged in such trials, maintenance of fidelity to intervention protocol in provider-delivered interventions, determination of intervention core elements versus aspects that require tailoring, selection of relevant phase 4 study outcomes, interpretation of findings indicative of field effectiveness, sustainability, and other aspects of phase 4 trial design.
PMCID: PMC2409151  PMID: 18301131
effectiveness trial; HIV prevention; phase 4 trial; methodology
20.  HIV risk behaviour patterns, predictors, and sexually transmitted disease prevalence in the social networks of young men who have sex with men in St Petersburg, Russia 
HIV seroconversions and sexually transmitted diseases (STDs) are often clustered in social networks within community populations. The present study was carried out among men who have sex with men in Russia, where a major HIV epidemic is unfolding, and where social networks have played a historically important role. In all, 38 social networks were recruited into the study, and members of all networks (n = 187) completed risk behaviour assessments and were tested for STDs. About 17% of participants had STDs, and 10% of men had syphilis. Over 64% of men had recent unprotected anal intercourse (UAI), including 51% who did so with main partners, 30% who did so with casual partners, and 32% who had UAI with multiple male partners. The strongest predictor of all risk behaviour indicators and STDs was the social network, to which an individual belonged, supplemented by peer norm perceptions and intentions to practise safer sex. There was a high level of correspondence in behaviour between the social leader of a network and its other members. Social networks should be directly targeted in HIV prevention efforts.
PMCID: PMC1514189  PMID: 16409680
HIV/AIDS; social networks; men who have sex with men; gay/bisexual men; sexually transmitted diseases; risk behaviour
21.  Psychological Distress, Substance Use, and Adjustment among Parents Living with HIV 
Background: Being a parent, especially a custodial parent, living with HIV was anticipated to increase psychological distress and challenges to self-care.
Methods: Mental health symptoms, substance use, and health care utilization were assessed among 3,818 HIV-infected adults, including custodial parents, noncustodial parents, and nonparents, in four AIDS epicenters.
Results: Custodial parents demonstrated significantly poorer medication adherence and attendance at medical appointments, but were similar to nonparents and noncustodial parents in mental health symptoms and treatment utilization for mental health and substance use problems. Noncustodial parents demonstrated the highest levels of recent substance use and substance abuse treatment. Many of the apparent psychosocial disadvantages exhibited by parents were moderated by other markers of risk, such as African-American ethnicity, lack of current employment income, and injection drug use.
Conclusions: Interventions specific to the psychosocial stressors facing families living with HIV are needed.
PMCID: PMC1395483  PMID: 16148246
22.  Prevention of HIV and sexually transmitted diseases in high risk social networks of young Roma (Gypsy) men in Bulgaria: randomised controlled trial 
BMJ : British Medical Journal  2006;333(7578):1098.
Objective To determine the effects of a behavioural intervention for prevention of HIV and sexually transmitted diseases that identified, trained, and engaged leaders of Roma (Gypsy) men's social networks to counsel their own network members.
Design A two arm randomised controlled trial.
Setting A disadvantaged, impoverished Roma settlement in Bulgaria.
Participants 286 Roma men from 52 social networks recruited in the community.
Intervention At baseline all participants were assessed for HIV risk behaviour, tested and treated for sexually transmitted diseases, counselled in risk reduction, and randomised to intervention or control groups. Network leaders learnt how to counsel their social network members on risk prevention. Networks were followed up three and 12 months after the intervention to determine evidence of risk reduction.
Main outcome measure Occurrence of unprotected intercourse during the three months before each assessment.
Results Reported prevalence of unprotected intercourse in the intervention group fell more than in control group (from 81% and 80%, respectively, at baseline to 65% and 75% at three months and 71% and 86% at 12 months). Changes were more pronounced among men with casual partners. Effects remained strong at long term follow-up, consistent with changes in risk reduction norms in the social network. Other measures of risk reduction corroborated the intervention's effects.
Conclusions Endorsement and advice on HIV prevention from the leader of a social network produces well maintained change in the reported sexual practices in members of that network. This model has particular relevance for health interventions in populations such as Roma who may be distrustful of outsiders.
Trial registration Clinical Trials NCT00310973.
PMCID: PMC1661707  PMID: 17040924
23.  Lesbian and Bisexual Women in Small Cities—At Risk for HIV? 
Public Health Reports  1996;111(4):347-352.
Women who have sex with women are a relatively hidden group that has been overlooked in most AIDS research and prevention efforts, primarily because the efficiency of HIV transmission between female partners is believed to be low. Although data are scant, it is commonly assumed that members of this population are not at high risk for HIV infection. However, a recent study of lesbian and bisexual women living in the San Francisco Bay area reported a relatively high seroprevalence rate and has raised additional questions about this group's HIV risk. The present study, the first to focus on lesbian and bisexual women living outside major AIDS epicenters, provides additional evidence. It describes risk factors for HIV transmission among lesbian and bisexual women living in small cities in four geographic regions of the United States.
On three consecutive evenings in 1992, members of the research team distributed anonymous structured written surveys to women patrons as they entered gay bars in each of 16 small cities.
Almost 17% of bisexual respondents and 0.5% of lesbians reported having had unprotected vaginal or anal sex with a male during the two months prior to the survey. Almost 10 percent of bisexual women and 8.8% of lesbians in the sample reported a history of injection drug use. Among those women surveyed who said they had been tested, 1.4% reported they were infected with HIV.
Self-identified sexual orientation was highly consistent with recent sexual behavior. HIV risk related to sexual behavior was concentrated among self-identified bisexual women. The prevalence of injection drug use was substantial among both bisexual and lesbians. Developers of HIV risk behavior programs should take the prevalence of these risk behaviors into consideration in the design of effective HIV prevention interventions tailored to the needs of this hidden population.
PMCID: PMC1381880  PMID: 8711103
24.  Levels and Predictors of HIV Risk Behavior Among Women in Low-Income Public Housing Developments 
Public Health Reports  1995;110(6):707-713.
THE PREVALENCE OF increases in human immunodeficiency virus infection and illness rates among urban disadvantaged women underscore the urgent need for acquired immunodeficiency syndrome prevention interventions for high-risk women.
Few studies, however, have examined the factors contributing to risk in this population or predictors of risk taking and risk reduction.
A total of 148 women, most of them of racial minorities, living in low-income public housing developments completed measures designed to assess risk for human immunodeficiency virus infection and to analyze factors related to risk taking, including knowledge about acquired immunodeficiency syndrome, behavior change self-efficacy, intention to use condoms, and social norm perception about safer sex practices. History of sexually transmitted diseases, low rates of condom use, and relationships with men who were injection drug users or who were not sexually exclusive were commonly reported.
Women were divided into high- or low-risk categories based on behavior during the two preceding months. Women at low risk believed more strongly in personal efficacy of behavior change, were more committed to using condoms, and perceived risk reduction steps as more socially normative than high-risk women. Culturally tailored human immunodeficiency virus prevention interventions that address these dimensions are needed.
PMCID: PMC1381813  PMID: 8570824
25.  Integrative Cloning, Expression, and Stability of the cryIA(c) Gene from Bacillus thuringiensis subsp. kurstaki in a Recombinant Strain of Clavibacter xyli subsp. cynodontis 
A bacterial endophyte was engineered for insecticidal activity against the European corn borer. The cryIA(c) gene from Bacillus thuringiensis subsp. kurstaki was introduced into the chromosome of Clavibacter xyli subsp. cynodontis by using an integrative plasmid vector. The integration vectors pCG740 and pCG741 included the replicon pGEM5Zf(+), which is maintained in Escherichia coli but not in C. xyli subsp. cynodontis; tetM as a marker for selection in C. xyli subsp. cynodontis; and a chromosomal fragment of C. xyli subsp. cynodontis to allow for homologous recombination between the vector and the bacterial chromosome. Insertion of vector DNA into the chromosome was demonstrated by DNA hybridization. Recombinant strains MDR1.583 and MDR1.586 containing the cryIA(c) gene were shown to produce the 133,000-kDa protoxin and several smaller immunoreactive proteins. Both strains were equally toxic to insect larvae in bioassays. Significant insecticidal activity was demonstrated in planta. The cryIA(c) gene and the tetM gene introduced into strain MDR1.586 were shown to be deleted from some cells, thereby giving rise to a noninsecticidal segregant population. In DNA hybridization experiments and insect bioassays, these segregants were indistinguishable from the wild-type strain. Overall, these results demonstrate the plausibility of genetically engineered bacterial endophytes for insect control.
PMCID: PMC201340  PMID: 16349179

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