A dileucine motif in HIV-1 Nef acts as an internalization signal for CD4 downregulation and binds the AP-1 clathrin adaptor

AbstractHuman immunodeficiency virus 1 (HIV-1) Nef downregulates surface expression of CD4, an integral component of the functional HIV receptor complex, through accelerated endocytosis of surface receptors and diminished transport of CD4 from the Golgi network to the plasma membrane [1–3]. HIV-1 Nef also diminishes surface expression of major histocompatibility complex (MHC) class I antigens [4]. In the case of HIV-2 and simian immunodeficiency virus 1 (SIV-1) Nef, aminoterminal tyrosine-based motifs mediate the binding of Nef to the AP-1 and AP-2 adaptors and this interaction appears to be required for CD4 downregulation [5,6]. As these tyrosine motifs are not present in the HIV-1 Nef protein, the molecular basis for the presumed interaction of Nef with components of the endocytic machinery is unknown. Here, we identify a highly conserved dileucine motif in HIV-1 Nef that is required for downregulation of CD4. This motif acts as an internalization signal in the context of a CD8-Nef chimera or in a fusion of the interleukin-2 receptor α with an 11-amino-acid region from Nef containing the dileucine motif. Finally, HIV-1 Nef binds to the AP-1 adaptor, both in vitro and in vivo, in a dileucine-dependent manner. We conclude that this conserved dileucine motif in HIV-1 Nef serves as a key interface for interaction with components of the host protein trafficking machinery. Our findings also reveal an evolutionary difference between HIV-1 and HIV-2/SIV in which the Nef proteins utilize structurally distinct motifs for binding cellular adaptors

P16 expression and recurrent cervical intraepithelial neoplasia after cryotherapy among women living with HIV

Background: The expression of p16 protein, a surrogate marker for high-risk human papillomavirus (hrHPV), is associated with cervical dysplasia. We evaluated correlates of p16 expression at treatment for high-grade cervical lesions and its utility in predicting the recurrence of cervical intraepithelial lesions grade 2 or higher (CIN2+) following cryotherapy among women with HIV. Methods: This is a subgroup analysis of women with HIV in Kenya with baseline cervical biopsy-confirmed CIN2+ who were randomized to receive cryotherapy and followed every six-months for two-years for biopsy-confirmed recurrence of CIN2+. P16 immunohistochemistry was performed on the baseline cervical biopsy with a positive result defined as strong abnormal nuclear expression in a continuous block segment of cells (at least 10–20 cells). Results: Among the 200 women with CIN2+ randomized to cryotherapy, 160 (80%) had a baseline cervical biopsy specimen available, of whom 94 (59%) were p16-positive. p16 expression at baseline was associated with presence of any one of 14 hrHPV genotypes [Odds Ratio (OR)  =  3.2; 95% Confidence Interval (CI), 1.03–9.78], multiple lifetime sexual partners (OR  =  1.6; 95% CI, 1.03–2.54) and detectable plasma HIV viral load (\u3e1,000 copies/mL; OR  =  1.43; 95% CI, 1.01– 2.03). Longer antiretroviral therapy duration (≥2  years) at baseline had lower odds of p16 expression (OR  =  0.46; 95% CI, 0.24–0.87) than \u3c2  years of antiretroviral therapy. Fifty-one women had CIN2+ recurrence over 2-years, of whom 33 (65%) were p16-positive at baseline. p16 was not associated with CIN2+ recurrence (Hazard Ratio  =  1.35; 95% CI, 0.76–2.40). Conclusion: In this population of women with HIV and CIN2+, 41% of lesions were p16 negative and baseline p16 expression did not predict recurrence of cervical neoplasia during two-year follow up

Concordance of Self-Report and Measured Height and Weight of College Students

Objective: This study examined associations between college students\u27 self-report and measured height and weight. Methods: Participants (N = 1,686) were 77% white, 62% female, aged 18–24 years (mean ± SD, 19.1 ± 1.1 years), and enrolled at 8 US universities. Body mass index (BMI) was calculated for self-report (via online survey); trained researchers measured height and weight and categorized them as normal (18.5 to \u3c 25), overweight (25 to \u3c 30), obese (30 to \u3c 35), and morbidly obese (≥ 35). Results: Concordance of self-report vs objectively measured BMI groups using chi-square revealed that 93% were accurate, 4% were underestimated, and 2.7% were overestimated. Pearson correlations and adjusted linear regression revealed significant associations between self-report and measured BMI (r = .97; P \u3c .001) and BMI adjusted for age, gender, and race/ethnicity (R2 = .94). Concordance was also high between BMI categories (kappa = 0.77; P \u3c .001). Conclusions and Implications: Findings provide support for the utility of self-report height and weight for survey research in college students

Informed choice about breast cancer prevention: randomized controlled trial of an online decision aid intervention

Abstract Introduction Tamoxifen and raloxifene are chemopreventive drugs that can reduce women's relative risk of primary breast cancer by 50%; however, most women eligible for these drugs have chosen not to take them. The reasons for low uptake may be related to women's knowledge or attitudes towards the drugs. We aimed to examine the impact of an online breast cancer chemoprevention decision aid (DA) on informed intentions and decisions of women at high risk of breast cancer. Methods We conducted a randomized clinical trial, assessing the effect of a DA about breast cancer chemoprevention on informed choices about chemoprevention. Women (n = 585), 46- to 74-years old old, completed online baseline, post-test, and three-month follow-up questionnaires. Participants were randomly assigned to either an intervention group, a standard control group that answered questions about chemoprevention at baseline, or a three-month control group that did not answer questions about chemoprevention at baseline. The main outcome measures were whether women's intentions and decisions regarding chemoprevention drugs were informed, and whether women who viewed the DA were more likely to make informed decisions than women who did not view the DA, using a dichotomous composite variable 'informed choice' (yes/no) to classify informed decisions as those reflecting sufficient knowledge and concordance between a woman's decision and relevant attitudes. Results Analyses showed that more intervention than standard control participants (52.7% versus 5.9%) made informed decisions at post-test, P <0.001. At the three-month follow-up, differences in rates of informed choice between intervention (16.9%) and both control groups (11.8% and 8.0%) were statistically non-significant, P = 0.067. Conclusions The DA increased informed decision making about breast cancer chemoprevention, although the impact on knowledge diminished over time. This study was not designed to determine how much knowledge decision makers must retain over time. Examining informed decisions increases understanding of the impact of DAs. A standard for defining and measuring sufficient knowledge for informed decisions is needed. Trial registration ClinicalTrials.gov: NCT00967824http://deepblue.lib.umich.edu/bitstream/2027.42/112557/1/13058_2013_Article_3282.pd

Informed choice about breast cancer prevention: randomized controlled trial of an online decision aid intervention

Abstract Introduction Tamoxifen and raloxifene are chemopreventive drugs that can reduce women's relative risk of primary breast cancer by 50%; however, most women eligible for these drugs have chosen not to take them. The reasons for low uptake may be related to women's knowledge or attitudes towards the drugs. We aimed to examine the impact of an online breast cancer chemoprevention decision aid (DA) on informed intentions and decisions of women at high risk of breast cancer. Methods We conducted a randomized clinical trial, assessing the effect of a DA about breast cancer chemoprevention on informed choices about chemoprevention. Women (n = 585), 46- to 74-years old old, completed online baseline, post-test, and three-month follow-up questionnaires. Participants were randomly assigned to either an intervention group, a standard control group that answered questions about chemoprevention at baseline, or a three-month control group that did not answer questions about chemoprevention at baseline . The main outcome measures were whether women's intentions and decisions regarding chemoprevention drugs were informed, and whether women who viewed the DA were more likely to make informed decisions than women who did not view the DA, using a dichotomous composite variable 'informed choice' (yes/no) to classify informed decisions as those reflecting sufficient knowledge and concordance between a woman's decision and relevant attitudes. Results Analyses showed that more intervention than standard control participants (52.7% versus 5.9%) made informed decisions at post-test, P <0.001. At the three-month follow-up, differences in rates of informed choice between intervention (16.9%) and both control groups (11.8% and 8.0%) were statistically non-significant, P = 0.067. Conclusions The DA increased informed decision making about breast cancer chemoprevention, although the impact on knowledge diminished over time. This study was not designed to determine how much knowledge decision makers must retain over time. Examining informed decisions increases understanding of the impact of DAs. A standard for defining and measuring sufficient knowledge for informed decisions is needed. Trial registration ClinicalTrials.gov: NCT00967824http://deepblue.lib.umich.edu/bitstream/2027.42/135728/1/13058_2013_Article_3282.pd

CSO Bolocam 1.1 mm continuum mapping of the Braid Nebula star formation region in Cygnus OB7

We present a 1.1 mm map of the Braid Nebula star formation region in Cygnus OB7 taken using Bolocam on the Caltech Submillimeter Observatory. Within the 1 deg2 covered by the map, we have detected 55 cold dust clumps all of which are new detections. A number of these clumps are coincident with IRAS point sources although the majority are not. Some of the previously studied optical/near-IR sources are detected at 1.1 mm. We estimate total dust/gas masses for the 55 clumps together with peak visual extinctions. We conclude that over the whole region, approximately 20% of the clumps are associated with IRAS sources suggesting that these are protostellar objects. The remaining 80% are classed as starless clumps. In addition, both FU Orionis (FUor) like objects in the field, the Braid Star and HH 381 IRS, are associated with strong millimeter emission. This implies that FUor eruptions can occur at very early stages of pre-main-sequence life. Finally, we determine that the cumulative clump mass function for the region is very similar to that found in both the Perseus and Ï? Ophiuchus star-forming regions. © 2011. The American Astronomical Society. All rights reserved

Increased Cervical Human Immunodeficiency Virus (HIV) RNA Shedding Among HIV-Infected Women Randomized to Loop Electrosurgical Excision Procedure Compared to Cryotherapy for Cervical Intraepithelial Neoplasia 2/3

Background Treatment of human immunodeficiency virus (HIV)–infected women to prevent cervical cancer may stimulate HIV RNA cervical shedding and risk HIV transmission. Methods From 2011 to 2014, 400 HIV-infected women diagnosed with cervical intraepithelial neoplasia 2/3 in Kenya were randomized to loop electrosurgical excision procedure (LEEP) or cryotherapy. Cervical samples were collected at baseline and 3 weekly intervals. Samples were tested for HIV RNA using the Gen-Probe Aptima HIV assay with a minimum detection level of 60 copies/swab and analyzed using generalized estimating equations. Results Women who received LEEP had significantly higher cervical HIV RNA levels than those who received cryotherapy at weeks 2 (adjusted incident rate ratio [aIRR], 1.07; P = .038) and 3 (aIRR, 1.08; P = .046). Within LEEP, significantly higher cervical shedding was found at weeks 2 (2.03 log10 copies/swab; P < .001) and 3 (2.04 log10 copies/swab; P < .001) compared to baseline (1.80 log10 copies/swab). Cervical HIV RNA was significantly higher following LEEP for up to 3 weeks among women on antiretroviral treatment (ART) (0.18 log10 copies/swab increase; P = .003) and in ART-naive women (1.13 log10 copies/swab increase; P < .001) compared to baseline. Within cryotherapy, cervical shedding increased in ART-naive women (0.72 log10 copies/swab increase; P = 0.004) but did not increase in women on ART. Conclusions Women randomized to LEEP had a larger increase in post-procedural cervical HIV shedding than cryotherapy. Benefits of cervical cancer prevention outweigh the risk of HIV sexual transmission; our findings underscore the importance of risk-reduction counseling

Multilevel Structural Equation Modeling of Students\u27 Dietary Intentions/Behaviors, BMI, and the Healthfulness of Convenience Stores.

BACKGROUND: When dietary behaviors are habitual, intentions are low, and environmental cues, such as the consumer food environment, might guide behavior. How might intentions to eat healthily and ultimately actual dietary behaviors, be influenced by the consumer food environment (including the availability and affordability of healthy foods) in convenience stores? This study will determine pathways between the healthfulness of convenience stores and college students\u27 dietary intentions/behaviors, and body mass index (BMI).METHODS: Through multilevel structural equation modeling, a comparison was made of students\u27 healthful meal intentions (HMI); intake (fruits/vegetables, %kcal/fat, sugar-sweetened beverages (SSBs) and whole-grains); and measured BMI; as well as the healthfulness of convenience stores (fruits/vegetables availability/quality, healthy food availability/affordability). Data was collected on 1401 students and 41 convenience stores across 13 US college campuses.RESULTS: Controlling for gender, HMI was negatively associated with SSBs (β = -0.859) and %kcal/fat (β = -1.057) and positively with whole-grains (β = 0.186) and fruits/vegetables intake (β = 0.267); %Kcal/fat was positively (β = 0.098) and fruits/vegetables intake (β = -0.055) negatively associated with BMI. Campus level, fruits/vegetables availability were positively associated to HMI (β = 0.214, β = 0.129) and directly/negatively to BMI (β = -2.657, β = -1.124).CONCLUSIONS: HMI modifies dietary behaviors, with energy from fat and fruit/vegetable intake the most predictive of weight. Availability of fruit/vegetables in convenience stores make it easier for young adults to eat well

Eruptive modes and hiatus of volcanism at West Mata seamount, NE Lau basin : 1996–2012

Author Posting. © American Geophysical Union, 2014. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry, Geophysics, Geosystems 15 (2014): 4093–4115, doi:10.1002/2014GC005387.We present multiple lines of evidence for years to decade-long changes in the location and character of volcanic activity at West Mata seamount in the NE Lau basin over a 16 year period, and a hiatus in summit eruptions from early 2011 to at least September 2012. Boninite lava and pyroclasts were observed erupting from its summit in 2009, and hydroacoustic data from a succession of hydrophones moored nearby show near-continuous eruptive activity from January 2009 to early 2011. Successive differencing of seven multibeam bathymetric surveys of the volcano made in the 1996–2012 period reveals a pattern of extended constructional volcanism on the summit and northwest flank punctuated by eruptions along the volcano's WSW rift zone (WSWRZ). Away from the summit, the volumetrically largest eruption during the observational period occurred between May 2010 and November 2011 at ∼2920 m depth near the base of the WSWRZ. The (nearly) equally long ENE rift zone did not experience any volcanic activity during the 1996–2012 period. The cessation of summit volcanism recorded on the moored hydrophone was accompanied or followed by the formation of a small summit crater and a landslide on the eastern flank. Water column sensors, analysis of gas samples in the overlying hydrothermal plume and dives with a remotely operated vehicle in September 2012 confirmed that the summit eruption had ceased. Based on the historical eruption rates calculated using the bathymetric differencing technique, the volcano could be as young as several thousand years.Support for R.W.E. during this study was by internal NOAA funding to the NOAA Vents Program (now Earth-Ocean Interactions Program). The NSF Ridge 2000 and MARGINS programs played a major role in the planning and justification for the 2009 rapid response proposal that funded the May 2009 expedition. MBARI provided support and outstanding postprocessing of the multibeam bathymetry from the D. Allan B. AUV multibeam sonar used in this study. NSF also provided major funding for the 2009 expedition (OCE930025 and OCE-0934660 to JAR) and for the 210Po-210Pb radiometric dating (OCE-0929881 and for the 210Po-210Pb radiometric dating (OCE-0929881 to KHR)). The NOAA Office of Exploration and Research provided major funding for the 2009 and 2012 field programs.2015-04-3

Guillain-Barré Syndrome, Influenza Vaccination, and Antecedent Respiratory and Gastrointestinal Infections: A Case-Centered Analysis in the Vaccine Safety Datalink, 2009–2011

Background: Guillain-Barré Syndrome (GBS) can be triggered by gastrointestinal or respiratory infections, including influenza. During the 2009 influenza A (H1N1) pandemic in the United States, monovalent inactivated influenza vaccine (MIV) availability coincided with high rates of wildtype influenza infections. Several prior studies suggested an elevated GBS risk following MIV, but adjustment for antecedent infection was limited. Methods: We identified patients enrolled in health plans participating in the Vaccine Safety Datalink and diagnosed with GBS from July 2009 through June 2011. Medical records of GBS cases with 2009–10 MIV, 2010–11 trivalent inactivated influenza vaccine (TIV), and/or a medically-attended respiratory or gastrointestinal infection in the 1 through 141 days prior to GBS diagnosis were reviewed and classified according to Brighton Collaboration criteria for diagnostic certainty. Using a case-centered design, logistic regression models adjusted for patient-level time-varying sources of confounding, including seasonal vaccinations and infections in GBS cases and population-level controls. Results: Eighteen confirmed GBS cases received vaccination in the 6 weeks preceding onset, among 1.27 million 2009–10 MIV recipients and 2.80 million 2010–11 TIV recipients. Forty-four confirmed GBS cases had infection in the 6 weeks preceding onset, among 3.77 million patients diagnosed with medically-attended infection. The observed-versus-expected odds that 2009–10 MIV/2010–11 TIV was received in the 6 weeks preceding GBS onset was odds ratio = 1.54, 95% confidence interval (CI), 0.59–3.99; risk difference = 0.93 per million doses, 95% CI, −0.71–5.16. The association between GBS and medically-attended infection was: odds ratio = 7.73, 95% CI, 3.60–16.61; risk difference = 11.62 per million infected patients, 95% CI, 4.49–26.94. These findings were consistent in sensitivity analyses using alternative infection definitions and risk intervals for prior vaccination shorter than 6 weeks. Conclusions: After adjusting for antecedent infections, we found no evidence for an elevated GBS risk following 2009–10 MIV/2010–11 TIV influenza vaccines. However, the association between GBS and antecedent infection was strongly elevated