Determinants of HIV-1 Gag Localization to Uropods in Polarized T Cells and the Role Uropods Play in Virus Spread.

HIV-1 is a deadly virus that has killed millions of people around the world. One of the primary targets of HIV-1 in the human body is T cells. In lymphoid organs, such as lymph nodes, T cells are highly motile and adopt a polarized morphology. However, little is known about how HIV-1 localizes, assembles or spreads in polarized T cells. Thus, determining the molecular mechanisms utilized by HIV-1 in polarized T cells can help to understand the virus in vivo. Polarized T cells are characterized by a leading edge at the front and a rear end protrusion called a uropod. In this thesis, it was determined that the HIV-1 structural protein Gag localizes to the uropod in polarized T cells. HIV-1-expressing T cells were found to contact uninfected target cells preferentially via uropods relative to leading edges. Also, uropods participated in virological synapses that mediate HIV-1 cell-to-cell transmission. Together, these findings indicate that uropods play an important role in HIV-1 spread in vivo. Nucleocapsid (NC) is a structural domain of Gag that promotes Gag multimerization by using RNA as a scaffold. NC-mediated multimerization, at the level of tetramerization or higher, was found to be required for uropod localization of Gag. Gag was found to copatch with some (CD43, PSGL-1, CD44), but not all (ICAM-1, ICAM-3, CD59) uropod markers, even in unpolarized T cells. These data, along with live cell analyses, indicate that Gag associates with a specific subset of uropod-directed microdomains (UDMs) that could carry Gag to the uropod. The specificity of Gag association with UDMs was found to be determined by matrix (MA), another Gag structural domain responsible for plasma membrane binding. The observations made in this thesis suggest a working model of HIV-1 replication and spread in polarized T cells: When NC-mediated multimerizaton reaches the level of tetramerization or higher, Gag associates with specific uropod-directed microdomains enriched in CD43, PSGL-1 and CD44 via an MA-mediated mechanism. These Gag-associated UDMs then laterally localize on the membrane to the uropod where virus particles assemble and accumulate. Uropods then mediate contact and VS formation with target cells to facilitate cell-to-cell transmission.Ph.D.Cellular & Molecular BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/91579/1/gnickl_1.pd

D6.2: A final proposal for a European community health worker survey (ECHOES)

This report was prepared as part of the ESTICOM (European Surveys and Training to Improve MSM Community Health) Project, which is a three year project from September 2016 to August 2019 funded by the Consumers, Health, Agriculture and Food Executive Agency (Chafea) of the European Commission. The ESTICOM Project involves nine European organisations under a consortium led by the Robert Koch Institute (RKI) in Berlin, Germany. The purpose of the ESTICOM project is to strengthen the community response and raise awareness about the persisting legal, structural, political and social barriers hindering a more effective response to the syndemics of HIV, hepatitis viruses B and C, and other sexually transmitted infections (STI) among gay, bisexual and other men having sex with men (MSM). To achieve this purpose, the consortium will deliver on three inter-linked projects or objectives over the next three years: * Objective 1: A European online survey of gay, bisexual and other MSM (EMIS 2017); * Objective 2: A European online survey of community health workers (CHW) who provide sexual health support in a community setting directly to gay, bisexual and other MSM (ECHOES); * Objective 3: Development and piloting of a training programme for MSM-focused CHW to be adaptable for all EU countries. This report falls under Objective 2 which is built on four Work Packages (WP): a review of CHW knowledge, attitudes and practices relating to the sexual health of gay, bisexual and other MSM, including existing surveys and training materials (WP5); a CHW online survey design (WP6); promotion and execution of the survey (WP7) and; an analysis and survey report (WP8). The tender specification for this report (Work Package 6) was outlined as follows: Work Package 6: To develop a questionnaire that will assess the knowledge, attitudes and practices of community-based health workers (CHW) providing sexual health services to gay men, bisexual men and other MSM

Revealing the dark matter halo with axion direct detection

The next generation of axion direct-detection experiments may rule out or confirm axions as the dominant source of dark matter. We develop a general likelihood-based framework for studying the time-series data at such experiments, with a focus on the role of dark matter astrophysics, to search for signatures of the QCD axion or axionlike particles. We illustrate how in the event of a detection the likelihood framework may be used to extract measures of the local dark matter phase-space distribution, accounting for effects such as annual modulation and gravitational focusing, which is the perturbation to the dark matter phase-space distribution by the gravitational field of the Sun. Moreover, we show how potential dark matter substructure, such as cold dark matter streams or a thick dark disk, could impact the signal. For example, we find that when the bulk dark matter halo is detected at 5σ global significance, the unique time-dependent features imprinted by the dark matter component of the Sagittarius stream, even if only a few percent of the local dark matter density, may be detectable at ∼2σ significance. A corotating dark disk, with lag speed ∼50  km/s, that is ∼20% of the local dark matter density could dominate the signal, while colder but as-of-yet unknown substructure may be even more important. Our likelihood formalism, and the results derived with it, are generally applicable to any time-series-based approach to axion direct detection.United States. Department of Energy (Grant DESC00012567)United States. Department of Energy (Grant DE-SC0013999

Gesture Analysis and Organizational Research : The Development and Application of a Protocol for Naturalistic Settings

International audienceGestures are an underresearched but potentially significant aspect of organizational conduct that is relevant to researchers across a range of theoretical and empirical domains. In engaging the cross-disciplinary field of gesture studies, we develop and apply a protocol for analyzing gestures produced in naturalistic settings during ongoing streams of talk and embodied activity. Analyzing video recordings of entrepreneurial investor pitches, we work through this protocol and demonstrate its usefulness. While doing so, we also explore methodological tensions in gesture studies and draw out methodological arguments as they relate to the analysis of these fleeting and often intricate bodily movements. The article contributes a generally applicable protocol for the analysis of gestures in naturalistic settings, and it assesses the methodological implications of this protocol both for research on entrepreneurship and new venture creation and management and organization research more generally.<br/

One-loop correction to heavy dark matter annihilation

We calculate the one-loop corrections to TeV-scale dark matter annihilation in a model where the dark matter is described by an SU(2)[subscript L] triplet of Majorana fermions, such as the wino. We use this framework to determine the high- and low-scale [bar over MS] matching coefficients at both the dark matter and weak boson mass scales at one loop. Part of this calculation has previously been performed in the literature numerically; we find our analytic result differs from the earlier work and discuss potential origins of this disagreement. Our result is used to extend the dark matter annihilation rate to next-to-leading logarithmic+O(α[subscript 2]) corrections (NLL[subscript ′]), which enables a precise determination of indirect detection signatures in present and upcoming experiments.United States. Dept. of Energy (Grants DE-SC00012567, DE-SC0013999, and DE-SC0011090)Simons Foundation (Investigator Grant 327942)American Australian Association (U.S.) (ConocoPhillips Fellowship

Que(e) rying undergraduate medical curricula: a cross-sectional online survey of lesbian, gay, bisexual, transgender, and queer content inclusion in UK undergraduate medical education

Background Lesbian, Gay, Bisexual, and Transgender (LGBT) individuals are more likely to have negative healthcare experiences and worse health outcomes when compared with their heterosexual and cisgender counterparts. A key recommendation of the 2018 Stonewall-commissioned “LGBT in Britain” report was that the curricula, standards, and training provided by medical schools should be reviewed in order to encompass mandatory teaching about LGBT health inequalities and discrimination, LGBT-inclusive care and the use of appropriate language. The aim of our study was to conduct an in-depth national review of the content of LGBT teaching within the curricula of UK Medical Schools. Methods Course leads at all 37 UK Medical Schools with students currently enrolled in a primary undergraduate medical training course were asked between December 2019–March 2020 to complete a cross-sectional online survey comprised of 30 questions; divided into three sections relating to the current LGBT teaching (Part 1), any planned or future LGBT teaching (Part 2), and the opinions of the survey respondent about the coverage of LGBT topics (Part 3) at their institution. Responses were analysed using descriptive statistics. Results Questionnaires were received from 19/37 institutions (response rate: 51%). The median estimated number of hours of LGBT-teaching across the entire undergraduate course was 11.0 (IQR: 12.25). Teaching on LGBT mental health, gender identity, sexual orientation, awareness of LGBT-health inequalities, and LGBT discrimination in healthcare were reported by almost all respondents, whilst maternity and childbirth, chronic disease and LGBT adolescent health were least represented within the curriculum. Almost all (18 medical schools; 95%) responding institutions were considering implementing new LGBT teaching within the next three academic years. A lack of space within the curriculum is a universally reported barrier to the implementation of LGBT teaching. Only 5 (26%) survey respondents consider their institution’s current coverage of LGBT topics to be “Good” or “Very good”. Conclusion Our study demonstrates a significant variation in the amount and breadth of content within the undergraduate curricula of UK medical schools. Recommendations for increasing the quantity and quality of LGBT content are provided, based upon areas of good practice

Gesture Analysis and Organizational Research: The Development and Application of a Protocol for Naturalistic Settings

Gestures are an underresearched but potentially significant aspect of organizational conduct that is relevant to researchers across a range of theoretical and empirical domains. In engaging the cross-disciplinary field of gesture studies, we develop and apply a protocol for analyzing gestures produced in naturalistic settings during ongoing streams of talk and embodied activity. Analyzing video recordings of entrepreneurial investor pitches, we work through this protocol and demonstrate its usefulness. While doing so, we also explore methodological tensions in gesture studies and draw out methodological arguments as they relate to the analysis of these fleeting and often intricate bodily movements. The article contributes a generally applicable protocol for the analysis of gestures in naturalistic settings, and it assesses the methodological implications of this protocol both for research on entrepreneurship and new venture creation and management and organization research more generally

Implementing Voluntary Medical Male Circumcision for HIV Prevention in Nyanza Province, Kenya: Lessons Learned during the First Year

In 2007, the World Health Organization endorsed male circumcision as an effective HIV prevention strategy. In 2008, the Government of Kenya (GoK) launched the national voluntary medical male circumcision (VMMC) program in Nyanza Province, the geographic home to the Luo, the largest non-circumcising ethnic group in Kenya. Currently, several other African countries are in the early stages of implementing this intervention.This paper uses data from a health facility needs assessment (n = 81 facilities) and a study to evaluate the implementation of VMMC services in 16 GoK facilities (n = 2,675 VMMC clients) to describe Kenya's experience in implementing the national program. The needs assessment revealed that no health facility was prepared to offer the minimum package of services as outlined by the national guidelines, and partner organizations were called upon to fill this gap. The findings concerning human resource shortages facilitated the GoK's decision to endorse trained nurses to provide VMMCs, enabling more facilities to offer the service. Findings from the evaluation study resulted in replacing voluntary counseling and testing (VCT) with provider-initiated testing and counseling (PITC) and subsequently doubling the proportion of VMMC clients tested for HIV.This paper outlines how certain challenges, like human resource shortages and low HIV test rates, were addressed through national policy changes, while other challenges, like large fluctuations in demand, were addressed locally. Currently, the program requires significant support from partner organizations, but a strategic plan is under development to continue to build capacity in GoK staff and facilities. Coordination between all parties was essential and was facilitated through the formation of national, provincial, and district VMMC task forces. The lessons learned from Kenya's VMMC implementation experience are likely generalizable to other African countries

Scientists\u27 Warning on Invasive Alien Species

Biological invasions are a global consequence of an increasingly connected world and the rise in human population size. The numbers of invasive alien species - the subset of alien species that spread widely in areas where they are not native, affecting the environment or human livelihoods - are increasing. Synergies with other global changes are exacerbating current invasions and facilitating new ones, thereby escalating the extent and impacts of invaders. Invasions have complex and often immense long-term direct and indirect impacts. In many cases, such impacts become apparent or problematic only when invaders are well established and have large ranges. Invasive alien species break down biogeographic realms, affect native species richness and abundance, increase the risk of native species extinction, affect the genetic composition of native populations, change native animal behaviour, alter phylogenetic diversity across communities, and modify trophic networks. Many invasive alien species also change ecosystem functioning and the delivery of ecosystem services by altering nutrient and contaminant cycling, hydrology, habitat structure, and disturbance regimes. These biodiversity and ecosystem impacts are accelerating and will increase further in the future. Scientific evidence has identified policy strategies to reduce future invasions, but these strategies are often insufficiently implemented. For some nations, notably Australia and New Zealand, biosecurity has become a national priority. There have been long-term successes, such as eradication of rats and cats on increasingly large islands and biological control of weeds across continental areas. However, in many countries, invasions receive little attention. Improved international cooperation is crucial to reduce the impacts of invasive alien species on biodiversity, ecosystem services, and human livelihoods. Countries can strengthen their biosecurity regulations to implement and enforce more effective management strategies that should also address other global changes that interact with invasions

Voluntary Medical Male Circumcision: Translating Research into the Rapid Expansion of Services in Kenya, 2008–2011

Zebedee Mwandi and colleagues discuss Kenya's scale-up of voluntary medical male circumcision services, highlighting government leadership, a clear implementation strategy, and program flexibility and innovation as keys to Kenya's success