Functional stability of HIV-1 envelope trimer affects accessibility to broadly neutralizing antibodies at its apex

ABSTRACT The trimeric envelope glycoprotein spike (Env) of HIV-1 is the target of vaccine development to elicit broadly neutralizing antibodies (bnAbs). Env trimer instability and heterogeneity in principle make subunit interfaces inconsistent targets for the immune response. Here, we investigate how functional stability of Env relates to neutralization sensitivity to V2 bnAbs and V3 crown antibodies that engage subunit interfaces upon binding to unliganded Env. Env heterogeneity was inferred when antibodies neutralized a mutant Env with a plateau of less than 100% neutralization. A statistically significant correlation was found between the stability of mutant Envs and the MPN of V2 bnAb, PG9, as well as an inverse correlation between stability of Env and neutralization by V3 crown antibody, 447-52D. A number of Env-stabilizing mutations and V2 bnAb-enhancing mutations were identified in Env, but they did not always overlap, indicating distinct requirements of functional stabilization versus antibody recognition. Blocking complex glycosylation of Env affected V2 bnAb recognition, as previously described, but also notably increased functional stability of Env. This study shows how instability and heterogeneity affect antibody sensitivity of HIV-1 Env, which is relevant to vaccine design involving its dynamic apex. IMPORTANCE The Env trimer is the only viral protein on the surface of HIV-1 and is the target of neutralizing antibodies that reduce viral infectivity. Quaternary epitopes at the apex of the spike are recognized by some of the most potent and broadly neutralizing antibodies to date. Being that their glycan-protein hybrid epitopes are at subunit interfaces, the resulting heterogeneity can lead to partial neutralization. Here, we screened for mutations in Env that allowed for complete neutralization by the bnAbs. We found that when mutations outside V2 increased V2 bnAb recognition, they often also increased Env stability-of-function and decreased binding by narrowly neutralizing antibodies to the V3 crown. Three mutations together increased neutralization by V2 bnAb and eliminated binding by V3 crown antibodies. These results may aid the design of immunogens that elicit antibodies to the trimer apex. </jats:p

Assessment of community awareness and risk perceptions of zoonotic causes of abortion in cattle at three selected livestock–wildlife interface areas of Zimbabwe

A study was conducted to assess the awareness of cattle abortions due to brucellosis, Rift Valley fever (RVF) and leptospirosis, and to compare frequencies of reported abortions in communities living at the periphery of the Great Limpopo Transfrontier Conservation Area in southeastern Zimbabwe. Three study sites were selected based on the type of livestock–wildlife interface: porous livestock–wildlife interface (unrestricted); non-porous livestock–wildlife interface (restricted by fencing); and livestock–wildlife non-interface (totally absent or control). Respondents randomly selected from a list of potential cattle farmers (N = 379) distributed at porous (40·1%), non-interface (35·5%) and non-porous (26·4%), were interviewed using a combined close- and open-ended questionnaire. Focus group discussions were conducted with 10–12 members of each community. More abortions in the last 5 years were reported from the porous interface (52%) and a significantly higher per cent of respondents from the porous interface (P < 0·05) perceived wildlife as playing a role in livestock abortions compared with the other interface types. The odds of reporting abortions in cattle were higher in large herd sizes (odds ratio (OR) = 2·6; 95% confidence interval (CI) 1·5–4·3), porous (OR = 1·9; 95% CI 1·0–3·5) and non-porous interface (OR = 2·2; 95% CI 1·1–4·3) compared with livestock–wildlife non-interface areas. About 21·6% of the respondents knew brucellosis as a cause of abortion, compared with RVF (9·8%) and leptospirosis (3·7%). These results explain to some extent, the existence of human/wildlife conflict in the studied livestock–wildlife interface areas of Zimbabwe, which militates against biodiversity conservation efforts. The low awareness of zoonoses means the public is at risk of contracting some of these infections. Thus, further studies should focus on livestock–wildlife interface areas to assess if the increased rates of abortions reported in cattle may be due to exposure to wildlife or other factors. The government of Zimbabwe needs to launch educational programmes on public health awareness in these remote areas at the periphery of transfrontier conservation areas where livestock–wildlife interface exists to help mitigate the morbidity and mortality. (Résumé d'auteur

A new differential configuration suitable for realization of high CMRR, all-pass/notch filters

#yayıncısurumuyok# ; Tam metin hakemden geçmiş kopyadır.In this paper, a new configuration suitable for realization of differential input-differential output first order, second order all-pass and notch filters with high CMRR is given. The proposed configuration uses two negative type second-generation current conveyors (CCII-), and three admittances. Two first order and one second order all-pass filters and a notch filter (tunable if current controlled conveyor CCCII is used) are extracted from the proposed configuration. Tracking error, element mismatch, sensitivity analysis, simulation and experimental results are included

COMPETITIVE STRATEGIES AND ORGANIZATIONAL SURVIVAL OF MANUFACTURING FIRMS IN RIVERS STATE

This study examined the association between competitive strategies and organizational survival of manufacturing firms in Rivers State, As well as the moderating effect of technology on the relationship between competitive strategies and organizational survival. The cross-sectional research design was applied in this study. A total of one hundred and eighty-one (181) managers and supervisors from ten (10) manufacturing firms, constituted the sample elements. The simple random sampling technique was used. Primary data was collected for this study and copies of questionnaire was the main instrument for collection of data. The instrument was subjected to face and content validity and the reliability of the instrument was checked using cronbach alpha test. Seven (7) null hypothesis were formulated and tested using partial least square -structural equation modelling (smart pls). The outcome of the analyses revealed a significant positive association between the dimensions of competitive strategies(cost leadership, differentiation and focus strategy) and the measures of organizational survival (innovation and adaptability). Technology was also found to significantly moderate the relationship. The study concluded that adoption of competitive strategies enhances the survival of organizations. The study recommended that Management should apply cost leadership strategies as it provides an opportunity to enhance the firms innovative capability and adaptability to internal and external environmental thereby maximizing its survival

Identification of priority health conditions for field-based screening in urban slums in Bangalore, India

BACKGROUND: Urban slums are characterised by unique challenging living conditions, which increase their inhabitants' vulnerability to specific health conditions. The identification and prioritization of the key health issues occurring in these settings is essential for the development of programmes that aim to enhance the health of local slum communities effectively. As such, the present study sought to identify and prioritise the key health issues occurring in urban slums, with a focus on the perceptions of health professionals and community workers, in the rapidly growing city of Bangalore, India. METHODS: The study followed a two-phased mixed methods design. During Phase I of the study, a total of 60 health conditions belonging to four major categories: - 1) non-communicable diseases; 2) infectious diseases; 3) maternal and women's reproductive health; and 4) child health - were identified through a systematic literature review and semi-structured interviews conducted with health professionals and other relevant stakeholders with experience working with urban slum communities in Bangalore. In Phase II, the health issues were prioritised based on four criteria through a consensus workshop conducted in Bangalore. RESULTS: The top health issues prioritized during the workshop were: diabetes and hypertension (non-communicable diseases category), dengue fever (infectious diseases category), malnutrition and anaemia (child health, and maternal and women's reproductive health categories). Diarrhoea was also selected as a top priority in children. These health issues were in line with national and international reports that listed them as top causes of mortality and major contributors to the burden of diseases in India. CONCLUSIONS: The results of this study will be used to inform the development of technologies and the design of interventions to improve the health outcomes of local communities. Identification of priority health issues in the slums of other regions of India, and in other low and lower middle-income countries, is recommended

Pastoral and Bio-medical Responses to HIV and AIDS by the Lutheran Communion in Southern Africa (LUCSA): Case Study of the Thusanang HIV & AIDS Project and Manama Mission Hospital in Zimbabwe

This article is an exposition of the Pastoral and Biomedical Responses to HIV and AIDS programming by LUCSA. This was done through engaging with members and workers of the church regarding their experiences of Home Based Care (HBC) training as a way of managing and holistically responding to the HIV and AIDS epidemic. This study explores the impact of the training for caregivers, nursing staff and pastors in HIV and AIDS management through a case study of the Thusanang HIV &amp; AIDS project and Manama Mission Hospital of the Western Diocese of the Evangelical Lutheran Church in Zimbabwe (ELCZ) in Gwanda South. The study concludes that skills training in HBC and Palliative Care have made a positive and remarkable impact on the lives and work of HBC givers and pastors and that such training has contributed to the retention of caregivers

EFFECT OF SOCIAL MEDIA MARKETING ON SALES VOLUME OF SELECTED E-BUSINESS IN LAGOS STATE, NIGERIA

Nigeria's e-business environment faces a significant gap in the wide adoption of appropriate technology to enhance marketing and improve sales. Lack of adequate technological infrastructure is a challenging factor to a larger extent to the achievement of sales volume through social media marketing in Nigeria. The study seeks to examine the effect of social media marketing on sales volume of e-business in Nigeria. The study used descriptive research design through stratified and simple random sampling techniques to determine the sample size from the population of 900 registered e-business customers. Two hundred and sixty-eight (268) copies of valid questionnaires were returned from the respondents representing 99.9% response rate. The results of the study revealed that social media marketing has significant effect on sales volume of e-business in Nigeria. The study recommended that managers of e-business should focus their efforts on exploiting widely used digital channels and improving customer service one-channel to achieve business competitive advantage and larger market share in this economic recession and disruptive business environment organisations are operating in

Sustained Sexual Behavior Change after Acute HIV Diagnosis in Malawi

Background Identification of acute HIV infection (AHI) allows for important opportunities for HIV prevention through behavior change and biomedical intervention. Here, we evaluate changes in sexual risk behaviors among persons with AHI enrolled in a combined behavioral and biomedical intervention designed to reduce onward transmission of HIV. Methods Participants were randomized to standard HIV counseling, a multisession behavioral intervention, or a multisession behavioral intervention plus antiretrovirals. Sexual behaviors were assessed periodically over 1 year. Results Four weeks after diagnosis, the predicted probability of reporting multiple sexual partners decreased from 24% to 9%, and the probability of reporting unprotected sex decreased from 71% to 27%. These declines in sexual risk behaviors were sustained over follow-up irrespective of study arm. Conclusions Diagnosis of AHI alone may be sufficient to achieve immediate and sustained behavior change during this highly infectious period

Evaluation of an Afrocentric Sexual Health Education Curriculum for Medical, Nursing and Midwifery Students in Tanzania

Background: Africa has the world’s highest rates of sexual health concerns, yet training programs to teach clinicians how to address sexual health concerns are rare. To address this gap, we developed a comprehensive sexual health curriculum tailored to Tanzania’s most common sexual health concerns. We use the curriculum to train sexual health education (SHE) to Tanzanian medical, nursing, and midwifery students. Aim: To evaluate training in sexual health in terms of structure, content, delivery, and cultural acceptability for medical, nursing, and midwifery professionals. Methods: First, we conducted a two-year formative research phase involving 18 Focused Group Discussions (FGD) with healthcare providers and students and 12 In-depth Interviews (IDIs) with sexual health stakeholders. The FGDs were stratified by discipline and working experience in years. The formative research phase was used to inform curriculum content and to tailor the SHE curriculum to the Tanzanian clinical context. Next, we developed a comprehensive sexual health curriculum tailored to Tanzania’s most common sexual health concerns. Given the lack of sex education that most students reported, we dedicated a day to normal sexual development and one to understanding the common sexual concerns of patients in Tanzania. We also had a strong emphasis on skills development by devoting one day for participants to practice skills. In addition, we ensured content to address cultural myths and taboos surrounding sexual health. We then trained a total of 206 students: the training was conducted in 2021. Immediately following the training evaluation was conducted as an online survey and qualitative responses were saved automatically in the Qualtrics database upon participants' completion. Results: Most participants (76.6%), evaluated the curriculum as culturally appropriate for Africa, personally valuable (96.1%) and would recommend it to a fellow student (98.5%). Furthermore, the curriculum was perceived as feasible, personally and culturally acceptable with endorsement of the training techniques employed, and suggestions on how to further improve the curriculum. Conclusion: Training the SHE curriculum is crucial to impact the core competencies of health professionals for addressing the sexual health concerns of their future clients. This study provides evidence that a sexual health curriculum tailored to the African context is highly needed, acceptable, and feasible

Human Immunodeficiency Virus (HIV)-1 Transmission among Persons with Acute HIV-1 Infection in Malawi: Demographic, Behavioral, and Phylogenetic Relationships

Background: Understanding sexual networks involving acute human immunodeficiency virus (HIV)-1 infections (AHI) may lead to prevention opportunities to mitigate high rates of onward transmission. We evaluated HIV-1 phylogenetic and behavioral characteristics among persons with AHI and their referred partners. Methods: Between 2012 and 2014, 46 persons with AHI in Malawi participated in a combined behavioral and biomedical intervention. Participants referred sexual partners by passive referral. Demographics and sexual behaviors were collected through interviews and HIV-1 genetic relationships were assessed with phylogenetics. Results: Among 45 AHI participants with HIV-1 sequences, none was phylogenetically-linked with another AHI index. There were 19 (42%) AHI participants who referred a single partner that returned for testing. Most partners (n = 17) were HIV-infected, with 15 (88%) presenting with an established infection. There were 14 index-partner pairs that had sequences available; 13 (93%) pairs were phylogenetically-linked dyads. The AHI index was female in 7/13 (54%) dyads. Age-disparate relationships among dyads were common (≥5-year age difference in 67% of dyads), including 3/6 dyads involving a male index and a younger woman. Index participants with a referred partner were more likely to report no casual partners and to be living with their current partner than participants not in dyads. Conclusions: Passive-partner referral successfully identified partners with genetically-similar HIV infections - the likely source of infection - but only 40% of index cases referred partners who presented for HIV-1 testing. Future work evaluating assisted partner notification may help reach susceptible partners or more people with untreated HIV-1 infections connected to acute transmission. Clinical Trials Registration: NCT01450189