The Formulated Microbicide RC-101 Was Safe and Antivirally Active Following Intravaginal Application in Pigtailed Macaques

Background: RC-101 is a congener of the antiretroviral peptide retrocyclin, which we and others have reported is active against clinical HIV-1 isolates from all major clades, does not hemagglutinate, and is non-toxic and non-inflammatory in cervicovaginal cell culture. Herein, film-formulated RC-101 was assessed for its antiviral activity in vitro, safety in vivo, retention in the cervix and vagina, and ability to remain active against HIV-1 and SHIV after intravaginal application in macaques. Methodology/Principal Findings: RC-101 was formulated as a quick-dissolving film (2000 μg/film), retained complete activity in vitro as compared to unformulated peptide, and was applied intravaginally in six pigtailed macaques daily for four days. At one and four days following the final application, the presence of RC-101 was assessed in peripheral blood, cervicovaginal lavage, cytobrushed cervicovaginal cells, and biopsied cervical and vaginal tissues by quantitative western blots. One day following the last film application, cervical biopsies from RC-101-exposed and placebo-controlled macaques were collected and were subjected to challenge with RT-SHIV in an ex vivo organ culture model. RC-101 peptide was detected primarily in the cytobrush and biopsied cervical and vaginal tissues, with little to no peptide detected in lavage samples, suggesting that the peptide was associated with the cervicovaginal epithelia. RC-101 remained in the tissues and cytobrush samples up to four days post-application, yet was not detected in any sera or plasma samples. RC-101, extracted from cytobrushes obtained one day post-application, remained active against HIV-1 BaL. Importantly, cervical biopsies from RC-101-treated animals reduced RT-SHIV replication in ex vivo organ culture as compared to placebo-treated animals. Conclusions/Significance:Formulated RC-101 was stable in vivo and was retained in the mucosa. The presence of antivirally active RC-101 after five days in vivo suggests that RC-101 would be an important molecule to develop further as a topical microbicide to prevent HIV-1 transmission. © 2010 Cole et al

Modelling timing and tempo of adrenarche in a prospective cohort study

To better understand how health risk processes are linked to adrenarche, measures of adrenarcheal timing and tempo are needed. Our objective was to describe and classify adrenal trajectories, in terms of timing and tempo, in a population of children transitioning to adolescence with repeated measurements of salivary dehydroepiandrosterone (DHEA), DHEAsulphate, and testosterone. We analysed data from the Childhood to Adolescence Transition Study (CATS), a longitudinal study of 1239 participants, recruited at 8-9 years old and followed up annually. Saliva samples were assayed for adrenal hormones. Linear mixedeffect models with subject-specific random intercepts and slopes were used to model longitudinal hormone trajectories by sex and derive measures of adrenarcheal timing and tempo. The median values for all hormones were higher at each consecutive study wave for both sexes, and higher for females than males. For all hormones, between-individual variation in hormone levels at age 9 (timing) was moderately large and similar for females and males. Between-individual variation in hormone progression over time (tempo) was of moderate magnitude compared with the population average age-slope, which itself was small compared with overall hormone level at each age. This suggests that between-individual variation in tempo was less important for modelling hormone trajectories. Between-individual variation in timing was more important for determining relative adrenal hormonal level in childhood than tempo. This finding suggests that adrenal hormonal levels at age 8-9 years can be used to predict relative levels in early adolescence (up to 13 years)

Forensic Investigation of Cyberstalking Cases using Behavioural Evidence Analysis

Behavioural Evidence Analysis (BEA) is, in theory, useful in developing an understanding of the offender, the victim, the crime scene, and the dynamics of the crime. It can add meaning to the evidence obtained through digital forensic techniques and assist investigators with reconstruction of a crime. There is, however, little empirical research examining the application of BEA to actual criminal cases, particularly cyberstalking cases. This study addresses this gap by examining the utility of BEA for such cases in terms of understanding the behavioural and motivational dimensions of offending, and the way in which digital evidence can be interpreted. It reports on the forensic analysis of 20 cyberstalking cases investigated by Dubai Police in the last five years. Results showed that BEA helps to focus an investigation, enables better understanding and interpretation of victim and offender behaviour, and assists in inferring traits of the offender from available digital evidence. These benefits can help investigators to build a stronger case, reduce time wasted to mistakes, and to exclude suspects wrongly accused in cyberstalking cases

Three faces of context and their implications for career: a study of public sector careers cut short

This paper examines the impact of context on careers. It is based on a study of senior managers in an English Local Authority. It offers two important contributions: first, an empirical contribution examining how context matters to individuals in their career-making in the setting of the UK public sector. Our findings point to three aspects or faces of context: proximal events, ideology and enduring structural features. The first, context as ideology, attends to meaning-making that is collective in nature, and that incorporates concepts of power, domination, subordination and resistance. Our second refers to the enduring structural features. These are on-going trends and developments, predictable and traceable over the medium to long-term which offer rules and resources, thus structuring opportunity and constraint. Finally, the third face, context as proximal events, refers to (often unexpected) contingencies that arise at particular moments. Although bounded both spatially and temporally, they can significantly impact on career decision making. The second contribution of the paper builds upon this empirical base to develop theoretical and conceptual understanding of the link between career and context, illustrating the interconnectedness of the various faces of context and the dynamic ways in which these influence career-making over time

'Hidden' expatriates: international mobility in the United Arab Emirates as a challenge to current understanding of expatriation

Expatriates are often assumed to have enhanced terms and conditions and, because that makes them expensive, to be in key managerial or technical specialist roles. Employees who come from abroad and are in more manual or even menial roles are usually referred to as ‘migrants’. However, there are millions of people around the world who are not migrants, their intended sojourn in a foreign country is seen by them and their employers as temporary, but their employment contracts are far from advantageous compared with those of locals. These ‘hidden’ expatriates are brought into focus in the emerging Arab Gulf States. In some of these countries, the population consists mainly of expatriates, with the local population a small minority: These expatriates include many in lower-management or manual or menial jobs. We demarcate these expatriates from organisationally assigned expatriates, self-initiated expatriates and migrants. We use qualitative data from such expatriates in the United Arab Emirates to explore the issues this raises for governments, employers and the expatriates – and for our understanding of the phenomenon of expatriation

Summarising the retinal vascular calibres in healthy, diabetic and diabetic retinopathy eyes

Retinal vessel calibre has been found to be an important biomarker of several retinal diseases, including diabetic retinopathy (DR). Quantifying the retinal vessel calibres is an important step for estimating the central retinal artery and vein equivalents. In this study, an alternative method to the already estab- lished branching coefficient(BC) is proposed for summarising the vessel calibres in retinal junctions. This new method combines the mean diameter ratio with an alternative to Murray’s cube law exponent, derived by the fractal dimen- sion,experimentally, and the branch exponent of cerebral vessels, as has been suggested in previous studies with blood flow modelling. For the above calcu- lations, retinal images from healthy, diabetic and DR subjects were used. In addition, the above method was compared with the BC and was also applied to the evaluation of arteriovenous ratio as a biomarker of progression from diabetes to DR in four consecutive years, i.e. three/two/one years before the onset of DR and the first year of DR. Moreover, the retinal arteries and veins around the optic nerve head were also evaluated. The new approach quantifies the vessels more accurately. The decrease in terms of the mean absolute percentage error was between 0.24% and 0.49%, extending at the same time the quantification beyond healthy subjects

Gorham-Stout case report: a multi-omic analysis reveals recurrent fusions as new potential drivers of the disease

BACKGROUND: Gorham-Stout disease is a rare condition characterized by vascular proliferation and the massive destruction of bone tissue. With less than 400 cases in the literature of Gorham-Stout syndrome, we performed a unique study combining whole-genome sequencing and RNA-Seq to probe the genomic features and differentially expressed pathways of a presented case, revealing new possible drivers and biomarkers of the disease. CASE PRESENTATION: We present a case report of a white 45-year-old female patient with marked bone loss of the left humerus associated with vascular proliferation, diagnosed with Gorham-Stout disease. The analysis of whole-genome sequencing showed a dominance of large structural DNA rearrangements. Particularly, rearrangements in chromosomes seven, twelve, and twenty could contribute to the development of the disease, especially a gene fusion involving ATG101 that could affect macroautophagy. The study of RNA-sequencing data from the patient uncovered the PI3K/AKT/mTOR pathway as the most affected signaling cascade in the Gorham-Stout lesional tissue. Furthermore, M2 macrophage infiltration was detected using immunohistochemical staining and confirmed by deconvolution of the RNA-seq expression data. CONCLUSIONS: The way that DNA and RNA aberrations lead to Gorham-Stout disease is poorly understood due to the limited number of studies focusing on this rare disease. Our study provides the first glimpse into this facet of the disease, exposing new possible therapeutic targets and facilitating the clinicopathological diagnosis of Gorham-Stout disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12920-022-01277-x