Leveraging on past investment in understanding the immunology of COVID-19 – the South African experience.

Significance:The COVID-19 pandemic, and in particular the emergence of viral variants, resulted in an enormous global public health crisis. South African scientists, with a long history of studying viral evolution and antibody responses, were well positioned to pivot their research to focus on SARS-CoV-2. Using the expertise and infrastructure developed over decades for HIV vaccine research, South Africa took a leadership role in studying the antibody response elicited by SARS-CoV-2 infection and vaccination. We describe key scientific outcomes of those studies, and the drivers of a successful national response

Young and Early Career Investigators: Report from a Global HIV Vaccine Enterprise Working Group

The scientific challenges facing HIV-1 vaccine development are unprecedented in the history of vaccinology. As a result, investigators, funders, and other stakeholders generally agree that “game-changing” ideas are required. While innovation can certainly arise from investigators at all career stages, young and early-career investigators, defined as those under 40 years of age or within 10 years of their final degree or clinical training, are especially key contributors of novel and transformative ideas. Young and early-career investigators bring energy, enthusiasm, and fresh perspectives that are unbiased by prevailing dogma and that are essential to scientific progress

Optimal immunization cocktails can promote induction of broadly neutralizing Abs against highly mutable pathogens

Strategies to elicit Abs that can neutralize diverse strains of a highly mutable pathogen are likely to result in a potent vaccine. Broadly neutralizing Abs (bnAbs) against HIV have been isolated from patients, proving that the human immune system can evolve them. Using computer simulations and theory, we study immunization with diverse mixtures of variant antigens (Ags). Our results show that particular choices for the number of variant Ags and the mutational distances separating them maximize the probability of inducing bnAbs. The variant Ags represent potentially conflicting selection forces that can frustrate the Darwinian evolutionary process of affinity maturation. An intermediate level of frustration maximizes the chance of evolving bnAbs. A simple model makes vivid the origin of this principle of optimal frustration. Our results, combined with past studies, suggest that an appropriately chosen permutation of immunization with an optimally designed mixture (using the principles that we describe) and sequential immunization with variant Ags that are separated by relatively large mutational distances may best promote the evolution of bnAbs

Hubble Space Telescope survey of the Perseus Cluster -III: The effect of local environment on dwarf galaxies

We present the results of a Hubble Space Telescope (HST) study of dwarf galaxies in the outer regions of the nearby rich Perseus Cluster, down to M_V = -12, and compare these with the dwarf population in the cluster core from our previous HST imaging. In this paper we examine how properties such as the colour magnitude relation, structure and morphology are affected by environment for the lowest mass galaxies. Dwarf galaxies are excellent tracers of the effects of environment due to their low masses, allowing us to derive their environmentally based evolution, which is more subtle in more massive galaxies. We identify 11 dwarf elliptical (dE) and dwarf spheroidal (dSph) galaxies in the outer regions of Perseus, all of which are previously unstudied. We measure the (V-I)_0 colours of our newly discovered dEs, and find that these dwarfs lie on the same red sequence as those in the cluster core. The morphologies of these dwarfs are examined by quantifying their light distributions using CAS parameters, and we find that dEs in the cluster outskirts are on average more disturbed than those in the core, with =0.13\pm0.09 and =0.18\pm0.08, compared to =0.02\pm0.04, =0.01\pm0.07 for those in the core. Based on these results, we infer that these objects are ``transition dwarfs'', likely in the process of transforming from late-type to early type galaxies as they infall into the cluster, with their colours transforming before their structures. When we compare the number counts for both the core and outer regions of the cluster, we find that below M_V = -12, the counts in the outer regions of the cluster exceed those in the core. This is evidence that in the very dense region of the cluster, dwarfs are unable to survive unless they are sufficiently massive to prevent their disruption by the cluster potential and interactions with other galaxies.Comment: 14 pages, 11 figures. MNRAS accepte

HIV-1 Subtype C-Infected Children with Exceptional Neutralization Breadth Exhibit Polyclonal Responses Targeting Known Epitopes

We have previously shown that HIV-1-infected children develop broader and more potent neutralizing antibody responses than adults. This study aimed to determine the antibody specificities in 16 HIV-1 subtype C-infected children who displayed exceptional neutralization breadth on a 22-multisubtype virus panel. All children were antiretroviral treatment (ART) naive with normal CD4 counts despite being infected for a median of 10.1 years with high viral loads. The specificity of broadly neutralizing antibodies (bNAbs) was determined using epitope-ablating mutants, chimeric constructs, and depletion or inhibition of activity with peptides and glycoproteins. We found that bNAbs in children largely targeted previously defined epitopes, including the V2-glycan, V3-glycan, CD4bs, and gp120-gp41 interface. Remarkably, 63% of children had antibodies targeting 2 or 3 and, in one case, 4 of these bNAb epitopes. Longitudinal analysis of plasma from a mother-child pair over 9 years showed that while they both had similar neutralization profiles, the antibody specificities differed. The mother developed antibodies targeting the V2-glycan and CD4bs, whereas bNAb specificities in the child could not be mapped until 6 years, when a minor V2-glycan response appeared. The child also developed high-titer membrane-proximal external region (MPER) binding antibodies not seen in the mother, although these were not a major bNAb specificity. Overall, exceptional neutralization breadth in this group of children may be the result of extended exposure to high antigenic load in the context of an intact immune system, which allowed for the activation of multiple B cell lineages and the generation of polyclonal responses targeting several bNAb epitopes. IMPORTANCE An HIV vaccine is likely to require bNAbs, which have been shown to prevent HIV acquisition in nonhuman primates. Recent evidence suggests that HIV-infected children are inherently better at generating bNAbs than adults. Here, we show that exceptional neutralization breadth in a group of viremic HIV-1 subtype C-infected children was due to the presence of polyclonal bNAb responses. These bNAbs targeted multiple epitopes on the HIV envelope glycoprotein previously defined in adult infection, suggesting that the immature immune system recognizes HIV antigens similarly. Since elicitation of a polyclonal bNAb response is the basis of next-generation HIV envelope vaccines, further studies of how bNAb lineages are stimulated in children is warranted. Furthermore, our findings suggest that children may respond particularly well to vaccines designed to elicit antibodies to multiple bNAb epitopes

Learning and performance outcomes of mental health staff training in de-escalation techniques for the management of violence and aggression

Background: De-escalation techniques are a recommended non-physical intervention for the management of violence and aggression in mental health. Although taught as part of mandatory training for all NHS mental health staff, there remains a lack of clarity around training effectiveness. Aim: To conduct a systematic review of the learning, performance and clinical safety outcomes of deescalation techniques training. Method: The review process involved a systematic literature search of 20 electronic databases, eligibility screening of results, data extraction, quality appraisal, and data synthesis. Results: 38 relevant studies were identified. The strongest impact of training appears to be on deescalation- related knowledge, confidence to manage aggression and de-escalation performance (although limited to artificial training scenarios). No strong conclusions could be drawn about the impact of training on assaults, injuries, containment and organisational outcomes owing to the low quality of evidence and conflicting results. Conclusions: It is assumed that de-escalation techniques training will improve staff’s ability to deescalate violent and aggressive behaviour and improve safety in practice. There is currently limited evidence that this training has these effects

3D Printed Franz cells - update on optimization of manufacture and evaluation

The evaluation of permeation profiles from cosmetic formulations is considered to be a crucial component in both the development and quality assurance of any new product [1, 2]. Data gathered from such studies allow researchers to assess the viability of delivering different materials to and through biological membranes. To date, laboratory in vitro permeation processes require the use of modified Franz type diffusion cells, conventionally fabricated from glass, which are available in different formats that can be customised to experimental requirements [3]

Hubble Space Telescope survey of the Perseus Cluster - I: The structure and dark matter content of cluster dwarf spheroidals

We present the results of a Hubble Space Telescope (HST) Advanced Camera for Surveys (ACS) study of dwarf galaxies in the core of the rich nearby Perseus Cluster, down to M_V=-12. We identify 29 dwarfs as cluster members, 17 of which are previously unstudied. All the dwarfs we examine are remarkably smooth in appearance, and lack internal features. Based on these observations, and the sizes of these dwarfs, we argue that some of the dwarfs in our sample must have a large dark matter content to prevent disruption by the cluster potential. We derive a new method, independent of kinematics, for measuring the dark matter content of dEs, based on the radius of the dwarf, the projected distance of the dwarf from the cluster centre, and the total mass of the cluster interior to it. We find that the mass-to-light ratios of these dwarfs are comparable to those of the Local Group dSphs, ranging between 1 and 120.Comment: accepted for publication by MNRA

Spermatogenesis-Specific Features of the Meiotic Program in Caenorhabditis elegans

In most sexually reproducing organisms, the fundamental process of meiosis is implemented concurrently with two differentiation programs that occur at different rates and generate distinct cell types, sperm and oocytes. However, little is known about how the meiotic program is influenced by such contrasting developmental programs. Here we present a detailed timeline of late meiotic prophase during spermatogenesis in Caenorhabditis elegans using cytological and molecular landmarks to interrelate changes in chromosome dynamics with germ cell cellularization, spindle formation, and cell cycle transitions. This analysis expands our understanding C. elegans spermatogenesis, as it identifies multiple spermatogenesis-specific features of the meiotic program and provides a framework for comparative studies. Post-pachytene chromatin of spermatocytes is distinct from that of oocytes in both composition and morphology. Strikingly, C. elegans spermatogenesis includes a previously undescribed karyosome stage, a common but poorly understood feature of meiosis in many organisms. We find that karyosome formation, in which chromosomes form a constricted mass within an intact nuclear envelope, follows desynapsis, involves a global down-regulation of transcription, and may support the sequential activation of multiple kinases that prepare spermatocytes for meiotic divisions. In spermatocytes, the presence of centrioles alters both the relative timing of meiotic spindle assembly and its ultimate structure. These microtubule differences are accompanied by differences in kinetochores, which connect microtubules to chromosomes. The sperm-specific features of meiosis revealed here illuminate how the underlying molecular machinery required for meiosis is differentially regulated in each sex