Midkine-A functions upstream of Id2a to regulate cell cycle kinetics in the developing vertebrate retina

BACKGROUND: Midkine is a small heparin binding growth factor expressed in numerous tissues during development. The unique midkine gene in mammals has two paralogs in zebrafish: midkine-a (mdka) and midkine-b (mdkb). In the zebrafish retina, during both larval development and adult photoreceptor regeneration, mdka is expressed in retinal stem and progenitor cells and functions as a molecular component of the retina’s stem cell niche. In this study, loss-of-function and conditional overexpression were used to investigate the function of Mdka in the retina of the embryonic zebrafish. RESULTS: The results show that during early retinal development Mdka functions to regulate cell cycle kinetics. Following targeted knockdown of Mdka synthesis, retinal progenitors cycle more slowly, and this results in microphthalmia, a diminished rate of cell cycle exit and a temporal delay of cell cycle exit and neuronal differentiation. In contrast, Mdka overexpression results in acceleration of the cell cycle and retinal overgrowth. Mdka gain-of-function, however, does not temporally advance cell cycle exit. Experiments to identify a potential Mdka signaling pathway show that Mdka functions upstream of the HLH regulatory protein, Id2a. Gene expression analysis shows Mdka regulates id2a expression, and co-injection of Mdka morpholinos and id2a mRNA rescues the Mdka loss-of-function phenotype. CONCLUSIONS: These data show that in zebrafish, Mdka resides in a shared Id2a pathway to regulate cell cycle kinetics in retinal progenitors. This is the first study to demonstrate the function of Midkine during retinal development and adds Midkine to the list of growth factors that transcriptionally regulate Id proteins

Strong Born—A First of Its Kind National FASD Prevention Campaign in Australia Led by the National Aboriginal Community Controlled Health Organisation (NACCHO) in Collaboration with the Aboriginal Community Controlled Health Organisations (ACCHOs)

The Strong Born Campaign (2022–2025) was launched by the National Aboriginal Community Controlled Health Organisation (NACCHO) in 2023. Strong Born is the first of its kind national Aboriginal and Torres Strait Islander health promotion campaign to address Fetal Alcohol Spectrum Disorder (FASD) within Australia. Strong Born was developed to address a longstanding, significant gap in health promotion and sector knowledge on FASD, a lifelong disability that can result from alcohol use during pregnancy. Utilizing a strengths-based and culturally sound approach, NACCHO worked closely with the Aboriginal Community Controlled Health Organisations (ACCHOs) to develop the campaign through co-design, as described in this paper. Since its inception, the ACCHOs have continually invested in driving change towards improvements in Aboriginal health determinants and health promotion. The Strong Born Campaign developed culturally safe health promotion tool kits designed for the community and health sector staff and also offered communities the opportunity to apply for FASD Communications and Engagement Grants to engage in local campaign promotion. The tool kits have been disseminated to 92 ACCHOs across Australia. This paper describes the development of the Strong Born Campaign and activities following its launch in February 2023 from an Indigenous context within Australia, as described by NACCHO

“You Think You’re Helping Them, But They’re Helping You Too”: Experiences of Scottish Male Young Offenders Participating in a Dog Training Program

increasingly popular in a range of contexts. Dog training programs (DTPs) are the most popular form of AAI in custodial contexts; prisoners often have multiple needs and DTPs seem to facilitate a diverse range of positive outcomes, including improvements in well-being, behavior, and offending behavior. However, evidence on the efficacy of prison-based DTPs is still limited and these evaluations often lack detail or methodological rigor. We examined the experiences of male young offenders (N = 70) using thematic analysis of semi-structured interviews conducted following completion of a DTP. The themes that emerged indicated a broad range of inter-related experiences and positive outcomes. The most prevalent theme related to their experiences with Dogs (including feelings and attitudes), and there were perceived improvements categorized as: Positive Effects (including mood and well-being), Motivation, Charitable Purpose, Self-Efficacy, Improved Skills, Impulsivity, and Emotional Management. These themes mapped well onto outcomes previously identified in research on DTPs, and to the program’s core aims of improving behavior, educational engagement, employability, and well-being. The diversity and nature of these themes indicates that DTPs have considerable potential to engage and benefit those individuals with multiple needs, such as young offenders, and ultimately to achieve positive long-term outcomes with significant social, health, and economic impact

Vaccine-elicited human T cells recognizing conserved protein regions inhibit HIV-1

Virus diversity and escape from immune responses are the biggest challenges to the development of an effective vaccine against HIV-1. We hypothesized that T-cell vaccines targeting the most conserved regions of the HIV-1 proteome, which are common to most variants and bear fitness costs when mutated, will generate effectors that efficiently recognize and kill virus-infected cells early enough after transmission to potentially impact on HIV-1 replication and will do so more efficiently than whole protein-based T-cell vaccines. Here, we describe the first-ever administration of conserved immunogen vaccines vectored using prime-boost regimens of DNA, simian adenovirus and modified vaccinia virus Ankara to uninfected UK volunteers. The vaccine induced high levels of effector T cells that recognized virus-infected autologous CD4+ cells and inhibited HIV-1 replication by up to 5.79 log10. The virus inhibition was mediated by both Gag- and Pol- specific effector CD8+ T cells targeting epitopes that are typically subdominant in natural infection. These results provide proof of concept for using a vaccine to target T cells at conserved epitopes, showing that these T cells can control HIV-1 replication in vitro

A major genetic locus in <i>Trypanosoma brucei</i> is a determinant of host pathology

The progression and variation of pathology during infections can be due to components from both host or pathogen, and/or the interaction between them. The influence of host genetic variation on disease pathology during infections with trypanosomes has been well studied in recent years, but the role of parasite genetic variation has not been extensively studied. We have shown that there is parasite strain-specific variation in the level of splenomegaly and hepatomegaly in infected mice and used a forward genetic approach to identify the parasite loci that determine this variation. This approach allowed us to dissect and identify the parasite loci that determine the complex phenotypes induced by infection. Using the available trypanosome genetic map, a major quantitative trait locus (QTL) was identified on T. brucei chromosome 3 (LOD = 7.2) that accounted for approximately two thirds of the variance observed in each of two correlated phenotypes, splenomegaly and hepatomegaly, in the infected mice (named &lt;i&gt;TbOrg1&lt;/i&gt;). In addition, a second locus was identified that contributed to splenomegaly, hepatomegaly and reticulocytosis (&lt;i&gt;TbOrg2&lt;/i&gt;). This is the first use of quantitative trait locus mapping in a diploid protozoan and shows that there are trypanosome genes that directly contribute to the progression of pathology during infections and, therefore, that parasite genetic variation can be a critical factor in disease outcome. The identification of parasite loci is a first step towards identifying the genes that are responsible for these important traits and shows the power of genetic analysis as a tool for dissecting complex quantitative phenotypic traits

Soluble Guanylate Cyclase α1–Deficient Mice: A Novel Murine Model for Primary Open Angle Glaucoma

Primary open angle glaucoma (POAG) is a leading cause of blindness worldwide. The molecular signaling involved in the pathogenesis of POAG remains unknown. Here, we report that mice lacking the $α_1$ subunit of the nitric oxide receptor soluble guanylate cyclase represent a novel and translatable animal model of POAG, characterized by thinning of the retinal nerve fiber layer and loss of optic nerve axons in the context of an open iridocorneal angle. The optic neuropathy associated with soluble guanylate cyclase $α_1$–deficiency was accompanied by modestly increased intraocular pressure and retinal vascular dysfunction. Moreover, data from a candidate gene association study suggests that a variant in the locus containing the genes encoding for the $α_1$ and $β_1$ subunits of soluble guanylate cyclase is associated with POAG in patients presenting with initial paracentral vision loss, a disease subtype thought to be associated with vascular dysregulation. These findings provide new insights into the pathogenesis and genetics of POAG and suggest new therapeutic strategies for POAG