Comparative quantitative monitoring of rabbit haemorrhagic disease viruses in rabbit kittens

BACKGROUND: Only one strain (the Czech CAPM-v351) of rabbit haemorrhagic disease virus (RHDV) has been released in Australia and New Zealand to control pest populations of the European rabbit O. cuniculus. Antigenic variants of RHDV known as RHDVa strains are reportedly replacing RHDV strains in other parts of the world, and Australia is currently investigating the usefulness of RHDVa to complement rabbit biocontrol efforts in Australia and New Zealand. RHDV efficiently kills adult rabbits but not rabbit kittens, which are more resistant to RHD the younger they are and which may carry the virus without signs of disease for prolonged periods. These different infection patterns in young rabbits may significantly influence RHDV epidemiology in the field and hence attempts to control rabbit numbers. METHODS: We quantified RHDV replication and shedding in 4–5 week old rabbits using quantitative real time PCR to assess their potential to shape RHDV epidemiology by shedding and transmitting virus. We further compared RHDV-v351 with an antigenic variant strain of RHDVa in kittens that is currently being considered as a potential RHDV strain for future release to improve rabbit biocontrol in Australia. RESULTS: Kittens were susceptible to infection with virus doses as low as 10 ID(50). Virus growth, shedding and transmission after RHDVa infection was found to be comparable or non-significantly lower compared to RHDV. Virus replication and shedding was observed in all kittens infected, but was low in comparison to adult rabbits. Both viruses were shed and transmitted to bystander rabbits. While blood titres indicated that 4–5 week old kittens mostly clear the infection even in the absence of maternal antibodies, virus titres in liver, spleen and mesenteric lymph node were still high on day 5 post infection. CONCLUSIONS: Rabbit kittens are susceptible to infection with very low doses of RHDV, and can transmit virus before they seroconvert. They may therefore play an important role in RHDV field epidemiology, in particular for virus transmission within social groups during virus outbreaks

A role for SNX5 in the regulation of macropinocytosis

Background: The mechanisms and components that regulate macropinocytosis are poorly understood. Here we have investigated the role of sorting nexin 5 (SNX5) in the regulation of macropinocytic activity

The Relevance of Advanced Therapy Medicinal Products in the Field of Transplantation and the Need for Academic Research Access:Overcoming Bottlenecks and Claiming a New Time

The field of transplantation has witnessed the emergence of Advanced Therapy Medicinal Products (ATMPs) as highly promising solutions to address the challenges associated with organ and tissue transplantation. ATMPs encompass gene therapy, cell therapy, and tissue-engineered products, hold immense potential for breakthroughs in overcoming the obstacles of rejection and the limited availability of donor organs. However, the development and academic research access to ATMPs face significant bottlenecks that hinder progress. This opinion paper emphasizes the importance of addressing bottlenecks in the development and academic research access to ATMPs by implementing several key strategies. These include the establishment of streamlined regulatory processes, securing increased funding for ATMP research, fostering collaborations and partnerships, setting up centralized ATMP facilities, and actively engaging with patient groups. Advocacy at the policy level is essential to provide support for the development and accessibility of ATMPs, thereby driving advancements in transplantation and enhancing patient outcomes. By adopting these strategies, the field of transplantation can pave the way for the introduction of innovative and efficacious ATMP therapies, while simultaneously fostering a nurturing environment for academic research.</p

THE UNIQUENESS THEOREM FOR ROTATING BLACK HOLE SOLUTIONS OF SELF-GRAVITATING HARMONIC MAPPINGS

We consider rotating black hole configurations of self-gravitating maps from spacetime into arbitrary Riemannian manifolds. We first establish the integrability conditions for the Killing fields generating the stationary and the axisymmetric isometry (circularity theorem). Restricting ourselves to mappings with harmonic action, we subsequently prove that the only stationary and axisymmetric, asymptotically flat black hole solution with regular event horizon is the Kerr metric. Together with the uniqueness result for non-rotating configurations and the strong rigidity theorem, this establishes the uniqueness of the Kerr family amongst all stationary black hole solutions of self-gravitating harmonic mappings.Comment: 18 pages, latex, no figure

Visualisation of macropinosome maturation by the recruitment of sorting nexins

We report that phosphoinositol-binding sorting nexin 5 ( SNX5) associates with newly formed macropinosomes induced by EGF stimulation. We used the recruitment of GFP-SNX5 to macropinosomes to track their maturation. Initially, GFP-SNX5 is sequestered to discrete subdomains of the macropinosome; these subdomains are subsequently incorporated into highly dynamic, often branched, tubular structures. Time-lapse videomicroscopy revealed the highly dynamic extension of SNX5-labelled tubules and their departure from the macropinosome body to follow predefined paths towards the perinuclear region of the cell, before fusing with early endosomal acceptor membranes. The extension and departure of these tubular structures occurs rapidly over 5-10 minutes and is dependent upon intact microtubules. As the tubular structures depart from the macropinosome there is a reduction in the surface area and an increase in tension of the limiting membrane of the macropinosome. In addition to the recruitment of SNX5 to the macropinosome, Rab5, SNX1 and EEA1 are also recruited by newly formed macropinosomes, followed by the accumulation of Rab7. SNX5 forms heterodimers with SNX1 and this interaction is required for endosome association of SNX5. We propose that the departure of SNX5-positive tubules represents a rapid mechanism of recycling components from macropinosomes thereby promoting their maturation into Rab7-positive structures. Collectively these findings provide a detailed real-time characterisation of the maturation process of the macropinocytic endosome

Early clinical markers of overweight/obesity onset and resolution by adolescence

Objectives: We examined how combinations of clinical indicators at various ages predict overweight/obesity development, as well as resolution, by 10–11 and 14–15 years of age.Methods: Data were derived from Birth (N = 3469) and Kinder (N = 3276) cohorts of the Longitudinal Study of Australian Children, followed from ages 2–3 and 4–5 years, respectively. Every two years, 25 potential obesity-relevant clinical indicators were quantified. Overweight/obesity was defined using International Obesity Taskforce cutpoints at 10–11 years and 14–15 years.Results: In both cohorts, three factors predicted both development and resolution of overweight/obesity in multivariable models. Among normal weight children, increased odds of developing overweight/obesity were associated with higher child (odd ratio (OR) 1.67–3.35 across different study waves) and maternal (OR 1.05–1.09) BMI, and inversely with higher maternal education (OR 0.60–0.62, when assessed at age 2–7 years). Lower odds of resolving existing overweight/obesity were related with higher child (OR 0.51–0.79) and maternal (OR 0.89–0.95) BMI, and inversely with higher maternal education (OR 1.62–1.92, when assessed at age 2–5 years). The prevalence of overweight/obesity at the age of 14–15 years was 13% among children with none of these risk factors at age 6–7 years, compared with 71% among those with all 3 risk factors (P Conclusions: From early childhood onwards, child and maternal BMI and maternal education predict overweight/obesity onset and resolution by adolescence. A simple risk score, easily available to child health clinicians, could help target treatment or prevention.</p

Do body mass index and waist-to-height ratio over the preceding decade predict retinal microvasculature in 11-12 year olds and midlife adults?

Background/objectives Microvascular changes may contribute to obesity-associated cardiovascular disease. We examined whether body mass index (BMI) and waist-to-height ratio (WHtR) (1) at multiple earlier time points and (2) decade-long trajectories predicted retinal microvascular parameters in mid-childhood/adulthood. Methods Participants/design: 1288 11-12 year olds (51% girls) and 1264 parents (87% mothers) in the population-based Child Health CheckPoint (CheckPoint) module within the Longitudinal Study of Australian Children (LSAC). LSAC exposure measures: biennial BMI z-score and WHtR for children at five time points from age 2-3 to 10-11 years and self-reported parent BMI at six time points from child age 0-1 years to 10-11 years. CheckPoint outcome measures: retinal arteriolar and venular caliber. Analyses: BMI/WHtR trajectories were identified by group-based trajectory modeling; linear regression models estimated associations between BMI/WHtR at each time point/trajectories and later retinal vascular caliber, adjusted for age, sex, and family socioeconomic status. Results In time point analyses, higher child BMI/WHtR from age 4 to 5 years was associated with narrower arteriolar caliber at the age of 11-12 years, but not venular caliber. For example, each standard deviation higher in BMI z-score at 4-5 years was associated with narrower arteriolar caliber at 11-12 years (standardized mean difference (SMD): -0.05, 95% confidence interval (CI): -0.10 to 0.01); by 10-11 years, associations had doubled to -0.10 (95% CI: -0.16 to -0.05). In adults, these finding were similar, except the magnitude of BMI and arteriolar associations were similar across all time points (SMD: -0.11 to -0.13). In child and adult BMI trajectory analyses, less favorable trajectories predicted narrower arteriolar (p-trend 0.1), caliber. Compared with those in the average BMI trajectory, SMDs in arterial caliber for children and adults in the highest trajectory were -0.25 (95% CI: -0.44 to -0.07) and -0.42 (95% CI: -0.73 to -0.10), respectively. Venular caliber showed late associations with child WHtR, but not with BMI in children or adults. Conclusions Associations of decade-long high BMI trajectories with narrowed retinal arteriolar caliber emerge in children, and are clearly evident by midlife. Adiposity appears to exert its early adverse life course impacts on the microcirculation more via arteriolar than venular mechanisms.</div