Brain microtubule-associated proteins modulate microtubule dynamic instability in vitro : real-time-observations using video microscopy

We used video assays to study the dynamic instability behavior of individual microtubules assembled in vitro with purified tau, purified MAP2 or a preparation of unfractionated heat-stable MAPs. Axoneme-nucleated microtubules were assembled from pure tubulin at concentrations between 4 and 9 microM in the presence of MAPs, and observed by video-differential interference contrast microscopy. Microtubules co-assembled with each MAP preparation exhibited the elongation and rapid shortening phases and the abrupt transitions (catastrophe and rescue) characteristic of dynamic instability. Each MAP preparation increased the microtubule elongation rate above that for purified tubulin alone by decreasing the tubulin subunit dissociation rate during elongation. The brain MAPs used in this study reduced the rate of microtubule rapid shortening, but allowed significant loss of polymer during the shortening phase. Purified tau and MAP2 decreased the frequency of catastrophe and increased the frequency of rescue, while the heat-stable MAPs suppressed catastrophe at all but the lowest tubulin concentrations. Thus, each of these MAPs modulates, but does not abolish, dynamic instability behavior of microtubules. We propose a model to explain how MAP2 and tau bind to the microtubule lattice at sites along protofilaments so that the MAPs promote polymerization, but do not significantly block the mechanism of rapid shortening inherent in the tubulin lattice. Rapid shortening, when it occurs, proceeds primarily by the dissociation of short fragments of protofilaments, which contain the bound MAPs

Evidence for susceptibility genes to familial Wilms tumour in addition to WT1, FWT1 and FWT2

Three loci have been implicated in familial Wilms tumour: WT1 located on chromosome 11p13, FWT1 on 17q12-q21, and FWT2 on 19q13. Two out of 19 Wilms tumour families evaluated showed strong evidence against linkage at all three loci. Both of these families contained at least three cases of Wilms tumour indicating that they were highly likely to be due to genetic susceptibility and therefore that one or more additional familial Wilms tumour susceptibility genes remain to be found. © 2000 Cancer Research Campaig

Identification of new Wilms tumour predisposition genes: an exome sequencing study

BACKGROUND: Wilms tumour is the most common childhood renal cancer and is genetically heterogeneous. While several Wilms tumour predisposition genes have been identified, there is strong evidence that further predisposition genes are likely to exist. Our study aim was to identify new predisposition genes for Wilms tumour. METHODS: In this exome sequencing study, we analysed lymphocyte DNA from 890 individuals with Wilms tumour, including 91 affected individuals from 49 familial Wilms tumour pedigrees. We used the protein-truncating variant prioritisation method to prioritise potential disease-associated genes for further assessment. We evaluated new predisposition genes in exome sequencing data that we generated in 334 individuals with 27 other childhood cancers and in exome data from The Cancer Genome Atlas obtained from 7632 individuals with 28 adult cancers. FINDINGS: We identified constitutional cancer-predisposing mutations in 33 individuals with childhood cancer. The three identified genes with the strongest signal in the protein-truncating variant prioritisation analyses were TRIM28, FBXW7, and NYNRIN. 21 of 33 individuals had a mutation in TRIM28; there was a strong parent-of-origin effect, with all ten inherited mutations being maternally transmitted (p=0·00098). We also found a strong association with the rare epithelial subtype of Wilms tumour, with 14 of 16 tumours being epithelial or epithelial predominant. There were no TRIM28 mutations in individuals with other childhood or adult cancers. We identified truncating FBXW7 mutations in four individuals with Wilms tumour and a de-novo non-synonymous FBXW7 mutation in a child with a rhabdoid tumour. Biallelic truncating mutations in NYNRIN were identified in three individuals with Wilms tumour, which is highly unlikely to have occurred by chance (p<0·0001). Finally, we identified two de-novo KDM3B mutations, supporting the role of KDM3B as a childhood cancer predisposition gene. INTERPRETATION: The four new Wilms tumour predisposition genes identified-TRIM28, FBXW7, NYNRIN, and KDM3B-are involved in diverse biological processes and, together with the other 17 known Wilms tumour predisposition genes, account for about 10% of Wilms tumour cases. The overlap between these 21 constitutionally mutated predisposition genes and 20 genes somatically mutated in Wilms tumour is limited, consisting of only four genes. We recommend that all individuals with Wilms tumour should be offered genetic testing and particularly, those with epithelial Wilms tumour should be offered TRIM28 genetic testing. Only a third of the familial Wilms tumour clusters we analysed were attributable to known genes, indicating that further Wilms tumour predisposition factors await discovery. FUNDING: Wellcome Trust

Healthcare workers' perspectives and practices regarding the disclosure of HIV status to children in Malawi: A cross-sectional study

Background: In 2011 the World Health Organisation recommended that children with a diagnosis of HIV be gradually informed about their HIV status between the ages of 6 and 12 years. However, to date, literature has focused mainly on primary caregiver and child experiences with HIV disclosure, little is known about healthcare workers' perspectives and practices of HIV status disclosure to children. The aim of this study was to assess healthcare workers' perspectives and practices regarding the disclosure of HIV status to children aged between 6 and 12 years in Malawi. Methods: A cross-sectional survey was used to collect data from 168 healthcare providers working in antiretroviral clinics in all government District and Tertiary Hospitals in Malawi. Participants were asked questions regarding their knowledge, practice, and barriers to HIV disclosure. Data were analysed using binary logistic regression. Results: Almost all healthcare workers (98%) reported that it was important to disclose HIV status to children. A significant proportion (37%) reported that they had never disclosed HIV status to a child and about half estimated that the rate of HIV disclosure at their facility was 25% or less. The main barriers to disclosure were lack of training on disclosure (85%) and lack of a standard tool for disclosure (84%). Female healthcare workers (aOR) 2.4; 95% CI: 1.1-5.5) and lack of training on disclosure (aOR 7.7; 95% CI: 3.4-10.7) were independently associated with never having disclosed HIV status to a child. Conclusions: This study highlights the need for providing appropriate training in HIV disclosure for healthcare workers and the provision of standardised disclosure materials

Improving early childhood care and development, HIV testing, treatment and support, and nutrition in Mokhotlong, Lesotho: study protocol for a cluster randomized controlled trial

Background Since 1990, the lives of 48 million children under the age of 5 have been saved because of increased investments in reducing child mortality. However, despite these unprecedented gains, more than 200 million children in low and middle income countries (LMIC) cannot meet their developmental potential due to poverty, poor health and nutrition, and lack of necessary stimulation and care. Lesotho has high levels of poverty, HIV and malnutrition, all of which affect child development outcomes. There is a unique opportunity to address these complex issues through the widespread network of informal preschools in rural villages in the country, which provide a setting for inclusive, integrated Early Childhood Care and Development (ECCD), HIV and nutrition interventions. Methods We are conducting a cluster randomised controlled trial in Mokhotlong district, Lesotho, to evaluate a newly developed community-based intervention programme to integrate HIV testing and treatment services, ECCD, and nutrition education for caregivers with children aged 1-5 years living in rural villages. Caregivers and their children are randomly assigned by village to intervention or control condition. We select, train, and supervise community health workers recruited to implement the intervention, which consists of nine group-based sessions with caregivers and children over 12 weeks (eight weekly sessions, and a ninth top up session one month later), followed by a locally hosted community health outreach day event. Group-based sessions focus on using early dialogic booksharing to promote cognitive development and caregiver-child interaction, health-related messages, including motivation for HIV-testing and treatment uptake for young children, and locally appropriate nutrition education. All children aged 1-5 years and their primary caregivers living in study villages are eligible for participation. Caregivers and their children will be interviewed and assessed at baseline, immediately after completion of the intervention, and 12 months post intervention. Discussion This study provides a unique opportunity to assess the potential of an integrated early childhood development intervention to prevent or mitigate developmental delays in children living in a context of extreme poverty and high HIV rates in rural Lesotho. This paper presents the intervention content and research protocol for the study

Properties of Rubble-Pile Asteroid (101955) Bennu from OSIRIS-REx Imaging and Thermal Analysis

Establishing the abundance and physical properties of regolith and boulders on asteroids is crucial for understanding the formation and degradation mechanisms at work on their surfaces. Using images and thermal data from NASA's Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer (OSIRIS-REx) spacecraft, we show that asteroid (101955) Bennu's surface is globally rough, dense with boulders, and low in albedo. The number of boulders is surprising given Bennu's moderate thermal inertia, suggesting that simple models linking thermal inertia to particle size do not adequately capture the complexity relating these properties. At the same time, we find evidence for a wide range of particle sizes with distinct albedo characteristics. Our findings imply that ages of Bennu's surface particles span from the disruption of the asteroid's parent body (boulders) to recent in situ production (micrometre-scale particles)

Environmental regulation of carbon isotope composition and crassulacean acid metabolism in three plant communities along a water availability gradient

Expression of crassulacean acid metabolism (CAM) is characterized by extreme variability within and between taxa and its sensitivity to environmental variation. In this study, we determined seasonal fluctuations in CAM photosynthesis with measurements of nocturnal tissue acidification and carbon isotopic composition (δ13C) of bulk tissue and extracted sugars in three plant communities along a precipitation gradient (500, 700, and 1,000 mm year−1) on the Yucatan Peninsula. We also related the degree of CAM to light habitat and relative abundance of species in the three sites. For all species, the greatest tissue acid accumulation occurred during the rainy season. In the 500 mm site, tissue acidification was greater for the species growing at 30% of daily total photon flux density (PFD) than species growing at 80% PFD. Whereas in the two wetter sites, the species growing at 80% total PFD had greater tissue acidification. All species had values of bulk tissue δ13C less negative than −20‰, indicating strong CAM activity. The bulk tissue δ13C values in plants from the 500 mm site were 2‰ less negative than in plants from the wetter sites, and the only species growing in the three communities, Acanthocereus tetragonus (Cactaceae), showed a significant negative relationship between both bulk tissue and sugar δ13C values and annual rainfall, consistent with greater CO2 assimilation through the CAM pathway with decreasing water availability. Overall, variation in the use of CAM photosynthesis was related to water and light availability and CAM appeared to be more ecologically important in the tropical dry forests than in the coastal dune

Exploring the intersection between violence against women and children from the perspective of parents convicted of child homicide

Violence against women and violence against children are distinct research fields. Quantitative studies have demonstrated their intersection, but qualitative data provides an opportunity for a comprehensive understanding of this interface. Interviews with 22 parents/caregivers convicted of child homicide provided an opportunity to explore the context of violent experiences in their lives including their use of violence and their experiences of it in their intimate and parenting relationships. Using a feminist framework, we found that patriarchal family structures, gender and power dynamics contribute to the use of violence. Revenge child homicide was common with distinct gendered differences. This study calls for closer collaboration between the two fields to assist in developing prevention interventions to address and eradicate both forms of violence