Tropical pseudolinear and pseudoquadratic optimization as parametric mean-payoff games

We apply an approach based on parametric mean-payoff games to develop bisection and Newton schemes for solving problems of tropical pseudolinear and pseudoquadratic optimisation with general two-sided constraints.Comment: 30 pages (with appendices), 9 figure

Strings in extremal BTZ black holes

We study the spectrum of the worldsheet theory of the bosonic closed string in the massless and extremal rotating BTZ black holes. We use a hyperbolic Wakimoto representation of the SL(2,R) currents to construct vertex operators for the string modes on these backgrounds. We argue that there are tachyons in the twisted sector, but these are not localised near the horizon. We study the relation to the null orbifold in the limit of vanishing cosmological constant. We also discuss the problem of extending this analysis to the supersymmetric case.Comment: 20 pages, no figure

A novel, high-rate, anaerobic digester to treat high-solids waste ensuring reuse and good sanitation planning

A consortium of UK universities is working on developing a novel anaerobic digester that will treat pit latrine waste and transform it into a safe and valuable product. Physico-chemical characteristics of fresh human waste and pit latrine sludge are being determined. This is informing the development of a bioreactor containing biofilms, or slimes, of several microbial ‘trophic’ groups growing preferentially on distinct surfaces and materials. The ecologically-engineered bioreactor design will optimise the efficiency of the treatment and underpin successful digestion of high-solids waste. The potential use of the digestate will be reused in agriculture to recycle nutrients and prevent environmental, and watercourse pollution. Attitudes to sanitation, as well as to resource recovery from, and reuse of, waste, are being investigated so the participatory sanitation planning process can work effectively

New ways for our families : Designing an Aboriginal and Torres Strait Islander cultural practice framework and system responses to address the impacts of domestic and family violence on children and young people

Little has been done to understand what works to support First Nations children and young people to heal from their experiences of violence. This research project explores how services and systems can better respond to the needs of Aboriginal and Torres Strait Islander children and young people exposed to DFV who come to the attention of child protection systems. Led by the Queensland Aboriginal and Torres Strait Islander Child Protection Peak (QATSICPP), a team of First Nations researchers, supported by non-Indigenous researchers, utilised a participatory action research methodology – ensuring cultural safety and adherence to cultural values and protocols, including co-creation of knowledge. This report, the first in a series for this project, presents the results of a literature review and the findings from the initial cycles of action research conducted with Aboriginal and Torres Strait Islander chief investigators, community researchers and practitioners working in eight community-controlled child and family services across Queensland. The literature review and the outcomes of the initial action research cycle confirmed that the experience of DFV in childhood is resulting in negative lifelong outcomes for First Nations children, including increased interactions with the child protection and justice systems. The researchers also found that these responses (child protection and justice) are not adequate or culturally safe. To support healing for these children and young people, the report recommends: • holistic healing opportunities • culturally strong and community-led whole-of-family support • therapeutic healing circles and camps • connection to and knowledge about traditional cultural values, systems and traditions • a framework of perpetrator accountability • system changes include procuring place-based and healing responses for Aboriginal and Torres Strait Islander community-controlled services that support self-determination, and working collectively with the whole family. Additionally, cultural capability across the service system needs to be enhanced, and structural racism needs to be eliminated in order to reduce the load on existing Aboriginal and Torres Strait Islander services. Future publications from this research project, due in 2022, will consist of a research report on the remaining action research cycles and a framework for working with Aboriginal and Torres Strait Islander children and young people who have experienced DFV and have also come in contact with the child protection system

Genetic Variation in VEGF Does Not Contribute Significantly to the Risk of Congenital Cardiovascular Malformation

Several previous studies have investigated the role of common promoter variants in the vascular endothelial growth factor (VEGF) gene in causing congenital cardiovascular malformation (CVM). However, results have been discrepant between studies and no study to date has comprehensively characterised variation throughout the gene. We genotyped 771 CVM cases, of whom 595 had the outflow tract malformation Tetralogy of Fallot (TOF), and carried out TDT and case-control analyses using haplotype-tagging SNPs in VEGF. We carried out a meta-analysis of previous case-control or family-based studies that had typed VEGF promoter SNPs, which included an additional 570 CVM cases. To identify rare variants potentially causative of CVM, we carried out mutation screening in all VEGF exons and splice sites in 93 TOF cases. There was no significant effect of any VEGF haplotype-tagging SNP on the risk of CVM in our analyses of 771 probands. When the results of this and all previous studies were combined, there was no significant effect of the VEGF promoter SNPs rs699947 (OR 1.05 [95% CI 0.95–1.17]); rs1570360 (OR 1.17 [95% CI 0.99–1.26]); and rs2010963 (OR 1.04 [95% CI 0.93–1.16]) on the risk of CVM in 1341 cases. Mutation screening of 93 TOF cases revealed no VEGF coding sequence variants and no changes at splice consensus sequences. Genetic variation in VEGF appears to play a small role, if any, in outflow tract CVM susceptibility

Evaluation of Southern Ocean cloud in the HadGEM3 general circulation model and MERRA-2 reanalysis using ship-based observations

Southern Ocean (SO) shortwave (SW) radiation biases are a common problem in contemporary general circulation models (GCMs), with most models exhibiting a tendency to absorb too much incoming SW radiation. These biases have been attributed to deficiencies in the representation of clouds during the austral summer months, either due to cloud cover or cloud albedo being too low. The problem has been the focus of many studies, most of which utilised satellite datasets for model evaluation. We use multi-year ship-based observations and the CERES spaceborne radiation budget measurements to contrast cloud representation and SW radiation in the atmospheric component Global Atmosphere (GA) version&nbsp;7.1 of the HadGEM3 GCM and the MERRA-2 reanalysis. We find that the prevailing bias is negative in GA7.1 and positive in MERRA-2. GA7.1 performs better than MERRA-2 in terms of absolute SW bias. Significant errors of up to 21&thinsp;W&thinsp;m&minus;2 (GA7.1) and 39&thinsp;W&thinsp;m&minus;2 (MERRA-2) are present in both models in the austral summer. Using ship-based ceilometer observations, we find low cloud below 2&thinsp;km to be predominant in the Ross Sea and the Indian Ocean sectors of the SO. Utilising a novel surface lidar simulator developed for this study, derived from an existing Cloud Feedback Model Intercomparison Project (CFMIP) Observation Simulator Package (COSP) &ndash; active remote sensing simulator (ACTSIM) spaceborne lidar simulator, we find that GA7.1 and MERRA-2 both underestimate low cloud and fog occurrence relative to the ship observations on average by 4&thinsp;%&ndash;9&thinsp;% (GA7.1) and 18&thinsp;% (MERRA-2). Based on radiosonde observations, we also find the low cloud to be strongly linked to boundary layer atmospheric stability and the sea surface temperature. GA7.1 and MERRA-2 do not represent the observed relationship between boundary layer stability and clouds well. We find that MERRA-2 has a much greater proportion of cloud liquid water in the SO in austral summer than GA7.1, a likely key contributor to the difference in the SW radiation bias. Our results suggest that subgrid-scale processes (cloud and boundary layer parameterisations) are responsible for the bias and that in GA7.1 a major part of the SW radiation bias can be explained by cloud cover underestimation, relative to underestimation of cloud albedo.</p

Genome-wide association study identifies loci on 12q24 and 13q32 associated with Tetralogy of Fallot

We conducted a genome-wide association study to search for risk alleles associated with Tetralogy of Fallot (TOF), using a northern European discovery set of 835 cases and 5159 controls. A region on chromosome 12q24 was associated (P = 1.4 × 10−7) and replicated convincingly (P = 3.9 × 10−5) in 798 cases and 2931 controls [per allele odds ratio (OR) = 1.27 in replication cohort, P = 7.7 × 10−11 in combined populations]. Single nucleotide polymorphisms in the glypican 5 gene on chromosome 13q32 were also associated (P = 1.7 × 10−7) and replicated convincingly (P = 1.2 × 10−5) in 789 cases and 2927 controls (per allele OR = 1.31 in replication cohort, P = 3.03 × 10−11 in combined populations). Four additional regions on chromosomes 10, 15 and 16 showed suggestive association accompanied by nominal replication. This study, the first genome-wide association study of a congenital heart malformation phenotype, provides evidence that common genetic variation influences the risk of TO

Differential sensitivity of Src-family kinases to activation by SH3 domain displacement

Src-family kinases (SFKs) are non-receptor protein-tyrosine kinases involved in a variety of signaling pathways in virtually every cell type. The SFKs share a common negative regulatory mechanism that involves intramolecular interactions of the SH3 domain with the PPII helix formed by the SH2-kinase linker as well as the SH2 domain with a conserved phosphotyrosine residue in the C-terminal tail. Growing evidence suggests that individual SFKs may exhibit distinct activation mechanisms dictated by the relative strengths of these intramolecular interactions. To elucidate the role of the SH3:linker interaction in the regulation of individual SFKs, we used a synthetic SH3 domain-binding peptide (VSL12) to probe the sensitivity of downregulated c-Src, Hck, Lyn and Fyn to SH3-based activation in a kinetic kinase assay. All four SFKs responded to VSL12 binding with enhanced kinase activity, demonstrating a conserved role for SH3:linker interaction in the control of catalytic function. However, the sensitivity and extent of SH3-based activation varied over a wide range. In addition, autophosphorylation of the activation loops of c-Src and Hck did not override regulatory control by SH3:linker displacement, demonstrating that these modes of activation are independent. Our results show that despite the similarity of their downregulated conformations, individual Src-family members show diverse responses to activation by domain displacement which may reflect their adaptation to specific signaling environments in vivo. © 2014 Moroco et al

Breast cancer risks associated with missense variants in breast cancer susceptibility genes

BACKGROUND: Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. METHODS: We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. RESULTS: The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. CONCLUSIONS: These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility

Deletion of individual Ku subunits in mice causes an NHEJ-independent phenotype potentially by altering apurinic/apyrimidinic site repair

Ku70 and Ku80 form a heterodimer called Ku that forms a holoenzyme with DNA dependent-protein kinase catalytic subunit (DNA-PKCS) to repair DNA double strand breaks (DSBs) through the nonhomologous end joining (NHEJ) pathway. As expected mutating these genes in mice caused a similar DSB repair-defective phenotype. However, ku70-/- cells and ku80 -/- cells also appeared to have a defect in base excision repair (BER). BER corrects base lesions, apurinic/apyrimidinic (AP) sites and single stand breaks (SSBs) utilizing a variety of proteins including glycosylases, AP endonuclease 1 (APE1) and DNA Polymerase β (Pol β). In addition, deleting Ku70 was not equivalent to deleting Ku80 in cells and mice. Therefore, we hypothesized that free Ku70 (not bound to Ku80) and/or free Ku80 (not bound to Ku70) possessed activity that influenced BER. To further test this hypothesis we performed two general sets of experiments. The first set showed that deleting either Ku70 or Ku80 caused an NHEJ-independent defect. We found ku80-/- mice had a shorter life span than dna-pkcs-/- mice demonstrating a phenotype that was greater than deleting the holoenzyme. We also found Ku70-deletion induced a p53 response that reduced the level of small mutations in the brain suggesting defective BER. We further confirmed that Ku80-deletion impaired BER via a mechanism that was not epistatic to Pol β. The second set of experiments showed that free Ku70 and free Ku80 could influence BER. We observed that deletion of either Ku70 or Ku80, but not both, increased sensitivity of cells to CRT0044876 (CRT), an agent that interferes with APE1. In addition, free Ku70 and free Ku80 bound to AP sites and in the case of Ku70 inhibited APE1 activity. These observations support a novel role for free Ku70 and free Ku80 in altering BER. © 2014 Choi et al