The Extinction of Dengue through Natural Vulnerability of Its Vectors

Dengue transmission has not always been confined to tropical areas. In some cases, this has been due to a reduced geographic range of the mosquitoes that are able to carry dengue viruses. In Australia, Aedes aegypti mosquitoes once occurred throughout temperate, drier parts of the country but are now restricted to the wet tropics. We used a computer modelling approach to determine whether these mosquitoes could inhabit their former range. This was done by simulating dengue mosquito populations in virtual environments that experienced 10 years of actual daily weather conditions (1998–2007) obtained for 13 locations inside and outside the current tropical range. We discovered that in areas outside the Australian wet tropics, Ae. aegypti often becomes extinct, particularly when conditions are too cool for year-round egg-laying activity, and/or too dry for eggs to hatch. Thus, despite being a global pest and disease vector, Ae. aegypti mosquitoes are naturally vulnerable to extinction in certain conditions. Such vulnerability should be exploited in vector control programs

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Photophysical and Biological Properties of Iridium Tetrazolato Complexes Functionalised with Fatty Acid Chains

Five cyclometalated Ir(III) tetrazolato complexes functionalised with fatty acid chains (octanoic, palmitic, stearic, palmitoleic, and oleic) have been synthesised. The fatty acids were chosen to evaluate the potential effect of the length and degree of unsaturation on the biological properties of the complexes for use as cellular imaging agents. The complexes were analysed in both organic and aqueous media to determine if the presence and nature of the fatty acid chains had a significant effect on their photophysical properties. The complexes display green&ndash;yellow emission in dichloromethane solutions with relatively long excited state decays, within the range 360&ndash;393 ns, and quantum yields between 5.4% and 6.7% (from degassed solutions). Temperature-dependent photophysical studies suggest that the emitting excited states of the complexes might be quenched by the thermal population of dark states. In water, the quantum yields drop within the range of 0.5%&ndash;2.4%, and the photophysical measurements are influenced by the variable degrees of aggregation. In general, the entire series displayed low cytotoxicity and relatively high photostability, which are favourable attributes in the design of cellular imaging agents. Images of live HeLa cells were obtained for all the complexes, but those functionalised with palmitic and stearic acids had limitations due the lower solubility conferred by the saturated aliphatic chains. The complexes were mainly detected within the endoplasmic reticulum

Prefix reversals on binary and ternary strings

Given a permutation $\pi$, the application of prefix reversal $f^{(i)}$ to $\pi$ reverses the order of the first $i$ elements of $\pi$. The problem of sorting by prefix reversals (also known as pancake flipping), made famous by Gates and Papadimitriou (Discrete Math., 27 (1979), pp. 47–57), asks for the minimum number of prefix reversals required to sort the elements of a given permutation. In this paper we study a variant of this problem where the prefix reversals act not on permutations but on strings over a fixed size alphabet. We determine the minimum number of prefix reversals required to sort binary and ternary strings, with polynomial-time algorithms for these sorting problems as a result; demonstrate that computing the minimum prefix reversal distance between two binary strings is NP-hard; give an exact expression for the prefix reversal diameter of binary strings; and give bounds on the prefix reversal diameter of ternary strings. We also consider a weaker form of sorting called grouping (of identical symbols) and give polynomial-time algorithms for optimally grouping binary and ternary strings. A number of intriguing open problems are also discusse

Breast Cancer Screening Amongst Arabic Women Living in the State of Qatar: Preliminary Results of the Cross-Sectional Community Based Survey

Background: Breast cancer is the most common cancer among women in Qatar, incidence rate is rising and it is often diagnosed at advanced stages. Early detection of breast cancer through regular screening activities has been found to decrease morbidity and mortality rates. Although research on breast cancer screening in the Middle East is scarce, low levels of knowledge and poor participation rates have been found to act as barriers towards breast cancer screening activities such as breast self-examination, clinical breast examination and mammography. Various other barriers have been described in the literature. Identification of these potential barriers and facilitators is urgently needed in order to develop culturally appropriate interventions aiming to improve awareness and breast cancer screening participation rates. Objectives: A three-phase research program for which the goals are to (1) Understand breast health issues in Qatar; (2) Identify and implement strategies that assist Arabic women’s participation in breast cancer screening activities (3) Evaluate, facilitate and sustain these strategies. Methods: In Phase 1 two studies are conducted. Study 1: this quantitative study examines data from a convenience sample of 1063 Arabic women in Qatar on a cross sectional community based survey. Face to face interviews are used to investigate knowledge, attitudes, practices, barriers and facilitators regarding breast cancer screening activities. Study 2: Using an ethnographic qualitative methodology, this study will capture the complexity and diversity of reasons of health behaviour choices on a purposive sample of 50 women, 50 men and 30 health care providers. Results: Preliminary results from study 1 will be presented. These will include: participation rates of breast cancer screening activities of Arabic women in Qatar such as breast self-examination, clinical breast examination and mammography; levels of knowledge of breast cancer and its screening; identified barriers and facilitators to breast cancer screening as experienced by these women. Conclusion: Combined results will enable development of culturally appropriate intervention strategies to raise awareness and participation rate in breast cancer screening among Arabic women living in Qatar and the Gulf regio