Open Problems on Central Simple Algebras

We provide a survey of past research and a list of open problems regarding central simple algebras and the Brauer group over a field, intended both for experts and for beginners.Comment: v2 has some small revisions to the text. Some items are re-numbered, compared to v

An investigation of causes of false positive single nucleotide polymorphisms using simulated reads from a small eukaryote genome

Background: Single Nucleotide Polymorphisms (SNPs) are widely used molecular markers, and their use has increased massively since the inception of Next Generation Sequencing (NGS) technologies, which allow detection of large numbers of SNPs at low cost. However, both NGS data and their analysis are error-prone, which can lead to the generation of false positive (FP) SNPs. We explored the relationship between FP SNPs and seven factors involved in mapping-based variant calling - quality of the reference sequence, read length, choice of mapper and variant caller, mapping stringency and filtering of SNPs by read mapping quality and read depth. This resulted in 576 possible factor level combinations. We used error- and variant-free simulated reads to ensure that every SNP found was indeed a false positive. Results: The variation in the number of FP SNPs generated ranged from 0 to 36,621 for the 120 million base pairs (Mbp) genome. All of the experimental factors tested had statistically significant effects on the number of FP SNPs generated and there was a considerable amount of interaction between the different factors. Using a fragmented reference sequence led to a dramatic increase in the number of FP SNPs generated, as did relaxed read mapping and a lack of SNP filtering. The choice of reference assembler, mapper and variant caller also significantly affected the outcome. The effect of read length was more complex and suggests a possible interaction between mapping specificity and the potential for contributing more false positives as read length increases. Conclusions: The choice of tools and parameters involved in variant calling can have a dramatic effect on the number of FP SNPs produced, with particularly poor combinations of software and/or parameter settings yielding tens of thousands in this experiment. Between-factor interactions make simple recommendations difficult for a SNP discovery pipeline but the quality of the reference sequence is clearly of paramount importance. Our findings are also a stark reminder that it can be unwise to use the relaxed mismatch settings provided as defaults by some read mappers when reads are being mapped to a relatively unfinished reference sequence from e.g. a non-model organism in its early stages of genomic exploration

Confirmation of childhood acute lymphoblastic leukemia variants, ARID5B and IKZF1, and interaction with parental environmental exposures.

Genome wide association studies (GWAS) have established association of ARID5B and IKZF1 variants with childhood acute lymphoblastic leukemia (ALL). Epidemiological studies suggest that environmental factors alone appear to make a relatively minor contribution to disease risk. The polygenic nature of childhood ALL predisposition together with the timing of environmental triggers may hold vital clues for disease etiology. This study presents results from an Australian GWAS of childhood ALL cases (n = 358) and population controls (n = 1192). Furthermore, we utilised family trio (n = 204) genotypes to extend our investigation to gene-environment interaction of significant loci with parental exposures before conception, and child's sex and age. Thirteen SNPs achieved genome wide significance in the population based case/control analysis; ten annotated to ARID5B and three to IKZF1. The most significant SNPs in these regions were ARID5B rs4245595 (OR 1.63, CI 1.38-1.93, P = 2.13×10(-9)), and IKZF1 rs1110701 (OR 1.69, CI 1.42-2.02, p = 7.26×10(-9)). There was evidence of gene-environment interaction for risk genotype at IKZF1, whereby an apparently stronger genetic effect was observed if the mother took folic acid or if the father did not smoke prior to pregnancy (respective interaction P-values: 0.04, 0.05). There were no interactions of risk genotypes with age or sex (P-values >0.2). Our results evidence that interaction of genetic variants and environmental exposures may further alter risk of childhood ALL however, investigation in a larger population is required. If interaction of folic acid supplementation and IKZF1 variants holds, it may be useful to quantify folate levels prior to initiating use of folic acid supplements

Elevated Ratio of Urinary Metabolites of Thromboxane and Prostacyclin Is Associated with Adverse Cardiovascular Events in ADAPT

Results from prevention trials, including the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT), have fueled discussion about the cardiovascular (CV) risks associated with non-steroidal anti-inflammatory drugs (NSAIDs). We tested the hypotheses that (i) adverse CV events reported among ADAPT participants (aged 70 years and older) are associated with increased ratio of urine 11-dehydrothromboxane B2 (Tx-M) to 2′3-donor–6-keto-PGF1 (PGI-M) attributable to NSAID treatments; (ii) coincident use of aspirin (ASA) would attenuate NSAID-induced changes in Tx-M/PGI-M ratio; and (iii) use of NSAIDs and/or ASA would not alter urine or plasma concentrations of F2-isoprostanes (IsoPs), in vivo biomarkers of free radical damage. We quantified urine Tx-M and PGI-M, and urine and plasma F2-IsoPs from 315 ADAPT participants using stable isotope dilution assays with gas chromatography/mass spectrometry, and analyzed these data by randomized drug assignment and self-report compliance as well as ASA use. Adverse CV events were significantly associated with higher urine Tx-M/PGI-M ratio, which seemed to derive mainly from lowered PGI-M. Participants taking ASA alone had reduced urine Tx-M/PGI-M compared to no ASA or NSAID; however, participants taking NSAIDs plus ASA did not have reduced urine Tx-M/PGI-M ratio compared to NSAIDs alone. Neither NSAID nor ASA use altered plasma or urine F2-IsoPs. These data suggest a possible mechanism for the increased risk of CV events reported in ADAPT participants assigned to NSAIDs, and suggest that the changes in the Tx-M/PGI-M ratio was not substantively mitigated by coincident use of ASA in individuals 70 years or older

Testing the theory of immune selection in cancers that break the rules of transplantation

Modification of cancer cells likely to reduce their immunogenicity, including loss or down-regulation of MHC molecules, is now well documented and has become the main support for the concept of immune surveillance. The evidence that these modifications, in fact, result from selection by the immune system is less clear, since the possibility that they may result from reorganized metabolism associated with proliferation or from cell de-differentiation remains. Here, we (a) survey old and new transplantation experiments that test the possibility of selection and (b) survey how transmissible tumours of dogs and Tasmanian devils provide naturally evolved tests of immune surveillance

Insight the C-Site Pocket Conformational Changes Responsible for Sirtuin 2 Activity Using Molecular Dynamics Simulations

Sirtuin belongs to a family of typical histone deacetylase which regulates the fundamental cellular biological processes including gene expression, genome stability, mitosis, nutrient metabolism, aging, mitochondrial function, and cell motility. Michael et. al. reported that B-site mutation (Q167A and H187A) decreased the SIRT2 activity but still the structural changes were not reported. Hence, we performed 5 ns molecular dynamics (MD) simulation on SIRT2 Apo-form and complexes with substrate/NAD+ and inhibitor of wild type (WT), Q167A, and H187A. The results revealed that the assembly and disassembly of C-site induced by presence of substrate/NAD+ and inhibitor, respectively. This assembly and disassembly was mainly due to the interaction between the substrate/NAD+ and inhibitor and F96 and the distance between F96 and H187 which are present at the neck of the C-site. MD simulations suggest that the conformational change of L3 plays a major role in assembly and disassembly of C-site. Our current results strongly suggest that the distinct conformational change of L3 as well as the assembly and disassembly of C-site plays an important role in SIRT2 deacetylation function. Our study unveiled the structural changes of SIRT2 in presence of NAD+ and inhibitor which should be helpful to improve the inhibitory potency of SIRT2

LKB1 as the ghostwriter of crypt history

Familial cancer syndromes present rare insights into malignant tumor development. The molecular background of polyp formation and the cancer prone state in Peutz-Jeghers syndrome remain enigmatic to this day. Previously, we proposed that Peutz-Jeghers polyps are not pre-malignant lesions, but an epiphenomenon to the malignant condition. However, Peutz-Jeghers polyp formation and the cancer-prone state must both be accounted for by the same molecular mechanism. Our contribution focuses on the histopathology of the characteristic Peutz-Jeghers polyp and recent research on stem cell dynamics and how these concepts relate to Peutz-Jeghers polyposis. We discuss a protracted clonal evolution scenario in Peutz-Jeghers syndrome due to a germline LKB1 mutation. Peutz-Jeghers polyp formation and malignant transformation are separately mediated through the same molecular mechanism played out on different timescales. Thus, a single mechanism accounts for the development of benign Peutz-Jeghers polyps and for malignant transformation in Peutz-Jeghers syndrome

Factors influencing citrus fruit scarring caused by Pezothrips kellyanus

[EN] Kelly s citrus thrips (KCT) Pezothrips kellyanus (Bagnall) (Thysanoptera: Thripidae) is a recently recorded cosmopolitan citrus pest, causing fruit scarring that results in downgrading of fruit. Due to the detrimental effects caused on fruits by KCT, we wanted to study some of the factors influencing fruit scarring. Specifically, the objectives were: (1) to determine the fruit development stage when citrus fruits are damaged by KCT and the population structure of KCT during this period, (2) to study the influence of temperature on intensity of damage, and finally, (3) to identify alternative host plants. KCT populations on flowers and fruitlets and alternate plant hosts were sampled in four citrus orchards from 2008 to 2010. The percentage of damaged fruits was also recorded. The exotic vine Araujia sericifera (Apocynaceae) was recorded as a new host for KCT. Thrips scarring started to increase at 350 650 degree-days (DD) above 10.2 C, coinciding with a peak abundance of the second instar larval stages over all 3 years of the study. The maximum percentage of larval stages of KCT was observed in the 3 years at about 500 DD, a period which corresponds to the end of May or early June. Variation in the severity of fruit scarring appeared to be related to air temperature. Temperature likely affects the synchronisation between the peak in abundance of KCT larvae, and the period when fruitlets are susceptible to thrips damage. Temperature can also influence the survival and development of KCT populations in citrus and other host plants in the citrus agro-ecosystem.The authors thank Alejandro Tena for his valuable suggestions and two anonymous referees for their careful review and helpful comments. We also extend our thanks to the owners of the commercial orchards for giving us permission to use their citrus orchards. The first author was awarded an FPI fellowship from the Polytechnic University of Valencia to obtain her PhD degree.Navarro Campos, C.; Pekas, A.; Aguilar Martí, MA.; Garcia Marí, F. (2013). Factors influencing citrus fruit scarring caused by Pezothrips kellyanus. Journal of Pest Science. (86):459-467. doi:10.1007/s10340-013-0489-7S45946786Baker GJ (2006) Kelly citrus thrips management. Fact sheet. Government of South Australia, primary industries and resources SA. http://www.sardi.sa.gov.au/__data/assets/pdf_file/0010/44875/kctfact_sheet.pdf . Accessed 16 July 2012Baker GJ, Jackman DJ, Keller M, MacGregor A, Purvis S (2002) Development of an integrated pest management system for thrips in Citrus. HAL Final Report CT97007. http://www.sardi.sa.gov.au/pestsdiseases/horticulture/horticultural_pests/kelly_citrus_thrips/research_report_1997-2000 . Accessed 16 July 2012Bedford ECG (1998) Thrips, wind and other blemishes. Citrus pests in the Republic of South Africa. 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Expression of a Dominant Negative CELF Protein In Vivo Leads to Altered Muscle Organization, Fiber Size, and Subtype

CUG-BP and ETR-3-like factor (CELF) proteins regulate tissue- and developmental stage-specific alternative splicing in striated muscle. We previously demonstrated that heart muscle-specific expression of a nuclear dominant negative CELF protein in transgenic mice (MHC-CELFΔ) effectively disrupts endogenous CELF activity in the heart in vivo, resulting in impaired cardiac function. In this study, transgenic mice that express the dominant negative protein under a skeletal muscle-specific promoter (Myo-CELFΔ) were generated to investigate the role of CELF-mediated alternative splicing programs in normal skeletal muscle.Myo-CELFΔ mice exhibit modest changes in CELF-mediated alternative splicing in skeletal muscle, accompanied by a reduction of endomysial and perimysial spaces, an increase in fiber size variability, and an increase in slow twitch muscle fibers. Weight gain and mean body weight, total number of muscle fibers, and overall muscle strength were not affected.Although these findings demonstrate that CELF activity contributes to the normal alternative splicing of a subset of muscle transcripts in vivo, the mildness of the effects in Myo-CELFΔ muscles compared to those in MHC-CELFΔ hearts suggests CELF activity may be less determinative for alternative splicing in skeletal muscle than in heart muscle. Nonetheless, even these small changes in CELF-mediated splicing regulation were sufficient to alter muscle organization and muscle fiber properties affected in myotonic dystrophy. This lends further evidence to the hypothesis that dysregulation of CELF-mediated alternative splicing programs may be responsible for the disruption of these properties during muscle pathogenesis

Predictors of sun protection behaviours and sunburn among Australian adolescents

BACKGROUND: Excessive sun exposure and sunburn increase individuals' risk of skin cancer. It is especially important to prevent sunburn in childhood due to the higher relative risk of skin cancer across the life span compared to risk associated with sunburn episodes experienced later in life. This study examined demographic and attitudinal factors associated with engagement in a range of sun protection behaviours (wearing a hat, wearing protective clothing, staying in the shade, and staying indoors during the middle of the day) and the frequency of sunburn among Western Australian adolescents to provide insights of relevance for future sun protection campaigns. METHODS: Cross-sectional telephone surveys were conducted annually with Western Australians between 2005/06 and 2014/15. The results from 4150 adolescents aged 14-17 years were used to conduct a path analysis of factors predicting various sun protection behaviours and sunburn. RESULTS: Significant primary predictors of the sun protection behaviours included in the study were skin type (sun sensitivity), gender, tanning-related attitudes and behaviours, and perceived relevance of public service advertisements that advocate sun protection. Of the four sun protection behaviours investigated, staying in the shade and staying indoors during the middle of the day were associated with a lower frequency of sunburn. CONCLUSION: There is a particular need to target sun protection messages at adolescent males who are less likely to engage in the most effective sun protection behaviours and demonstrate an increased propensity to experience sunburn. The results suggest that such future sun protection messages should include a focus on the importance of staying in the shade or indoors during periods of high UV radiation to increase awareness of the efficacy of these methods of avoiding skin cancer