Fossil evidence for key innovations in the evolution of insect diversity

Explaining the taxonomic richness of the insects, comprising over half of all described species, is a major challenge in evolutionary biology. Previously, several evolutionary novelties (key innovations) have been posited to contribute to that richness, including the insect bauplan, wings, wing folding and complete metamorphosis, but evidence over their relative importance and modes of action is sparse and equivocal. Here, a new dataset on the first and last occurrences of fossil hexapod (insects and close relatives) families is used to show that basal families of winged insects (Palaeoptera, e.g. dragonflies) show higher origination and extinction rates in the fossil record than basal wingless groups (Apterygota, e.g. silverfish). Origination and extinction rates were maintained at levels similar to Palaeoptera in the more derived Polyneoptera (e.g. cockroaches) and Paraneoptera (e.g. true bugs), but extinction rates subsequently reduced in the very rich group of insects with complete metamorphosis (Holometabola, e.g. beetles). Holometabola show evidence of a recent slow-down in their high net diversification rate, whereas other winged taxa continue to diversify at constant but low rates. These data suggest that wings and complete metamorphosis have had the most effect on family-level insect macroevolution, and point to specific mechanisms by which they have influenced insect diversity through time

A randomised controlled trial to compare a range of commercial or primary care led weight reduction programmes with a minimal intervention control for weight loss in obesity: the Lighten Up trial

<p>Abstract</p> <p>Background</p> <p>Developed countries are facing a huge rise in the prevalence of obesity and its associated chronic medical problems. In the UK Primary Care Trusts are charged with addressing this in the populations they serve, but evidence about the most effective ways of delivering services is not available. The aim of this study is to determine the effectiveness of a range of weight loss programmes for obese patients in primary care and to determine the characteristics of patients who respond to an invitation to a free weight management programme.</p> <p>Methods/Design</p> <p>Lighten Up is a randomised controlled trial comparing a range of 12-week commercial and NHS weight reduction programmes with a comparator group who are provided with 12 vouchers enabling free entrance to a local leisure centre. The weight reduction programmes are: (i) Weight Watchers, (ii) Slimming World, (iii) Rosemary Conley, (iv) a group-based dietetics-led programme (Size Down), (v) general practice one-to-one counselling, (vi) pharmacy-led one-to-one counselling, (vii) choice of any of the 6 programmes. People with obesity or overweight with a co-morbid disorder are invited to take part by a letter from their general practitioner. The sample size is 740 participants.</p> <p>The primary outcome is weight loss at programme-end (3 months). Secondary outcomes are weight-loss at one year, self-reported physical activity at 3 and 12 months follow-up and percentage weight-loss at 3 months and one year.</p> <p>Discussion</p> <p>This trial will provide evidence about the effectiveness of a range of different weight management programmes in a primary care population.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN25072883</p

Nonlinear mixed effects modeling of gametocyte carriage in patients with uncomplicated malaria

<p>Abstract</p> <p>Background</p> <p>Gametocytes are the sexual form of the malaria parasite and the main agents of transmission. While there are several factors that influence host infectivity, the density of gametocytes appears to be the best single measure that is related to the human host's infectivity to mosquitoes. Despite the obviously important role that gametocytes play in the transmission of malaria and spread of anti-malarial resistance, it is common to estimate gametocyte carriage indirectly based on asexual parasite measurements. The objective of this research was to directly model observed gametocyte densities over time, during the primary infection.</p> <p>Methods</p> <p>Of 447 patients enrolled in sulphadoxine-pyrimethamine therapeutic efficacy studies in South Africa and Mozambique, a subset of 103 patients who had no gametocytes pre-treatment and who had at least three non-zero gametocyte densities over the 42-day follow up period were included in this analysis.</p> <p>Results</p> <p>A variety of different functions were examined. A modified version of the critical exponential function was selected for the final model given its robustness across different datasets and its flexibility in assuming a variety of different shapes. Age, site, initial asexual parasite density (logged to the base 10), and an empirical patient category were the co-variates that were found to improve the model.</p> <p>Conclusions</p> <p>A population nonlinear modeling approach seems promising and produced a flexible function whose estimates were stable across various different datasets. Surprisingly, dihydrofolate reductase and dihydropteroate synthetase mutation prevalence did not enter the model. This is probably related to a lack of power (quintuple mutations n = 12), and informative censoring; treatment failures were withdrawn from the study and given rescue treatment, usually prior to completion of follow up.</p

Decorin and TGF-β(1 )polymorphisms and development of COPD in a general population

BACKGROUND: Decorin, an extracellular matrix (ECM) proteoglycan, and TGF-β(1 )are both involved in lung ECM turnover. Decorin and TGF-β(1 )expression are decreased respectively increased in COPD lung tissue. Interestingly, they act as each other's feedback regulator. We investigated whether single nucleotide polymorphisms (SNPs) in decorin and TGF-β(1 )underlie accelerated decline in FEV(1 )and development of COPD in the general population. METHODS: We genotyped 1390 subjects from the Vlagtwedde/Vlaardingen cohort. Lung function was measured every 3 years for a period of 25 years. We tested whether five SNPs in decorin (3'UTR and four intron SNPs) and three SNPs in TGF-β(1 )(3'UTR rs6957, C-509T rs1800469 and Leu10Pro rs1982073), and their haplotypes, were associated with COPD (last survey GOLD stage = II). Linear mixed effects models were used to analyze genotype associations with FEV(1 )decline. RESULTS: We found a significantly higher prevalence of carriers of the minor allele of the TGF-β(1 )rs6957 SNP (p = 0.001) in subjects with COPD. Additionally, we found a significantly lower prevalence of the haplotype with the major allele of rs6957 and minor alleles for rs1800469 and rs1982073 SNPs in TGF-β(1 )in subjects with COPD (p = 0.030), indicating that this association is due to the rs6957 SNP. TGF-β(1 )SNPs were not associated with FEV(1 )decline. SNPs in decorin, and haplotypes constructed of both TGF-β(1 )and decorin SNPs were not associated with development of COPD or with FEV(1 )decline. CONCLUSION: Our study shows for the first time that SNPs in decorin on its own or in interaction with SNPs in TGF-β(1 )do not underlie the disturbed balance in expression between these genes in COPD. TGF-β(1 )SNPs are associated with COPD, yet not with accelerated FEV(1 )decline in the general population

Social and contextual influences on antibiotic prescribing and antimicrobial stewardship: a qualitative study with clinical commissioning group and general practice professionals

Antibiotic prescribing in England varies considerably between Clinical Commissioning Groups (CCGs) and general practices. We aimed to assess social and contextual factors affecting antibiotic prescribing and engagement with antimicrobial stewardship (AMS) initiatives. Semi-structured telephone interviews were conducted with 22 CCG professionals and 19 general practice professionals. Interviews were audio-recorded, transcribed, and analyzed thematically. Social/contextual influences were grouped into the following four categories: (1) Immediate context, i.e., patients’ social characteristics (e.g., deprivation and culture), clinical factors, and practice and clinician characteristics (e.g., “struggling” with staff shortage/turnover) were linked to higher prescribing. (2) Wider context, i.e., pressures on the healthcare system, limited resources, and competing priorities were seen to reduce engagement with AMS. (3) Collaborative and whole system approaches, i.e., communication, multidisciplinary networks, leadership, and teamwork facilitated prioritizing AMS, learning, and consistency. (4) Relativity of appropriate prescribing, i.e., “high” or “appropriate” prescribing was perceived as relative, depending on comparators, and disregarding different contexts, but social norms around antibiotic use among professionals and patients seemed to be changing. Further optimization of antibiotic prescribing would benefit from addressing social/contextual factors and addressing wider health inequalities, not only targeting individual clinicians. Tailoring and adapting to local contexts and constraints, ensuring adequate time and resources for AMS, and collaborative, whole system approaches to promote consistency may help promote AMS

Evaluating the association of common APOA2 variants with type 2 diabetes

<p>Abstract</p> <p>Background</p> <p><it>APOA2 </it>is a positional and biological candidate gene for type 2 diabetes at the chromosome 1q21-q24 susceptibility locus. The aim of this study was to examine if HapMap phase II tag SNPs in <it>APOA2 </it>are associated with type 2 diabetes and quantitative traits in French Caucasian subjects.</p> <p>Methods</p> <p>We genotyped the three HapMap phase II tagging SNPs (rs6413453, rs5085 and rs5082) required to capture the common variation spanning the <it>APOA2 </it>locus in our type 2 diabetes case-control cohort comprising 3,093 French Caucasian subjects. The association between these variants and quantitative traits was also examined in the normoglycaemic adults of the control cohort. In addition, meta-analysis of publicly available whole genome association data was performed.</p> <p>Results</p> <p>None of the <it>APOA2 </it>tag SNPs were associated with type 2 diabetes in the French Caucasian case-control cohort (rs6413453, <it>P </it>= 0.619; rs5085, <it>P </it>= 0.245; rs5082, <it>P </it>= 0.591). However, rs5082 was marginally associated with total cholesterol levels (<it>P </it>= 0.026) and waist-to-hip ratio (<it>P </it>= 0.029). The meta-analysis of data from 12,387 subjects confirmed our finding that common variation at the <it>APOA2 </it>locus is not associated with type 2 diabetes.</p> <p>Conclusion</p> <p>The available data does not support a role for common variants in <it>APOA2 </it>on type 2 diabetes susceptibility or related quantitative traits in Northern Europeans.</p

Regional differences in mitochondrial DNA methylation in human post-mortem brain tissue

Background: DNA methylation is an important epigenetic mechanism involved in gene regulation, with alterations in DNA methylation in the nuclear genome being linked to numerous complex diseases. Mitochondrial DNA methylation is a phenomenon that is receiving ever-increasing interest, particularly in diseases characterized by mitochondrial dysfunction; however, most studies have been limited to the investigation of specific target regions. Analyses spanning the entire mitochondrial genome have been limited, potentially due to the amount of input DNA required. Further, mitochondrial genetic studies have been previously confounded by nuclear-mitochondrial pseudogenes. Methylated DNA Immunoprecipitation Sequencing is a technique widely used to profile DNA methylation across the nuclear genome; however, reads mapped to mitochondrial DNA are often discarded. Here, we have developed an approach to control for nuclear-mitochondrial pseudogenes within Methylated DNA Immunoprecipitation Sequencing data. We highlight the utility of this approach in identifying differences in mitochondrial DNA methylation across regions of the human brain and pre-mortem blood. Results: We were able to correlate mitochondrial DNA methylation patterns between the cortex, cerebellum and blood. We identified 74 nominally significant differentially methylated regions (p < 0.05) in the mitochondrial genome, between anatomically separate cortical regions and the cerebellum in matched samples (N = 3 matched donors). Further analysis identified eight significant differentially methylated regions between the total cortex and cerebellum after correcting for multiple testing. Using unsupervised hierarchical clustering analysis of the mitochondrial DNA methylome, we were able to identify tissue-specific patterns of mitochondrial DNA methylation between blood, cerebellum and cortex. Conclusions: Our study represents a comprehensive analysis of the mitochondrial methylome using pre-existing Methylated DNA Immunoprecipitation Sequencing data to identify brain region-specific patterns of mitochondrial DNA methylation

Comorbidities of obesity in school children: a cross-sectional study in the PIAMA birth cohort

<p>Abstract</p> <p>Background</p> <p>There is ample evidence that childhood overweight is associated with increased risk of chronic disease in adulthood. The aim of this study was to investigate associations between childhood overweight and common childhood health problems.</p> <p>Methods</p> <p>Data were used from a general population sample of 3960 8-year-old children, participating in the Dutch PIAMA birth cohort study. Weight and height, measured by the investigators, were used to define BMI status (thinness, normal weight, moderate overweight, obesity). BMI status was studied cross-sectionally in relation to the following parental reported outcomes: a general health index, GP visits, school absenteeism due to illness, health-related functional limitations, doctor diagnosed respiratory infections and use of antibiotics.</p> <p>Results</p> <p>Obesity was significantly associated with a lower general health score, more GP visits, more school absenteeism and more health-related limitations, (adjusted odds ratios around 2.0 for most outcomes). Obesity was also significantly associated with bronchitis (adjusted odds ratio (aOR) and 95% confidence intervals (95%CI): 5.29 (2.58;10.85) and with the use of antibiotics (aOR (95%CI): 1.79 (1.09;2.93)). Associations with flu/serious cold, ear infection and throat infection were positive, but not statistically significant. Moderate overweight was not significantly associated with the health outcomes studied.</p> <p>Conclusion</p> <p>Childhood obesity is not merely a risk factor for disease in adulthood, but obese children may experience more illness and health related problems already in childhood. The high prevalence of the outcomes studied implies a high burden of disease in terms of absolute numbers of sick children.</p

Evaluating methods for ranking differentially expressed genes applied to microArray quality control data

<p>Abstract</p> <p>Background</p> <p>Statistical methods for ranking differentially expressed genes (DEGs) from gene expression data should be evaluated with regard to high sensitivity, specificity, and reproducibility. In our previous studies, we evaluated eight gene ranking methods applied to only Affymetrix GeneChip data. A more general evaluation that also includes other microarray platforms, such as the Agilent or Illumina systems, is desirable for determining which methods are suitable for each platform and which method has better inter-platform reproducibility.</p> <p>Results</p> <p>We compared the eight gene ranking methods using the MicroArray Quality Control (MAQC) datasets produced by five manufacturers: Affymetrix, Applied Biosystems, Agilent, GE Healthcare, and Illumina. The area under the curve (AUC) was used as a measure for both sensitivity and specificity. Although the highest AUC values can vary with the definition of "true" DEGs, the best methods were, in most cases, either the weighted average difference (WAD), rank products (RP), or intensity-based moderated <it>t </it>statistic (ibmT). The percentages of overlapping genes (POGs) across different test sites were mainly evaluated as a measure for both intra- and inter-platform reproducibility. The POG values for WAD were the highest overall, irrespective of the choice of microarray platform. The high intra- and inter-platform reproducibility of WAD was also observed at a higher biological function level.</p> <p>Conclusion</p> <p>These results for the five microarray platforms were consistent with our previous ones based on 36 real experimental datasets measured using the Affymetrix platform. Thus, recommendations made using the MAQC benchmark data might be universally applicable.</p