When the Genome Plays Dice: Circumvention of the Spindle Assembly Checkpoint and Near-Random Chromosome Segregation in Multipolar Cancer Cell Mitoses

Background: Normal cell division is coordinated by a bipolar mitotic spindle, ensuring symmetrical segregation of chromosomes. Cancer cells, however, occasionally divide into three or more directions. Such multipolar mitoses have been proposed to generate genetic diversity and thereby contribute to clonal evolution. However, this notion has been little validated experimentally.Principal Findings: Chromosome segregation and DNA content in daughter cells from multipolar mitoses were assessed by multiphoton cross sectioning and fluorescence in situ hybridization in cancer cells and non-neoplastic transformed cells. The DNA distribution resulting from multipolar cell division was found to be highly variable, with frequent nullisomies in the daughter cells. Time-lapse imaging of H2B/GFP-labelled multipolar mitoses revealed that the time from the initiation of metaphase to the beginning of anaphase was prolonged and that the metaphase plates often switched polarity several times before metaphase-anaphase transition. The multipolar metaphase-anaphase transition was accompanied by a normal reduction of cellular cyclin B levels, but typically occurred before completion of the normal separase activity cycle. Centromeric AURKB and MAD2 foci were observed frequently to remain on the centromeres of multipolar ana-telophase chromosomes, indicating that multipolar mitoses were able to circumvent the spindle assembly checkpoint with some sister chromatids remaining unseparated after anaphase. Accordingly, scoring the distribution of individual chromosomes in multipolar daughter nuclei revealed a high frequency of nondisjunction events, resulting in a near-binomial allotment of sister chromatids to the daughter cells.Conclusion: The capability of multipolar mitoses to circumvent the spindle assembly checkpoint system typically results in a near-random distribution of chromosomes to daughter cells. Spindle multipolarity could thus be a highly efficient generator of genetically diverse minority clones in transformed cell populations

Extraction of bodily features for gait recognition and gait attractiveness evaluation

This is the author's accepted manuscript. The final publication is available at Springer via http://dx.doi.org/10.1007/s11042-012-1319-2. Copyright @ 2012 Springer.Although there has been much previous research on which bodily features are most important in gait analysis, the questions of which features should be extracted from gait, and why these features in particular should be extracted, have not been convincingly answered. The primary goal of the study reported here was to take an analytical approach to answering these questions, in the context of identifying the features that are most important for gait recognition and gait attractiveness evaluation. Using precise 3D gait motion data obtained from motion capture, we analyzed the relative motions from different body segments to a root marker (located on the lower back) of 30 males by the fixed root method, and compared them with the original motions without fixing root. Some particular features were obtained by principal component analysis (PCA). The left lower arm, lower legs and hips were identified as important features for gait recognition. For gait attractiveness evaluation, the lower legs were recognized as important features.Dorothy Hodgkin Postgraduate Award and HEFCE

Insulin promoter DNA methylation correlates negatively with insulin gene expression and positively with HbA1c levels in human pancreatic islets

Aims/hypothesis: Although recent studies propose that epigenetic factors influence insulin expression, the regulation of the insulin gene in type 2 diabetic islets is still not fully understood. Here, we examined DNA methylation of the insulin gene promoter in pancreatic islets from patients with type 2 diabetes and non-diabetic human donors and related it to insulin expression, HbA levels, BMI and age. Methods: DNA methylation was analysed in 25 CpG sites of the insulin promoter and insulin mRNA expression was analysed using quantitative RT-PCR in pancreatic islets from nine donors with type 2 diabetes and 48 non-diabetic donors. Results: Insulin mRNA expression (p = 0.002), insulin content (p = 0.004) and glucose-stimulated insulin secretion (p = 0.04) were reduced in pancreatic islets from patients with type 2 diabetes compared with non-diabetic donors. Moreover, four CpG sites located 234 bp, 180 and 102 bp upstream and 63 bp downstream of the transcription start site (CpG -234, -180, -102 and +63, respectively), showed increased DNA methylation in type 2 diabetic compared with non-diabetic islets (7.8%, p = 0.03; 7.1%, p = 0.02; 4.4%, p = 0.03 and 9.3%, p = 0.03, respectively). While insulin mRNA expression correlated negatively (p < 1 × 10), the level of HbA correlated positively (p ≤ 0.01) with the degree of DNA methylation for CpG -234, -180 and +63. Furthermore, DNA methylation for nine additional CpG sites correlated negatively with insulin mRNA expression (p ≤ 0.01). Also, exposure to hyperglycaemia for 72 h increased insulin promoter DNA methylation in clonal rat beta cells (p = 0.005). Conclusions/interpretations: This study demonstrates that DNA methylation of the insulin promoter is increased in patients with type 2 diabetes and correlates negatively with insulin gene expression in human pancreatic islets

Increasing socioeconomic inequalities in first acute myocardial infarction in Scotland, 1990–92 and 2000–02

&lt;p&gt;Background: Despite substantial declines, Ischaemic Heart Disease (IHD) remains the largest cause of death in Scotland and mortality rates are among the worst in Europe. There is evidence of strong, persisting regional and socioeconomic inequalities in IHD mortality, with the majority of such deaths being due to Acute Myocardial Infarction (AMI). We examine the changes in socioeconomic and geographic inequalities in first AMI events in Scotland and their interactions with age and gender.&lt;/p&gt; &lt;p&gt;Methods: We used linked hospital discharge and death records covering the Scottish Population (5.1 million). Risk ratios (RR) of AMI incidence by area deprivation and age for men and women were estimated using multilevel Poisson modelling. Directly standardised rates were presented within these stratifications.&lt;/p&gt; &lt;p&gt;Results: During 1990–92 74,213 people had a first AMI event and 56,995 in 2000–02. Adjusting for area deprivation accounted for 59% of the geographic variability in AMI incidence rates in 1990–92 and 33% in 2000–02. Geographic inequalities in male incidence reduced; RR for smaller areas (comparing area on 97.5th centile to 2.5th) reduced from 1.42 to 1.19. This was not true for women; RR increased from 1.45 to 1.59. The socioeconomic gradient in AMI incidence increased over time (p-value &#60; 0.001) but this varied by age and gender. The gradient across deprivation categories for male incidence in 1990–92 was most pronounced at younger ages; RR of AMI in the most deprived areas compared to the least was 2.6 (95% CI: 1.6–4.3) for those aged 45–59 years and 1.6 (1.1–2.5) at 60–74 years. This association was also evident in women with even stronger socioeconomic gradients; RRs for these age groups were 4.4 (3.4–5.5), and 1.9 (1.7–2.2). Inequalities increased by 2000–02 for both sexes; RR for men aged 45–59 years was 3.3 (3.0–3.6) and for women was 5.6 (4.1–7.7)&lt;/p&gt; &lt;p&gt;Conclusion: Relative socioeconomic inequalities in AMI incidence have increased and gradients are steepest in young women. The geographical patterning of AMI incidence cannot be fully explained by socioeconomic deprivation. The reduction of inequalities in AMI incidence is key to reducing overall inequalities in mortality and must be a priority if Scotland is to achieve its health potential.&lt;/p&gt

Convergent development of low-relatedness supercolonies in Myrmica ants.

Many ant species have independently evolved colony structures with multiple queens and very low relatedness among nestmate workers, but it has remained unclear whether low-relatedness kin structures can repeatedly arise in populations of the same species. Here we report a study of Danish island populations of the red ant Myrmica sulcinodis and show that it is likely that such repeated developments occur. Two microsatellite loci were used to estimate genetic differentiation (F(ST)) among three populations and nestmate relatedness within these populations. The F(ST) values were highly significant due to very different allele frequencies among the three populations with relatively few common alleles and relatively many rare alleles, possibly caused by single queen foundation and rare subsequent immigration. Given the isolation of the islands and the low investment in reproduction, we infer that each of the populations was most likely established by a single queen, even though all three extant populations now have within-colony relatedness 95%), and the genetic differentiation of nests showed a significantly positive correlation with the distance between them. Both male-biased sex-ratio and genetic viscosity are expected characteristics of populations where queens have very local dispersal and where new colonies are initiated through nest-budding. Based on a comparison with other M. sulcinodis populations we hypothesise a distinct succession of population types and suggest that this may be a possible pathway to unicoloniality, ie, development towards a complete lack of colony kin structure and unrelated nestmate workers

Variants of ADRA2A are associated with fasting glucose, blood pressure, body mass index and type 2 diabetes risk: meta-analysis of four prospective studies

AIMS/HYPOTHESIS: We quantified the effect of ADRA2A (encoding α-2 adrenergic receptor) variants on metabolic traits and type 2 diabetes risk, as reported in four studies. METHODS: Genotype data for ADRA2A single nucleotide polymorphisms (SNPs) rs553668 and rs10885122 were analysed in >17,000 individuals (1,307 type 2 diabetes cases) with regard to metabolic traits and type 2 diabetes risk. Two studies (n = 9,437), genotyped using the Human Cardiovascular Disease BeadChip, provided 12 additional ADRA2A SNPs. RESULTS: Rs553668 was associated with per allele effects on fasting glucose (0.03 mmol/l, p = 0.016) and type 2 diabetes risk (OR 1.17, 95% CI 1.04-1.31; p = 0.01). No significant association was observed with rs10885122. Of the 12 SNPs, several showed associations with metabolic traits. Overall, after variable selection, rs553668 was associated with type 2 diabetes risk (OR 1.38, 95% CI 1.09-1.73; p = 0.007). rs553668 (per allele difference 0.036 mmol/l, 95% CI 0.008-0.065) and rs17186196 (per allele difference 0.066 mmol/l, 95% CI 0.017-0.115) were independently associated with fasting glucose, and rs17186196 with fasting insulin and HOMA of insulin resistance (4.3%, 95% CI 0.6-8.1 and 4.9%, 95% CI 1.0-9.0, respectively, per allele). Per-allele effects of rs491589 on systolic and diastolic blood pressure were 1.19 mmHg (95% CI 0.43-1.95) and 0.61 mmHg (95% CI 0.11-1.10), respectively, and those of rs36022820 on BMI 0.58 kg/m(2) (95% CI 0.15-1.02). CONCLUSIONS/INTERPRETATION: Multiple ADRA2A SNPs are associated with metabolic traits, blood pressure and type 2 diabetes risk. The α-2 adrenergic receptor should be revisited as a therapeutic target for reduction of the adverse consequences of metabolic trait disorders and type 2 diabetes

Paternal and Maternal History of Myocardial Infarction and Cardiovascular Diseases Incidence in a Dutch Cohort of Middle-Aged Persons

Background - A positive parental history of myocardial infarction (MI) is an independent risk factor for cardiovascular diseases (CVD). However, different definitions of parental history have been used. We evaluated the impact of parental gender and age of onset of MI on CVD incidence. Methods - Baseline data were collected between 1993 and 1997 in 10¿524 respondents aged 40–65 years. CVD events were obtained from the National Hospital Discharge Register and Statistics Netherlands. We used proportional hazard models to calculate hazard ratios (HR) and 95% confidence intervals (CI) for CVD incidence and adjusted for lifestyle and biological risk factors. Results - At baseline, 36% had a parental history of MI. During 10-year follow-up, 914 CVD events occurred. The age and gender adjusted HR was 1.3 (95% CI 1.1–1.5) for those with a paternal MI, 1.5 (1.2–1.8) for those with a maternal MI and 1.6 (1.2–2.2) for those with both parents with an MI. With decreasing parental age of MI, HR increased from 1.2 (1.0–1.6) for age =70 years to 1.5 (1.2–1.8) for ag

Elevated Stress-Hemoconcentration in Major Depression Is Normalized by Antidepressant Treatment: Secondary Analysis from a Randomized, Double-Blind Clinical Trial and Relevance to Cardiovascular Disease Risk

Major depressive disorder (MDD) is an independent risk factor for cardiovascular disease (CVD); the presence of MDD symptoms in patients with CVD is associated with a higher incidence of cardiac complications following acute myocardial infarction (MI). Stress-hemoconcentration, a result of psychological stress that might be a risk factor for the pathogenesis of CVD, has been studied in stress-challenge paradigms but has not been systematically studied in MDD.Secondary analysis of stress hemoconcentration was performed on data from controls and subjects with mild to moderate MDD participating in an ongoing pharmacogenetic study of antidepressant treatment response to desipramine or fluoxetine. Hematologic and hemorheologic measures of stress-hemoconcentration included blood cell counts, hematocrit, hemoglobin, total serum protein, and albumin, and whole blood viscosity.Subjects with mild to moderate MDD had significantly increased hemorheologic measures of stress-hemoconcentration and blood viscosity when compared to controls; these measures were correlated with depression severity. Measures of stress-hemoconcentration improved significantly after 8 weeks of antidepressant treatment. Improvements in white blood cell count, red blood cell measures and plasma volume were correlated with decreased severity of depression.Our secondary data analyses support that stress-hemoconcentration, possibly caused by decrements in plasma volume during psychological stress, is present in Mexican-American subjects with mild to moderate MDD at non-challenged baseline conditions. We also found that after antidepressant treatment hemorheologic measures of stress-hemoconcentration are improved and are correlated with improvement of depressive symptoms. These findings suggest that antidepressant treatment may have a positive impact in CVD by ameliorating increased blood viscosity. Physicians should be aware of the potential impact of measures of hemoconcentration and consider the implications for cardiovascular risk in depressed patients

Should Global Burden of Disease Estimates Include Depression as a Risk Factor for Coronary Heart Disease?

The 2010 Global Burden of Disease Study estimates the premature mortality and disability of all major diseases and injuries. In addition it aims to quantify the risk that diseases and other factors play in the aetiology of disease and injuries. Mental disorders and coronary heart disease are both significant public health issues due to their high prevalence and considerable contribution to global disease burden. For the first time the Global Burden of Disease Study will aim to assess mental disorders as risk factors for coronary heart disease. We show here that current evidence satisfies established criteria for considering depression as an independent risk factor in development of coronary heart disease. A dose response relationship appears to exist and plausible biological pathways have been proposed. However, a number of challenges exist when conducting a rigorous assessment of the literature including heterogeneity issues, definition and measurement of depression and coronary heart disease, publication bias and residual confounding. Therefore, despite some limitations in the available data, it is now appropriate to consider major depression as a risk factor for coronary heart disease in the new Global Burden of Disease Study