Chaste: an open source C++ library for computational physiology and biology

Chaste - Cancer, Heart And Soft Tissue Environment - is an open source C++ library for the computational simulation of mathematical models developed for physiology and biology. Code development has been driven by two initial applications: cardiac electrophysiology and cancer development. A large number of cardiac electrophysiology studies have been enabled and performed, including high performance computational investigations of defibrillation on realistic human cardiac geometries. New models for the initiation and growth of tumours have been developed. In particular, cell-based simulations have provided novel insight into the role of stem cells in the colorectal crypt. Chaste is constantly evolving and is now being applied to a far wider range of problems. The code provides modules for handling common scientific computing components, such as meshes and solvers for ordinary and partial differential equations (ODEs/PDEs). Re-use of these components avoids the need for researchers to "re-invent the wheel" with each new project, accelerating the rate of progress in new applications. Chaste is developed using industrially-derived techniques, in particular test-driven development, to ensure code quality, re-use and reliability. In this article we provide examples that illustrate the types of problems Chaste can be used to solve, which can be run on a desktop computer. We highlight some scientific studies that have used or are using Chaste, and the insights they have provided. The source code, both for specific releases and the development version, is available to download under an open source Berkeley Software Distribution (BSD) licence at http://www.cs.ox.ac.uk/chaste, together with details of a mailing list and links to documentation and tutorials

Geographical Affinities of the HapMap Samples

The HapMap samples were collected for medical-genetic studies, but are also widely used in population-genetic and evolutionary investigations. Yet the ascertainment of the samples differs from most population-genetic studies which collect individuals who live in the same local region as their ancestors. What effects could this non-standard ascertainment have on the interpretation of HapMap results?We compared the HapMap samples with more conventionally-ascertained samples used in population- and forensic-genetic studies, including the HGDP-CEPH panel, making use of published genome-wide autosomal SNP data and Y-STR haplotypes, as well as producing new Y-STR data. We found that the HapMap samples were representative of their broad geographical regions of ancestry according to all tests applied. The YRI and JPT were indistinguishable from independent samples of Yoruba and Japanese in all ways investigated. However, both the CHB and the CEU were distinguishable from all other HGDP-CEPH populations with autosomal markers, and both showed Y-STR similarities to unusually large numbers of populations, perhaps reflecting their admixed origins.The CHB and JPT are readily distinguished from one another with both autosomal and Y-chromosomal markers, and results obtained after combining them into a single sample should be interpreted with caution. The CEU are better described as being of Western European ancestry than of Northern European ancestry as often reported. Both the CHB and CEU show subtle but detectable signs of admixture. Thus the YRI and JPT samples are well-suited to standard population-genetic studies, but the CHB and CEU less so

Waist circumference and waist-to-height ratio of Hong Kong Chinese children

<p>Abstract</p> <p>Background</p> <p>Central body fat is a better predictor than overall body fat for cardiovascular (CV) risk factors in both adults and children. Waist circumference (WC) has been used as a proxy measure of central body fat. Children at high CV risk may be identified by WC measurements. Waist-to-height ratio (WHTR) has been proposed as an alternative, conveniently age-independent measure of CV risk although WHTR percentiles have not been reported. We aim to provide age- and sex-specific reference values for WC and WHTR in Hong Kong Chinese children.</p> <p>Methods</p> <p>Cross sectional study in a large representative sample of 14,842 children aged 6 to 18 years in 2005/6. Sex-specific descriptive statistics for whole-year age groups and smoothed percentile curves of WC and WHTR were derived and presented.</p> <p>Results</p> <p>WC increased with age, although less after age 14 years in girls. WHTR decreased with age (particularly up to age 14). WHTR correlated less closely than WC with BMI (r = 0.65, 0.59 cf. 0.93, 0.91, for boys and girls respectively).</p> <p>Conclusion</p> <p>Reference values and percentile curves for WC and WHRT of Chinese children and adolescents are provided. Both WC and WHTR are age dependent. Since the use of WHRT does not obviate the need for age-related reference standards, simple WC measurement is a more convenient method for central fat estimation than WHRT.</p

Diverse Profiles of Anxiety Related Disorders in Fragile X, Cornelia de Lange and Rubinstein–Taybi Syndromes

Anxiety disorders are heightened in specific genetic syndromes in comparison to intellectual disability of heterogeneous aetiology. In this study, we described and contrasted anxiety symptomatology in fragile X (FXS), Cornelia de Lange (CdLS) and Rubinstein–Taybi syndromes (RTS), and compared the symptomatology to normative data for typically-developing children and children diagnosed with an anxiety disorder. Scores did not differ between children diagnosed with an anxiety disorder and (a) participants with FXS on social phobia, panic/agoraphobia, physical injury fears, and obsessive–compulsive subscales (b) participants with CdLS on separation anxiety, generalized anxiety, panic/agoraphobia, physical injury fears and obsessive–compulsive subscales, and (c) participants with RTS on panic/agoraphobia and obsessive–compulsive subscales. The results highlight divergent profiles of anxiety symptomatology between these groups

Protective Efficacy of Serially Up-Ranked Subdominant CD8+ T Cell Epitopes against Virus Challenges

Immunodominance in T cell responses to complex antigens like viruses is still incompletely understood. Some data indicate that the dominant responses to viruses are not necessarily the most protective, while other data imply that dominant responses are the most important. The issue is of considerable importance to the rational design of vaccines, particularly against variable escaping viruses like human immunodeficiency virus type 1 and hepatitis C virus. Here, we showed that sequential inactivation of dominant epitopes up-ranks the remaining subdominant determinants. Importantly, we demonstrated that subdominant epitopes can induce robust responses and protect against whole viruses if they are allowed at least once in the vaccination regimen to locally or temporally dominate T cell induction. Therefore, refocusing T cell immune responses away from highly variable determinants recognized during natural virus infection towards subdominant, but conserved regions is possible and merits evaluation in humans

Significant Effects of Antiretroviral Therapy on Global Gene Expression in Brain Tissues of Patients with HIV-1-Associated Neurocognitive Disorders

Antiretroviral therapy (ART) has reduced morbidity and mortality in HIV-1 infection; however HIV-1-associated neurocognitive disorders (HAND) persist despite treatment. The reasons for the limited efficacy of ART in the brain are unknown. Here we used functional genomics to determine ART effectiveness in the brain and to identify molecular signatures of HAND under ART. We performed genome-wide microarray analysis using Affymetrix U133 Plus 2.0 Arrays, real-time PCR, and immunohistochemistry in brain tissues from seven treated and eight untreated HAND patients and six uninfected controls. We also determined brain virus burdens by real-time PCR. Treated and untreated HAND brains had distinct gene expression profiles with ART transcriptomes clustering with HIV-1-negative controls. The molecular disease profile of untreated HAND showed dysregulated expression of 1470 genes at p<0.05, with activation of antiviral and immune responses and suppression of synaptic transmission and neurogenesis. The overall brain transcriptome changes in these patients were independent of histological manifestation of HIV-1 encephalitis and brain virus burdens. Depending on treatment compliance, brain transcriptomes from patients on ART had 83% to 93% fewer dysregulated genes and significantly lower dysregulation of biological pathways compared to untreated patients, with particular improvement indicated for nervous system functions. However a core of about 100 genes remained similarly dysregulated in both treated and untreated patient brain tissues. These genes participate in adaptive immune responses, and in interferon, cell cycle, and myelin pathways. Fluctuations of cellular gene expression in the brain correlated in Pearson's formula analysis with plasma but not brain virus burden. Our results define for the first time an aberrant genome-wide brain transcriptome of untreated HAND and they suggest that antiretroviral treatment can be broadly effective in reducing pathophysiological changes in the brain associated with HAND. Aberrantly expressed transcripts common to untreated and treated HAND may contribute to neurocognitive changes defying ART

Characterizing Acupuncture Stimuli Using Brain Imaging with fMRI - A Systematic Review and Meta-Analysis of the Literature

Background The mechanisms of action underlying acupuncture, including acupuncture point specificity, are not well understood. In the previous decade, an increasing number of studies have applied fMRI to investigate brain response to acupuncture stimulation. Our aim was to provide a systematic overview of acupuncture fMRI research considering the following aspects: 1) differences between verum and sham acupuncture, 2) differences due to various methods of acupuncture manipulation, 3) differences between patients and healthy volunteers, 4) differences between different acupuncture points. Methodology/Principal Findings We systematically searched English, Chinese, Korean and Japanese databases for literature published from the earliest available up until September 2009, without any language restrictions. We included all studies using fMRI to investigate the effect of acupuncture on the human brain (at least one group that received needle-based acupuncture). 779 papers were identified, 149 met the inclusion criteria for the descriptive analysis, and 34 were eligible for the meta-analyses. From a descriptive perspective, multiple studies reported that acupuncture modulates activity within specific brain areas, including somatosensory cortices, limbic system, basal ganglia, brain stem, and cerebellum. Meta-analyses for verum acupuncture stimuli confirmed brain activity within many of the regions mentioned above. Differences between verum and sham acupuncture were noted in brain response in middle cingulate, while some heterogeneity was noted for other regions depending on how such meta-analyses were performed, such as sensorimotor cortices, limbic regions, and cerebellum. Conclusions Brain response to acupuncture stimuli encompasses a broad network of regions consistent with not just somatosensory, but also affective and cognitive processing. While the results were heterogeneous, from a descriptive perspective most studies suggest that acupuncture can modulate the activity within specific brain areas, and the evidence based on meta-analyses confirmed some of these results. More high quality studies with more transparent methodology are needed to improve the consistency amongst different studies