Mathematical modelling of polyamine metabolism in bloodstream-form trypanosoma brucei: An application to drug target identification

© 2013 Gu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedThis article has been made available through the Brunel Open Access Publishing Fund.We present the first computational kinetic model of polyamine metabolism in bloodstream-form Trypanosoma brucei, the causative agent of human African trypanosomiasis. We systematically extracted the polyamine pathway from the complete metabolic network while still maintaining the predictive capability of the pathway. The kinetic model is constructed on the basis of information gleaned from the experimental biology literature and defined as a set of ordinary differential equations. We applied Michaelis-Menten kinetics featuring regulatory factors to describe enzymatic activities that are well defined. Uncharacterised enzyme kinetics were approximated and justified with available physiological properties of the system. Optimisation-based dynamic simulations were performed to train the model with experimental data and inconsistent predictions prompted an iterative procedure of model refinement. Good agreement between simulation results and measured data reported in various experimental conditions shows that the model has good applicability in spite of there being gaps in the required data. With this kinetic model, the relative importance of the individual pathway enzymes was assessed. We observed that, at low-to-moderate levels of inhibition, enzymes catalysing reactions of de novo AdoMet (MAT) and ornithine production (OrnPt) have more efficient inhibitory effect on total trypanothione content in comparison to other enzymes in the pathway. In our model, prozyme and TSHSyn (the production catalyst of total trypanothione) were also found to exhibit potent control on total trypanothione content but only when they were strongly inhibited. Different chemotherapeutic strategies against T. brucei were investigated using this model and interruption of polyamine synthesis via joint inhibition of MAT or OrnPt together with other polyamine enzymes was identified as an optimal therapeutic strategy.The work was carried out under a PhD programme partly funded by Prof. Ray Welland, School of Computing Science, University of Glasgo

An evaluation of a combined psychological and parenting intervention for HIV-positive women depressed in the perinatal period, to enhance child development and reduce maternal depression: study protocol for the Insika Yomama cluster randomised controlled trial

The combination of poverty, HIV and depression in the perinatal period represents a major public health challenge in many Southern African countries. In some areas, up to a third of HIV-positive women experience perinatal depression. Perinatal depression is associated with negative effects on parenting and key domains of child development including cognitive, behavioural and growth, especially in socio-economically disadvantaged communities. Several studies have documented the benefits of psychological interventions for perinatal depression in low- and middle-income countries, but none have evaluated an integrated psychological and parenting intervention for HIV-positive women using task-sharing. This randomised controlled trial aims to evaluate the effect of a home-based intervention, combining a psychological treatment for depression and a parenting programme for perinatally depressed HIV-positive women

Burden of mental disorders and unmet needs among street homeless people in Addis Ababa, Ethiopia

BACKGROUND: The impact of mental disorders among homeless people is likely to be substantial in low income countries because of underdeveloped social welfare and health systems. As a first step towards advocacy and provision of care, we conducted a study to determine the burden of psychotic disorders and associated unmet needs, as well as the prevalence of mental distress, suicidality, and alcohol use disorder among homeless people in Addis Ababa, the capital of Ethiopia. METHODS: A cross-sectional survey was conducted among street homeless adults. Trained community nurses screened for potential psychosis and administered standardized measures of mental distress, alcohol use disorder and suicidality. Psychiatric nurses then carried out confirmatory diagnostic interviews of psychosis and administered a locally adapted version of the Camberwell Assessment of Needs Short Appraisal Schedule. RESULTS: We assessed 217 street homeless adults, about 90% of whom had experienced some form of mental or alcohol use disorder: 41.0% had psychosis, 60.0% had hazardous or dependent alcohol use, and 14.8% reported attempting suicide in the previous month. Homeless people with psychosis had extensive unmet needs with 80% to 100% reporting unmet needs across 26 domains. Nearly 30% had physical disability (visual and sensory impairment and impaired mobility). Only 10.0% of those with psychosis had ever received treatment for their illness. Most had lived on the streets for over 2 years, and alcohol use disorder was positively associated with chronicity of homelessness. CONCLUSION: Psychoses and other mental and behavioural disorders affect most people who are street homeless in Addis Ababa. Any programme to improve the condition of homeless people should include treatment for mental and alcohol use disorders. The findings have significant implications for advocacy and intervention programmes, particularly in similar low income settings. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12916-014-0138-x) contains supplementary material, which is available to authorized users

CNV Analysis in Tourette Syndrome Implicates Large Genomic Rearrangements in COL8A1 and NRXN1.

Tourette syndrome (TS) is a neuropsychiatric disorder with a strong genetic component. However, the genetic architecture of TS remains uncertain. Copy number variation (CNV) has been shown to contribute to the genetic make-up of several neurodevelopmental conditions, including schizophrenia and autism. Here we describe CNV calls using SNP chip genotype data from an initial sample of 210 TS cases and 285 controls ascertained in two Latin American populations. After extensive quality control, we found that cases (N = 179) have a significant excess (P = 0.006) of large CNV (>500 kb) calls compared to controls (N = 234). Amongst 24 large CNVs seen only in the cases, we observed four duplications of the COL8A1 gene region. We also found two cases with ∼400kb deletions involving NRXN1, a gene previously implicated in neurodevelopmental disorders, including TS. Follow-up using multiplex ligation-dependent probe amplification (and including 53 more TS cases) validated the CNV calls and identified additional patients with rearrangements in COL8A1 and NRXN1, but none in controls. Examination of available parents indicates that two out of three NRXN1 deletions detected in the TS cases are de-novo mutations. Our results are consistent with the proposal that rare CNVs play a role in TS aetiology and suggest a possible role for rearrangements in the COL8A1 and NRXN1 gene regions

Wide genome transcriptional analysis of the hippocampus in segmental models of trisomy 21 (Down syndrome) presenting learning impairment and atypical brain morphometry

43rd Annual Meeting of the Behavior-Genetics-Association, Marseille, FRANCE, JUN 28-JUL 02, 2013International audienceno abstrac

Genomic sequencing is required for identification of tuberculosis transmission in Hawaii

Abstract Background Tuberculosis (TB) caused an estimated 1.4 million deaths and 10.4 million new cases globally in 2015. TB rates in the United States continue to steadily decline, yet rates in the State of Hawaii are perennially among the highest in the nation due to a continuous influx of immigrants from the Western Pacific and Asia. TB in Hawaii is composed of a unique distribution of genetic lineages, with the Beijing and Manila families of Mycobacterium tuberculosis (Mtb) comprising over two-thirds of TB cases. Standard fingerprinting methods (spoligotyping plus 24-loci Mycobacterial Interspersed Repetitive Units-Variable Number Tandem Repeats [MIRU-VNTR] fingerprinting) perform poorly when used to identify actual transmission clusters composed of isolates from these two families. Those typing methods typically group isolates from these families into large clusters of non-linked isolates with identical fingerprints. Next-generation whole-genome sequencing (WGS) provides a new tool for molecular epidemiology that can resolve clusters of isolates with identical spoligotyping and MIRU-VNTR fingerprints. Methods We performed WGS and SNP analysis and evaluated epidemiological data to investigate 19 apparent TB transmission clusters in Hawaii from 2003 to 2017 in order to assess WGS’ ability to resolve putative Mtb clusters from the Beijing and Manila families. This project additionally investigated MIRU-VNTR allele prevalence to determine why standard Mtb fingerprinting fails to usefully distinguish actual transmission clusters from these two Mtb families. Results WGS excluded transmission events in seven of these putative clusters, confirmed transmission in eight, and identified both transmission-linked and non-linked isolates in four. For epidemiologically identified clusters, while the sensitivity of MIRU-VNTR fingerprinting for identifying actual transmission clusters was found to be 100%, its specificity was only 28.6% relative to WGS. We identified that the Beijing and Manila families’ significantly lower Shannon evenness of MIRU-VNTR allele distributions than lineage 4 was the cause of standard fingerprinting’s poor performance when identifying transmission in Beijing and Manila family clusters. Conclusions This study demonstrated that WGS is necessary for epidemiological investigation of TB in Hawaii and the Pacific

Comparison of Restriction Fragment Length Polymorphism with the Polymorphic Guanine-Cytosine-Rich Sequence and Spoligotyping for Differentiation of Mycobacterium tuberculosis Isolates with Five or Fewer Copies of IS6110▿

The use of IS6110 as a marker for molecular epidemiological studies is limited when a Mycobacterium tuberculosis isolate has five or fewer copies of IS6110. Restriction fragment length polymorphism analysis with a highly polymorphic GC-rich repetitive sequence located in the plasmid pTBN12 (PGRS RFLP) and spoligotyping (based on the polymorphism of the DR region) are two frequently used secondary typing methods. The aim of this study was to compare the performance of these two methods in a population-based study in San Francisco. We included all patients with culture-positive tuberculosis from 1999 to 2007 with IS6110 RFLP results presenting five or fewer bands. PGRS RFLP and spoligotyping were performed using standardized methods. We determined the concordance between the two methods regarding cluster status and the risk factors for an isolate to be in a cluster with each of the methods. Our data indicate that both methods had similar discriminatory power and that the risk factors associated with clustering by either method were the same. Although the cluster/unique status was concordant in 84% of the isolates, patients were clustered differently depending on the method. Therefore, the methods are not interchangeable, and the same method should be used for longitudinal studies