Statistical significance based on length and position of the local score in a model of i.i.d. sequences.

Motivation: The local score of a biological sequence analysis is a mathematical tool largely used to analyse biological sequences. Consequently, determining an accurate estimation of its distribution is crucial. Results: First, we study the accuracy of classical results on the local score distribution in independent and identically distributed model using a Kolmogorov-Smirnov goodness of fit test. Second, we highlight how the length of the segment that realizes the local score improves the classical setting based on local score only. Finally, we study which part of the sequence contributes to the local score. Contact: mercier@univ-tlse2.fr.

Accounting for linkage disequilibrium in genome scans for selection without individual genotypes: The local score approach.

Detecting genomic footprints of selection is an important step in the understanding of evolution. Accounting for linkage disequilibrium in genome scans increases detection power, but haplotype-based methods require individual genotypes and are not applicable on pool-sequenced samples. We propose to take advantage of the local score approach to account for linkage disequilibrium in genome scans for selection, cumulating (possibly small) signals from single markers over a genomic segment, to clearly pinpoint a selection signal. Using computer simulations, we demonstrate that this approach detects selection with higher power than several state-of-the-art single-marker, windowing or haplotype-based approaches. We illustrate this on two benchmark data sets including individual genotypes, for which we obtain similar results with the local score and one haplotype-based approach. Finally, we apply the local score approach to Pool-Seq data obtained from a divergent selection experiment on behaviour in quail and obtain precise and biologically coherent selection signals: while competing methods fail to highlight any clear selection signature, our method detects several regions involving genes known to act on social responsiveness or autistic traits. Although we focus here on the detection of positive selection from multiple population data, the local score approach is general and can be applied to other genome scans for selection or other genomewide analyses such as GWAS.

Healthy food, unhealthy food: Indigenous perspectives on the nutrition transition.

Amazonian Indigenous Peoples are undergoing drastic changes in their ways of life including the quality and availability of food and its impact on their health and well-being. Indigenous populations have their own perspectives and interpretations of dietary changes unfolding in their communities. Based on in-depth interviews, observations and validation workshops we explored the way Awajún describe and problematise the concept of healthy and unhealthy food in the context of the nutrition transition. We learn that the characteristics of 'good food' are informed by their capacity to give strength, protect health and enable them to be hardworking people. On the contrary, food that comes from the city weakens the body and may result in health problems. For the Awajún, chicken with hormones, fish preserved in cans, and powdered milk negatively affect their health. We argue that the dichotomy 'healthy' and 'unhealthy' used to classify food provides information not only about Indigenous conceptualisations of health and die, but is also a critique of broader structural processes affecting their well-being. The terms, explanations and idioms used by the Awajún to talk about food, provide an insight into Indigenous perspectives and knowledge key to informing global health interventions in culturally appropriate ways.

New Approximate Statistical Significance of Gapped Alignments Based on the Greedy Extension Model.

Sequence alignment is a fundamental concept in bioinformatics to distinguish regions of similarity among various sequences. The degree of similarity has been considered as a score. There are a number of various methods to find the statistical significance of similarity in the gapped and ungapped cases. In this article, we improve the statistical significance accuracy of the local score by introducing a new approximate p-value. This is developed according to Poisson clumping and the exact distribution of a partial sum of random variables. The efficiency of the proposed method is compared with that of previous methods on real and simulated data. The results yield a remarkable improvement in accuracy of the p-value in the gapped case. This is an evidence for the method to be considered as a prospective candidate for sequences comparison.

H-tuple approach to evaluate statistical significance of biological sequence comparison with gaps.

We propose an approximate distribution for the gapped local score of a two sequence comparison. Our method stands on combining an adapted scoring scheme that includes the gaps and an approximate distribution of the ungapped local score of two independent sequences of i.i.d. random variables. The new scoring scheme is defined on h-tuples of the sequences, using the gapped global score. The influence of h and the accuracy of the p-value are numerically studied and compared with obtained p-value of BLAST. The numerical experiments emphasize that our approximate p-values outperform the BLAST ones, particularly for both simulated and real short sequences.

Methionine kinetics are altered in the elderly both in the basal state and after vaccination.

BACKGROUND: Inflammation is known to affect sulfur amino acid metabolism. Aging is associated with an increased prevalence of inflammatory conditions, but the metabolism of methionine has been poorly explored in the elderly. OBJECTIVES: The aims of this study were to compare methionine kinetics between elderly and young subjects and to explore the effect of aging on the response to a mild inflammatory challenge induced by a vaccination. DESIGN: Seven elderly volunteers aged 66-76 y and 8 young volunteers aged 22-26 y were studied before and 2 d after a vaccination (diphtheria, tetanus, poliomyelitis, and typhoid vaccines). Methionine kinetics were measured by using an infusion of L-[1-13C, methyl-2H3]methionine in the postabsorptive and fed states. RESULTS: Before vaccination, the contribution of homocysteine remethylation to methionine-methyl flux (Qm) and the ratio of remethylation to homocysteine transsulfuration were significantly lower in the elderly subjects than in the young subjects (P < 0.05). In contrast, the contribution of transsulfuration to methionine transmethylation was higher in the elderly (P < 0.05). Vaccination significantly increased the ratio of transsulfuration to transmethylation and decreased the ratio of remethylation to Qm (P < 0.05). CONCLUSIONS: The preferential methionine metabolism toward cysteine synthesis observed after vaccination suggests an increased requirement of sulfur amino acids even in mild inflammatory situations. The main finding of this study is a higher proportion of methionine entering the transsulfuration pathway in elderly subjects before vaccination. This finding suggests an increased cysteine demand during aging.

The inflammatory response to vaccination is altered in the elderly.

To further explore whether immune function and acute phase response are altered during ageing, the response to a mild inflammatory stress (DT-Polio-Typhim vaccination) was studied in elderly and young subjects. Cytokine production (IFN-gamma, TNF-alpha, IL-6, IL-10) by whole blood cultures, circulating cytokines and acute phase proteins were analysed before and 2 days after vaccination. Prior to vaccination, only IFN-gamma production was lower in the elderly than in the young subjects due to a lower mononuclear cell number. In the same time, although in the normal range, several acute phase proteins were greater in elderly than in young subjects, suggesting a low-grade inflammatory state in the elderly. After vaccination, IFN-gamma production remained lower in the elderly than in the young, supporting an altered cell-mediated immunity with advancing age. TNF-alpha production was unaffected by either ageing or vaccination. IL-6 production was stimulated by vaccination in young subjects but not significantly in the elderly. IL-10 production was inhibited by vaccination in the elderly but not in the young. Acute phase proteins were less increased in elderly than in young subjects. Taken together, these results support a general lack of inflammatory response in the elderly exposed to an immune challenge and suggest that immune deficiency may concern both Th1 and Th2 responses. However, the interpretation must respect the limitation of small subjects number.

Lipodystrophy and metabolic disorders in HIV-1-infected adults on 4- to 9-year antiretroviral therapy in Senegal: a case-control study.

OBJECTIVE: To assess adverse effects of long-term highly active antiretroviral therapy (HAART), that is, lipodystrophy and metabolic disorders, in a cohort of African patients. METHODS: One hundred eighty HIV-1-infected patients treated with HAART for 4-9 years in Dakar and 180 age-matched and sex-matched controls were enrolled. Regional subcutaneous fat changes were assessed by physicians, and fasting blood samples were drawn. Centralization of body fat was estimated using skinfold ratio, waist circumference, and waist to hip ratio (WHR). RESULTS: Mean duration of HAART was 5.4 years. Main drugs received were zidovudine, stavudine, and protease inhibitors. The prevalence of moderate-severe lipodystrophy was 31.1% (95% confidence interval: 24.3 to 37.9), with 13.3%, 14.5%, and 3.3% for lipoatrophy, lipohypertrophy, and mixed forms, respectively. Mild-severe lipodystrophy affected 65.0% (58.0; 72.0) of patients. Stavudine was the only independent risk factor (any vs. none: odds ratio = 2.8; 1.4 to 5.5). Patients had lower body mass index and skinfolds but greater centralization of body fat (WHR, P < 0.0001 and skinfold ratio, P < 0.001), fasting glucose (P < 0.0001), homeostasis model assessment insulin resistance, and triglyceride levels (P < 0.01 for both) than controls. Moderately-severely lipodystrophic patients had higher triglyceride and low-density lipoprotein cholesterol than other patients (P < 0.001 and P < 0.05, respectively). CONCLUSIONS: Moderate-severe lipodystrophy affected one third of West African patients on long-term HAART and was associated with a less favorable metabolic profile.

CD4 cell response before and after HAART initiation according to viral load and growth indicators in HIV-1-infected children in Abidjan, Côte d'Ivoire.

OBJECTIVE: To analyze the determinants of CD4 change in children during 3 periods: before highly active antiretroviral therapy (HAART), during the first year after HAART initiation, and past 1 year after HAART initiation. METHODS: One hundred seventy-seven children enrolled in a prospective cohort in Abidjan received HAART during a mean follow-up of 30 months. A linear mixed-effects model was used for the first period, a mixed-effects piecewise model for the second period, and an asymptotic mixed-effects model for long-term CD4 dynamics. RESULTS: Before HAART initiation, CD4 percentage decreased along time [beta = -0.59 (-0.92 to -0.26)] was positively associated with body mass index for age [beta = 0.47 (0.22 to 0.72)] and negatively associated with viral load [beta = -1.01 (-1.90 to -0.13)]. During the first year of treatment, the CD4 decrease reverted to a steep increase that was negatively associated with age at HAART initiation [beta = -0.24 (-0.4 to -0.07)] and with the mean viral load under HAART [beta = -1.51 (-2.21 to -0.81)]. The long-term CD4 percentage was also negatively associated with the mean viral load under HAART [beta = -4.97 (-6.22 to -3.72)] and age at HAART initiation [beta = -0.82 (-1.12 to -0.51)]. CONCLUSIONS: Before HAART initiation, the CD4 cell percentage was associated with growth indicators whereas, after HAART, an early increase and a long-term plateau were negatively associated with the viral load and age at HAART initiation.

Chronic inflammation alters protein metabolism in several organs of adult rats.

Despite the prevalence of chronic inflammatory diseases in developed countries, few studies have considered the metabolic alterations observed in these disorders. To determine which perturbations in protein metabolism occur during chronic inflammation, and the consequences they have on nutritional requirements, a model of ulcerative colitis was adapted for use in adult rats. Adult Sprague-Dawley male rats (9 mo old) received dextran sulfate sodium (DSS) in their drinking water at 50 g/L for 9 d, then at 20 g/L for 18 d. A group of control rats, matched for age and weight, was pair-fed to the treated rats. DSS induced body weight loss and chronic inflammation characterized by an increase of spleen, liver, ileum and colon weights, of blood leukocytes and acute-phase protein levels. The main inflammatory site was the colon, which presented characteristic histological alterations and increased myeloperoxydase activity. Inflammation was accompanied by oxidative stress, characterized by increased plasma protein carbonyl content and increased liver glutathione concentration, but decreased glutathione concentration in muscle. This DSS-induced colitis led to a stimulation of protein synthesis in spleen (+223%), ileum (+40%) and colon (+63%). By contrast, protein synthesis in muscle slowed down (-23%). In conclusion, like acute inflammation, chronic inflammation induced a stimulation of protein metabolism in several splanchnic organs. In muscle, both protein synthesis and degradation were reduced. Taken together, these data are consistent with inadequate amino acid supply to meet the increased requirement resulting from chronic inflammation.