Viral Evolution and Adaptation as a Multivariate Branching Process

In the present work we analyze the problem of adaptation and evolution of RNA virus populations, by defining the basic stochastic model as a multivariate branching process in close relation with the branching process advanced by Demetrius, Schuster and Sigmund ("Polynucleotide evolution and branching processes", Bull. Math. Biol. 46 (1985) 239-262), in their study of polynucleotide evolution. We show that in the absence of beneficial forces the model is exactly solvable. As a result it is possible to prove several key results directly related to known typical properties of these systems like (i) proof, in the context of the theory of branching processes, of the lethal mutagenesis criterion proposed by Bull, Sanju\'an and Wilke ("Theory of lethal mutagenesis for viruses", J. Virology 18 (2007) 2930-2939); (ii) a new proposal for the notion of relaxation time with a quantitative prescription for its evaluation and (iii) the quantitative description of the evolution of the expected values in four distinct regimes: transient, "stationary" equilibrium, extinction threshold and lethal mutagenesis. Moreover, new insights on the dynamics of evolving virus populations can be foreseen.Comment: 39 pages, 3 figures. International Symposium on Mathematical and Computational Biology, Tempe, Arizona, USA, 6 - 10 November 2012. Fernando Antoneli, Francisco Bosco, Diogo Castro, And Luiz Mario Janini (2013) Viral Evolution and Adaptation as a Multivariate Branching Process. Biomat 2012: pp. 217-243. Ed.: R. P. Mondaini. World Scientific, Singapor

Virus Replication as a Phenotypic Version of Polynucleotide Evolution

In this paper we revisit and adapt to viral evolution an approach based on the theory of branching process advanced by Demetrius, Schuster and Sigmund ("Polynucleotide evolution and branching processes", Bull. Math. Biol. 46 (1985) 239-262), in their study of polynucleotide evolution. By taking into account beneficial effects we obtain a non-trivial multivariate generalization of their single-type branching process model. Perturbative techniques allows us to obtain analytical asymptotic expressions for the main global parameters of the model which lead to the following rigorous results: (i) a new criterion for "no sure extinction", (ii) a generalization and proof, for this particular class of models, of the lethal mutagenesis criterion proposed by Bull, Sanju\'an and Wilke ("Theory of lethal mutagenesis for viruses", J. Virology 18 (2007) 2930-2939), (iii) a new proposal for the notion of relaxation time with a quantitative prescription for its evaluation, (iv) the quantitative description of the evolution of the expected values in in four distinct "stages": extinction threshold, lethal mutagenesis, stationary "equilibrium" and transient. Finally, based on these quantitative results we are able to draw some qualitative conclusions.Comment: 23 pages, 1 figure, 2 tables. arXiv admin note: substantial text overlap with arXiv:1110.336

Prevalence of transmitted HIV-1 antiretroviral resistance among patients initiating antiretroviral therapy in Brazil: a surveillance study using dried blood spots

Introduction: in Brazil, the use of antiretrovirals is widespread: more than 260,000 individuals are currently undergoing treatment. We conducted a survey targeting antiretroviral-naive individuals who were initiating antiretroviral therapy (ART) according to local guidelines. This survey covered five Brazilian regions.Methods: the HIV Threshold Survey methodology (HIV-THS) of the World Health Organization was utilized, and subjects were selected from seven highly populated cities representative of all Brazilian macro-regions. Dried blood spots (DBS) were collected on SS903 collection cards and were transported by regular mail at room temperature to a single central laboratory for genotyping.Results: We analysed samples from 329 individuals initiating highly active antiretroviral therapy (HAART), 39 (11.8%) of whom were harbouring transmitted drug resistance (TDR). the mean CD4+ T cell count was 253 cells/mu L, and the mean viral load was 142,044 copies/mL. the regional prevalence of resistance was 17.0% in the Northeast, 12.8% in the Southeast, 10.6% in the Central region, 8.5% in the North and 8.5% in the South. the inhibitor-specific TDR prevalence was 6.9% for nucleoside reverse transcriptase inhibitors, 4.9% for non-nucleoside reverse transcriptase inhibitors and 3.9% for protease inhibitors; 3.6% of individuals presented resistance to more than one class of inhibitors. Overall, there were trends towards higher prevalences of subtype C towards the South and subtype F towards the North. of the DBS samples collected, 9.3% failed to provide reliable results.Discussion: We identified variable TDR prevalence, ranging from intermediate to high levels, among individuals in whom HIV disease progressed, thus implying that resistance testing before initiating ART could be effective in Brazil. Our results also indicate that the use of DBS might be especially valuable for providing access to testing in resource-limited and remote settings.Abbott BrazilFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Universidade Federal de São Paulo, Infect Dis Unit, São Paulo, BrazilUniv Fed Bahia, Virol Res Lab, Salvador, BA, BrazilFed Dist Hosp Fdn, Brasilia, DF, BrazilLusiada Univ, Mol Biol Lab, Santos, SP, BrazilMunicipal Itajai, Itajai, BrazilMunicipal Porto Alegre, Porto Alegre, RS, BrazilState Univ Amazonas, Div Infect Dis, Manaus, Amazonas, BrazilUniversidade Federal de São Paulo, Infect Dis Unit, São Paulo, BrazilFAPESP: 2007/54923-1CNPq: 479957/2010-0CAPES: 2496/08Web of Scienc

The Role of the Exerkine Apelin in Age-related Sarcopenia

Apelin is an exercise-induced peptide that declines with age and is positively associated with exercise-induced benefits in older individuals. This molecule may therein have a potential role in combatting sarcopenia—age-related progressive loss of muscle mass and strength—when combined with exercise; however, the molecular mechanisms behind its autocrine function remain unclear. PURPOSE: To investigate how aerobic exercise impacts skeletal muscle apelin signaling, focusing on its potential in counteracting the age-related loss of skeletal muscle. METHODS: 22 Fisher 344 male rats (3- and 21-month-old) were obtained from NIA rodent colonies. Experimental groups were randomly divided: young sedentary (Y, n=5); young exercise (YEx, n=5); old sedentary (O, n=6); old exercise (OEx, n=6). YEx and OEx groups were subjected to an aerobic training protocol (10–12 m/min, 15° incline, 60 min/day, 5 days/10 weeks). At the end of the experiment, the tibialis anterior muscle (TA) was collected, weighed, and snap frozen for subsequent biochemical analysis. Specifically, gene expression of apelin (APLN) and Murf-1 (TRIM63) were detected by reverse transcription polymerase chain reaction (RT-PCR). Separate two-way ANOVAs were used to evaluate significance at a level of pRESULTS: Both O (pCONCLUSION: These results demonstrated that the old rats showed maladaptive responses to the aerobic training in this study, such as reduced body mass, reduced apelin levels, and increased expression of an atrophy-related gene. Our data further emphasizes the importance of exercise dosing, wherein more research is needed to evaluate muscle fiber size, the mechanisms underlying age-related and training-induced changes, and to determine the best exercise regimen for improving muscle quality during aging

Acute vs. Chronic Response to Doxorubicin Treatment with Endurance Training in Non-Tumor-Bearing Rats

Doxorubicin (DOX) is a chemotherapy agent widely used to treat many types of cancer; however, DOX use is limited due to its adverse effects. While cardiotoxicity is the most well-recognized issue, skeletal muscle wasting and weakness is another significant adverse effect that can decrease quality of life, manifested clinically through weakness and exercise intolerance. PURPOSE: We aimed to investigate the effects of DOX treatment on exercise intolerance and muscle function in preclinical models of both acute and chronic effects of chemotherapy using non-tumor-bearing rats. We also investigated the preventive and therapeutic effects of endurance training in these models. METHODS: 55 male Wistar rats were split into two studies: acute (A; n=28) and chronic (C; n=27). Four groups were constituted per study: control sedentary (CS), control exercise (CE), DOX sedentary (DOXS), and DOX exercise (DOXE). For the acute study (A), CE-A and DOXE-A groups were subjected to a preconditioning endurance training (treadmill run 60% max capacity 5d/wk for 4 wks). Following training period, DOXS-A and DOXE-A groups received a single DOX injection (20mg/kg) while control rats received saline solution and were euthanized 48h after the injections. For the chronic study (C), DOX groups (DOXS-C and DOXE-C) received 4 DOX injections (4mg/kg/week) concomitantly with endurance training (groups CE-C and DOXE-C). Animals were euthanized 48h after the last exercise session. All rats completed in vivo functional experiments before euthanasia and had blood collected for the measurement of tumor necrosis factor-alpha [TNF-alpha]. RESULTS: DOX treatment caused exercise intolerance chronically (pDOX=0.0095) but not acutely. Endurance training improved exercise tolerance (Acute: pETpET=0.0005). Regarding muscle function, rats treated with DOX showed a higher muscle torque than controls in the acute phase (pDOXpDOX=0.0114; pI=0.0401), observed only in sedentary animals. Finally, we found circulating levels of TNF-alpha increased in DOX-treated animals at the acute (pDOXCONCLUSION: Our data suggest that the increased contractility at the acute phase of DOX chemotherapy may be due a compensatory mechanism (such as TNF-alpha-induced Ca2+ release), which chronically led to a reduction in muscle function. Endurance training seemed to partially protect the chronic effect of DOX on muscle function. Further analyzes are needed to investigate the mechanisms behind DOX-induced muscle dysfunction

Estimation of genetic diversity in viral populations from next generation sequencing data with extremely deep coverage

In this paper we propose a method and discuss its computational implementation as an integrated tool for the analysis of viral genetic diversity on data generated by high-throughput sequencing. Most methods for viral diversity estimation proposed so far are intended to take benefit of the longer reads produced by some NGS platforms in order to estimate a population of haplotypes. Our goal here is to take advantage of distinct virtues of a certain kind of NGS platform - the platform SOLiD (Life Technologies) is an example - that has not received much attention due to the short length of its reads, which renders haplotype estimation very difficult. However, this kind of platform has a very low error rate and extremely deep coverage per site and our method is designed to take advantage of these characteristics. We propose to measure the populational genetic diversity through a family of multinomial probability distributions indexed by the sites of the virus genome, each one representing the populational distribution of the diversity per site. The implementation of the method focuses on two main optimization strategies: a read mapping/alignment procedure that aims at the recovery of the maximum possible number of short-reads; the estimation of the multinomial parameters through a Bayesian approach, which, unlike simple frequency counting, allows one to take into account the prior information of the control population within the inference of a posterior experimental condition and provides a natural way to separate signal from noise, since it automatically furnishes Bayesian confidence intervals. The methods described in this paper have been implemented as an integrated tool called Tanden (Tool for Analysis of Diversity in Viral Populations).Comment: 30 pages, 5 figures, 2 tables, Tanden is written in C# (Microsoft), runs on the Windows operating system, and can be downloaded from: http://tanden.url.p

Prognostic value of immunoexpression of CCR4, CCR5, CCR7 and CXCR4 in squamous cell carcinoma of tongue and floor of the mouth

Diverse studies have evidenced that chemokines can play a critical role in pathogenesis of oral squamous cell carcinoma (SCC). The main chemokines involved in oral carcinogenesis, tumor invasion and metastasis are CCR4, CCR5, CCR7 and CXCR4, and our aim was to evaluate the prognostic value of the immunoexpression of these chemokines in SCC of tongue and floor of the mouth. A retrospective descriptive study of the immunohistochemical expression of CCR4, CCR5, CCR7 and CXCR4 in paraffin-embedded samples of 124 patients with SCC of the tongue and floor of the mouth was performed, considering 98 cases from Brazil and 26 cases from Chile. Associations between variables were analyzed using chi-square test. Survival curves were performed using the Kaplan-Meier method and compared with long-rank test. For multivariate survival analysis, the Cox hazard model was established. The level of significance established was p?0.05. The statistical analysis showed that samples with well or moderate WHO model differentiation (p=0.001) and a high expression of CCR5 (p=0.05) were significantly associated with a higher disease specific survival, which were also observed in Cox´s multivariate analysis (p=0.01). A higher expression of CCR7 (p=0.01) interfered significantly in disease-free survival in univariate analysis and in Cox´s multivariate analysis (p=0.05). These results support additional evidence, showing that chemokine receptors CCR5 and CCR7 are helpful as biomarkers of poor prognosis in patients with SCC of the tongue and floor of the mouth

Photoimmunotherapy Using Cationic and Anionic Photosensitizer-Antibody Conjugates against HIV Env-Expressing Cells.

Different therapeutic strategies have been investigated to target and eliminate HIV-1-infected cells by using armed antibodies specific to viral proteins, with varying degrees of success. Herein, we propose a new strategy by combining photodynamic therapy (PDT) with HIV Env-targeted immunotherapy, and refer to it as HIV photoimmunotherapy (PIT). A human anti-gp41 antibody (7B2) was conjugated to two photosensitizers (PSs) with different charges through different linking strategies; "Click" conjugation by using an azide-bearing porphyrin attached via a disulfide bridge linker with a drug-to-antibody ratio (DAR) of exactly 4, and "Lysine" conjugation by using phthalocyanine IRDye 700DX dye with average DARs of 2.1, 3.0 and 4.4. These photo-immunoconjugates (PICs) were compared via biochemical and immunological characterizations regarding the dosimetry, solubility, and cell targeting. Photo-induced cytotoxicity of the PICs were compared using assays for apoptosis, reactive oxygen species (ROS), photo-cytotoxicity, and confocal microscopy. Targeted phototoxicity seems to be primarily dependent on the binding of PS-antibody to the HIV antigen on the cell membrane, whilst being independent of the PS type. This is the first report of the application of PIT for HIV immunotherapy by killing HIV Env-expressing cells

Occurrence of Magellanic Penguins along the Northeast Brazilian Coast during 2008 Austral Winter

During the austral winter of 2008, thousands of penguins traveled to low latitudes along the South Atlantic coast of South America. The atmospheric and oceanic conditions from April to July 2008 may account for the penguins' unusual geographic distribution. During that period, South Atlantic coastal waters were cooler; the wind anomalies had northward and onshore components; the ocean's coastal region presented northward currents that favored the penguins to travel toward lower latitudes. This anomalous climate regime resulted from extreme meteorological frontal systems that occurred mainly during June 2008. Three consecutive extreme midlatitude cyclones produced strong wind shear that resulted in the northward oceanic flow along the South American eastern shoreline favoring the penguins to be spotted in northern tropical waters