Challenges and Perspectives in Target Identification and Mechanism Illustration for Chinese Medicine / 中国结合医学杂志

Chinese medicine (CM) is an important resource for human life understanding and discovery of drugs. However, due to the unclear pharmacological mechanism caused by unclear target, research and international promotion of many active components have made little progress in the past decades of years. CM is mainly composed of multi-ingredients with multi-targets. The identification of targets of multiple active components and the weight analysis of multiple targets in a specific pathological environment, that is, the determination of the most important target is the main obstacle to the mechanism clarification and thus hinders its internationalization. In this review, the main approach to target identification and network pharmacology were summarized. And BIBm (Bayesian inference modeling), a powerful method for drug target identification and key pathway determination was introduced. We aim to provide a new scientific basis and ideas for the development and international promotion of new drugs based on CM.

El Enfoque Bayesiano en las Ciencias de la Salud / The Bayesian Approach in the Health Sciences

En estadística existen dos enfoques básicos, la estadística frecuentista que es la corriente principal y la estadística bayesiana. La mayoría de los principales métodos estadísticos son frecuentistas siendo el enfoque bayesiano más desconocido entre los investigadores. En el presente artículo se exponen los fundamentos lógicos del enfoque bayesiano y su uso mediante un ejemplo de aplicación. En este contexto, más que presentar un debate entre la lógica clásica y la bayesiana, se pretende mostrar de manera introductoria las enormes posibilidades que el enfoque bayesiano puede aportar a la investigación en las Ciencias de la Salud.

In the stadistic field there are two basic approaches, the Frequentist Statistics which is the primary one, and the Bayesian Statistics. The most used statistical methods are the Frequentist methods, being the Bayesian approach the most popular among researchers. In this article, the logical basis of the Bayendian approach and its use are exposed through an application example. In this context, rather than presenting a debate between the classic and the Bayensian logic, it is intended to demonstrate in an introductory method the considerable possibilities how Bayesian approach can contribute to Health and Sciences research.

Phylogenetic relationships of the supercontig of sodium channel subunit I (NaV) in 17 species of Anopheles (Diptera: Culicidae)

ABSTRACT Background: Malaria is a global health problem and is transmitted by the Anopheles species. Due to the epidemiological importance of the genus, studies on biological, phylogenetic, and evolutionary aspects have contributed to the understanding of adaptation, vector capacity, and resistance to insecticides. The latter may result from different causes such as mutations in the gene that encodes the sodium channel (NaV). Methods: In this study, the NaV subunit I scaffold of 17 anopheline species was used to infer phylogenetic relationships of the genus Anopheles using Bayesian inference. The evolutionary phylogenetic tree of the NaV gene was aligned in the AliView program and analyzed utilizing Bayesian inference, using the software MrBayes. Results: The anophelines were grouped into five well-supported clusters: 1 - Anopheles darlingi and Anopheles albimanus; 2 - Anopheles sinensis and Anopheles atroparvus; 3 - Anopheles dirus; 4 - Anopheles minimus, Anopheles culicifacies, Anopheles funestus, Anopheles maculatus, and Anopheles stephensi; and 5 - Anopheles christyi, Anopheles epiroticus, Anopheles merus, Anopheles melas, Anopheles gambiae, Anopheles coluzzii, and Anopheles arabiensis. Conclusions: The topology confirms the phylogenetic relationships proposed in studies based on the genome of some anophelines and reflects the current taxonomy of the genus, which suggests that NaV undergoes selection pressure during the evolution of the species. These data are useful tools for inferring their ability to resist insecticides and also help in better understanding the evolutionary processes of the genus Anopheles.

Genotype by environment interactions for body weight in Mediterranean buffaloes using reaction norm models / Interacción genotipo × ambiente para peso corporal de búfalos Mediterráneos utilizando modelos de norma de reacción / Interação genótipo × ambiente para peso corporal de búfalos Mediterrâneos utilizando modelos de norma de reação

Abstract Background: Buffalo breeding has significantly increased in Brazil over recent years. However, few genetic evaluations have been conducted. Objective: To assess Genotype x Environment Interactions in the Mediterranean Water Buffalo in Brazil, for weight at 205 days of age, using reaction norm models via random regression. Methods: Data for buffaloes born between 1990 and 2014 were collected from five farms ascribed to the Brazilian Buffaloe Improvement Program, located in the North (1), Northeast (1), South (2) and Southeast (1) regions of Brazil. The initial database consisted of 5,280 observations at 205 days of age (W205). We assessed fit using two hierarchical reaction norm models: a two-step (HRNM2s) and a one-step (HRNM1s). Model fit was estimated using the Deviance Information Criterion, Deviance Based on Bayes Factors and Deviance based on Conditional Predictive Ordinate. The environmental descriptors were created to group individuals into common production environments based on year, season, herd and sex. Results: The best fit was obtained for the hierarchical reaction norm model with one-step (HRNM1s). Direct heritability estimates for this model ranged from 0.17 to 0.67 and the maternal heritability from 0.02 to 0.11 with increasing environmental gradient. Lower correlations among the sire classifications were obtained in comparison with HRNM1s in environments with low and high management, confirming the presence of genotype x environment interactions. Conclusion: We recommend a wider application of genetic evaluation in buffalo aimed at identifying optimal genotypes within specific environments.

Resumen Antecedentes: La cría de búfalos ha aumentado significativamente en Brasil en los últimos años. Sin embargo, se han realizado escasas evaluaciones genéticas. Objetivo: Evaluar las interacciones genotipo x ambiente en búfalos de agua Mediterráneos criados en Brasil, para peso a los 205 días de edad, utilizando modelos de reacción mediante regresión aleatoria. Métodos: Los datos de búfalos nacidos entre 1990 y 2014 se obtuvieron de cinco granjas situadas en el Norte (1), Nordeste (1), Sur (2) y del Sureste (1) de Brasil. Todas estas haciendas participan en el Programa Brasileño de Mejoramiento de Búfalos. Nuestra base de datos inicial consistió de 5.280 observaciones a los 205 días de edad (P205). Evaluamos el ajuste utilizando dos modelos de norma de reacción jerárquica: de dos pasos (HRNM2s) y un paso (HRNM1s). El ajuste del modelo se estimó usando el Criterio de información de la desviación, desviación basado en los factores de bayes y desviación basado en la ordenación predictiva condicional. Los descriptores ambientales fueron creados para agrupar individuos en ambientes de producción comunes basados en año, estación, rebaño y sexo. Resultados: El mejor ajuste se obtuvo para el modelo de norma de reacción jerárquica con un paso (HRNM1s). Las estimaciones de heredabilidad directa para este modelo variaron de 0,17 a 0,67 y la heredabilidad materna de 0,02 a 0,11 con gradiente ambiental creciente. Las correlaciones más bajas entre las clasificaciones de los reproductores se obtuvieron en comparación con las HRNM1s, en ambientes con bajo y alto manejo, confirmando la presencia de interacciones genotipo x ambiente. Conclusiones: Recomendamos la aplicación amplia de la evaluación genética en búfalos para identificar genotipos óptimos en ambientes específicos.

Resumo Antecedentes: A criação de búfalos aumentou significativamente no Brasil nos últimos anos. No entanto, eles raramente foram objeto de avaliações genéticas. Objetivo: Avaliar as interações genótipo x ambiente em búfalo Mediterrâneo criados no Brasil, para peso aos 205 dias de idade, utilizando modelos de reação por meio de regressão aleatória. Métodos: Os dados para búfalos de água do Mediterrâneo nascidos entre 1990 e 2014 foram coletados de cinco fazendas localizadas nas regiões Norte (1), Nordeste (1), Sul (2) e Sudeste (1) do Brasil. Todas essas fazendas participam do Programa Brasileiro de Melhoramento dos Búfalos. Nosso banco de dados inicial consistiu de 5.280 observações aos 205 dias de idade (P205). Nós avaliamos o ajuste usando dois modelos de norma de reação hierárquica: um de dois passos (HRNM2s) e um passo (HRNM1s). O ajuste do modelo foi estimado usando o Critério de informações do desvio, desvio baseado nos fatores de bayes e desvio baseado na ordenação preditiva condicional. Os descritores ambientais foram criados para agrupar indivíduos em ambientes de produção comuns baseados em ano, estação, rebanho e sexo. Resultados: O melhor ajuste foi obtido para o modelo de norma de reação hierárquica com um passo (HRNM1s). As estimativas de herdabilidade direta para este modelo variaram de 0,17 a 0,67 e a herdabilidade materna de 0,02 a 0,11 com gradiente ambiental crescente. As correlações mais baixas entre as classificações dos reprodutores foram obtidas em comparação com as HRNM1s, em ambientes com baixo e alto manejo, confirmando a presença de interações genótipo x ambiente. Conclusões: Recomendamos a aplicação mais ampla da avaliação genética em búfalos visando identificar genótipos ótimos em ambientes específicos.

Genetic parameters for ultrasound-evaluated carcass and body traits in Anglo-Nubian goats / Parámetros genéticos para las características de la canal y del cuerpo evaluadas por ultrasonido en cabras Anglo-Nubianas / Parâmetros genéticos para características da carcaça avaliadas por ultrassom e corporais em caprinos Anglo-Nubianos

Abstract Background: Meat goat breeding programs should prioritize the identification and selection of genetically superior animals for traits related to meat quality and carcass yield in order to increase the value of the final product. Objective: To estimate (co)variance components and genetic parameters for ultrasound-measured carcass traits, body size and body weight in Anglo- Nubian breed goats raised in the Mid-North region of Brazil. Methods: (Co)variance components and genetic parameters were estimated using the single and two-trait animal model analyses via Bayesian inference for loin eye dimensions (area, length, and depth), sternal fat thickness, rump height, chest circumference and depth, leg perimeter, and body weight. Results: Heritability estimates were higher when two-trait analyses were used. This finding implies that it is possible to recover part of the additive genetic variance included in the residual variance due to the correlation between traits. Genetic correlations between carcass and body size traits showed different magnitudes. On the other hand, genetic correlations between the traits related to muscularity showed high magnitudes. Conclusions: Body weight was not a good indicator of muscularity; therefore, it is not recommended as a criterion for indirect selection to improve carcass traits of Anglo-Nubian goats. Leg perimeter and chest circumference may be important to construct selection indexes in meat goat breeding programs.

Resumen Antecedentes: los programas de mejoramiento de caprinos de carne deben priorizar la identificación y selección de animales genéticamente superiores para características relacionadas con la calidad de la carne y rendimiento de la canal, con el fin de agregar valor al producto final. Objetivo: estimar los componentes de (co)varianza y parámetros genéticos para características de canal obtenidas por ultrasonografía, características de tamaño y peso corporal en caprinos de la raza Anglonubiana, criados en la región medio-norte de Brasil. Métodos: los componentes de (co)varianza y parámetros genéticos fueron estimados mediante un modelo animal usando análisis uni y bi-carácter vía metodología Bayesiana para las dimensiones del ojo de lomo (área, profundidad y longitud), grosor de la grasa esternal, altura de la grupa, circunferencia y profundidad torácica, perímetro de la pierna y peso corporal. Resultados: las estimativas de heredabilidad obtenidas a partir del análisis bi-carácteristico fueron mayores que las obtenidas a partir del análisis uni-carácteristico. Este supuesto implica que es posible recuperar parte de la variancia genética aditiva incluida en la variancia residual, debido a la correlación entre las características. Las correlaciones genéticas entre las características de canal y las medidas corporales presentaron diferentes magnitudes. Por otro lado, las correlaciones genéticas entre las características relacionadas con musculatura presentaron alta magnitud. Conclusiones: el peso corporal no fue un buen indicador de musculatura; por eso no es recomendado como criterio de selección indirecta para mejorar la canal de caprinos Anglonubianos. El perímetro de la pierna y la circunferencia del pecho pueden ser importantes para la construcción de índices de selección en programas de mejoramiento de carne caprina.

Resumo Antecedentes: programas de melhoramento de caprinos de corte devem priorizar a identificação e seleção de animais geneticamente superiores para características relacionadas à qualidade da carne e rendimento de carcaça, para aumentar o valor ao produto final. Objetivo: estimar componentes de (co)variância e parâmetros genéticos para características de carcaça obtidas por ultrassonografia, características de tamanho e peso corporal em caprinos da raça Anglo-Nubiana criados na região Meio-Norte do Brasil. Métodos: os componentes de (co)variância e parâmetros genéticos foram estimados usando análises uni e bicaracterísticas de um modelo animal via metodologia Bayesiana para área, profundidade e comprimento de olho de lombo, espessura da gordura esternal, altura da garupa, circunferência e profundidade torácica, perímetro da perna e peso corporal. Resultados: as estimativas de herdabilidade obtidas a partir das análises bicaracterísticas foram maiores que as obtidas a partir das análises unicaracterísticas. Esse resultado implica que é possível recuperar parte da variância genética aditiva incluída na variância residual devido à correlação entre as características. As correlações genéticas entre as características de carcaça e as medidas corporais apresentaram magnitudes variáveis. Por outro lado, as correlações genéticas entre as características relacionadas à musculosidade apresentaram altas magnitudes. Conclusões: o peso corporal não se mostrou um bom indicador de muscularidade, de modo que não é recomendado como critério de seleção indireta para melhorar a carcaça de caprinos Anglo-Nubiano. O perímetro de perna e a circunferência torácica podem ser importantes para a construção de índices de seleção em programas de melhoramento de carne caprina.

Como o desmatamento influencia a ocorrência de leishmaniose visceral? Uma abordagem contrafactual / How deforestation influence tha occurrence of Visceral Leishmaniasis? A counterfactual approach

A leishmaniose visceral (LV) é uma doença sistêmica de transmissão vetorial. No Brasil, ela é causada pelo protozoário Leishmania infantum e é transmitida por flebotomíneos do gênero Lutzomyia, tendo os cães como a principal fonte de infecção em áreas urbanas. Historicamente a LV era conhecida como uma doença endêmica rural, porém desde a década de 1980, ela atingiu proporções endêmicas e epidêmicas em grandes cidades brasileiras. Desde então vários fatores são considerados como norteadores da expansão da LV, como variáveis socioeconômicas, climáticas e ambientais. Mais especificamente sobre o efeito do desmatamento e perturbações antrópicas no ambiente, a maioria do que se encontra na literatura tem natureza qualitativa ou utiliza de abordagens reducionistas, sem considerar a complexidade da dinâmica de uma doença infecciosa de transmissão vetorial e de caráter zoonóticos. Na presente dissertação, investigamos o efeito do desmatamento na ocorrência de Lutzomyia longipalpis (Lu. longipalpis), leishmaniose visceral canina (LVC) e leishmaniose visceral humana (LVH), tomando como exemplo o estado de São Paulo. Para isso, utilizamos uma abordagem contrafactual para estimar os efeitos (geral, direto e indireto) do desmatamento na ocorrência do Lu. longipalpis/LVC/LVH. Isso foi feito em dois passos, primeiro estimamos os parâmetros por meio de um algoritmo de Metropolis-Hastings duplo e, por fim, estimamos os efeitos causais através de um amostrador de Gibbs, por meio do pacote autognet no R.Vimos que municípios desmatados apresentam 2.63, 2.07 e 3.18 maiores chances de apresentar o vetor, LVC e LVH, respectivamente quando comparados com os municípios que não apresentaram desmatamento. Foi observada também uma forte influência da presença do vetor, LVC e LVH dos municípios vizinhos na ocorrência dos mesmos em municípios previamente livres dos desfechos (6.67, 4.26 e 4.27). Já sob mudanças hipotéticas de prevalência do desmatamento de 50% para 0% no estado, são esperadas quedas na prevalência do vetor, LVC e LVH de 11%, 6.67% e 29.87% respectivamente. O desmatamento influi na ocorrência do vetor, doença em cães e humanos por duas principais vias, (i) alterando o funcionamento do ecossistema e estrutura da comunidade, permitindo a reprodução e colonização do vetor; e (ii) promovendo uma aproximação entre todos os componentes do ciclo da LV. De tal modo, para correto controle da LV e doenças infecciosas como um todo, é imprescindível um desenvolvimento ecologicamente correto com soluções viáveis para as compensações entre a agricultura, urbanização e conservação. urbanização e conservação.

Visceral leishmaniasis (VL) is a systemic vector-borne disease. In Brazil, it caused by the protozoan Leishmania infantum and is transmitted by sandflies of the genus Lutzomyia, with dogs as the principal source of infection in urban areas. Historically, VL was known as a rural endemic disease, since the 80's it has become endemic and epidemic in large Brazilian cities. Since then, many factors were hypothesised as driving VL expansion, as socioeconomic, climatic and environmental variables. More specifically, concerning deforestation and human-made actions in the environment, most studies tend to be qualitative in nature or use traditional reductionist approaches, ignoring the complexities that are inherent of vector-borne zoonotic infectious diseases. The present study aimed to investigate the effect of deforestation in the occurrence of Lutzomyia longipalpis, canine visceral leishmaniasis (CVL), and human visceral leishmaniasis (HVL), taking as a motivating example the São Paulo state (Brazil). To this end, we chose a counterfactual approach to estimate the effects (overall, direct and indirect) of deforestation in the occurrence of vector/CVL/HVL. We did it in two steps; first, we estimated the parameters through a double Metropolis-Hastings algorithm and, finally, we estimated the causal effects through a Gibbs sampler, using the autognet package in R. We observe that deforested cities show 2.63, 2.07, and 3.18 higher odds of vector/CVL/HVL occurrence, respectively, when compared to non-deforested municipalities. We also see a significant influence of vector, CVL, and HVL presence in the neighbours in its appearance in previous naive cities, 6.67, 4.26, 4,27 respectively. Lastly, under hypothetical changes in deforestation's prevalence from 50% to 0% in the whole state, is expected a decrease in its prevalence of the vector, LVC and LVH of 11%, 6.67% and 29.87% respectively. Deforestation in the occurrence of infectious diseases and, more specifically, VL importance, is two-folded: (i) changing's the ecosystem equilibrium and community structure, allowing its vector to reproduce and colonise; (ii) promoting a close contact through the VL cycle components. In such a way, for correct control of VL and infectious disease as a whole, it is essential an eco-friendly development with viable solutions for trade-offs between agriculture, urbanization and conservation.

Colletotrichum fructicola, a Member of Colletotrichum gloeosporioides sensu lato, is the Causal Agent of Anthracnose and Soft Rot in Avocado Fruits cv. “Hass”

The filamentous Ascomycota Colletotrichum gloeosporioides sensu lato is a fungus that has been reported worldwide as a causal agent of anthracnose disease in avocado and other crops. In Mexico, this species affects fruits from an early stage of development in the orchard until the post-harvest stage. Although fungicides are continuously applied to control Colletotrichum species, pericarp cankers and soft rot mesocarp in fruits are still frequently observed. Considering the lack of a precise description of the causative agent, the aim of the current study was to determine the pathogens involved in this symptomatology. Twenty-four isolates were consistently obtained from the pericarp of avocado fruits cv. “Hass” collected in the central avocado-producing area of Mexico. Morphological features such as colony growth, conidia size, and mycelial appressorium were assessed. Bayesian multilocus phylogenetic analyses were performed using amplified sequences of the internal transcribed spacer region of the nuclear ribosomal DNA; actin, chitin synthase, glyceraldehyde-3-phosphate dehydrogenase partial genes; and APn2-Mat1-2 intergenic spacer and mating type Mat1-2 partial gene from the nine selected isolates. In addition, fruits were inoculated with a conidial suspension and reproducible symptoms confirmed the presence of Colletotrichum fructicola in this area. This pathogenic species can now be added to those previously reported in the country, such as C. acutatum, C. boninense, C. godetiae, C. gloeosporioides, and C. karstii. Disease management programs to reduce the incidence of anthracnose should include C. fructicola to determine its response to fungicides that are routinely applied, considering that the appearance of new species is affecting the commercial quality of the fruits and shifting the original population structure.

A comparison of breast cancer survival among young, middle-aged, and elderly patients in southern Iran using Cox and empirical Bayesian additive hazard models / 한국역학회지

OBJECTIVES: A survival analysis of breast cancer patients in southern Iran according to age has yet to be conducted. This study aimed to quantify the factors contributing to a poor prognosis, using Cox and empirical Bayesian additive hazard (EBAH) models, among young (20-39 years), middle-aged (40-64 years), and elderly (≥ 65 years) women.METHODS: Data from 1,574 breast cancer patients diagnosed from 2002 to 2012 in the cancer registry of Fars Province (southern Iran) were stratified into 3 age groups. The Kaplan-Meier method was used to estimate the overall survival rates. Cox and EBAH models were applied to each age category, and the Akaike information criterion was used to assess the goodness-of-fit of the 2 hazard models.RESULTS: As of December 2012, 212 women (13.5%) in our study population had died, of whom 43 were young (15.3%), 134 middle-aged (11.8%), and 35 elderly (22.3%). The 5-year survival probability by age category was 0.83 (standard error [SE], 0.03), 0.88 (SE, 0.01), and 0.75 (SE, 0.04), respectively.CONCLUSIONS: The Nottingham Prognostic Index was the most effective prognostic factor. The model based on Bayesian methodology performed better with various sample sizes than the Cox model, which is the most widely used method of survival analysis.

A comparison of breast cancer survival among young, middle-aged, and elderly patients in southern Iran using Cox and empirical Bayesian additive hazard models / 한국역학회지

OBJECTIVES: A survival analysis of breast cancer patients in southern Iran according to age has yet to be conducted. This study aimed to quantify the factors contributing to a poor prognosis, using Cox and empirical Bayesian additive hazard (EBAH) models, among young (20-39 years), middle-aged (40-64 years), and elderly (≥ 65 years) women. METHODS: Data from 1,574 breast cancer patients diagnosed from 2002 to 2012 in the cancer registry of Fars Province (southern Iran) were stratified into 3 age groups. The Kaplan-Meier method was used to estimate the overall survival rates. Cox and EBAH models were applied to each age category, and the Akaike information criterion was used to assess the goodness-of-fit of the 2 hazard models. RESULTS: As of December 2012, 212 women (13.5%) in our study population had died, of whom 43 were young (15.3%), 134 middle-aged (11.8%), and 35 elderly (22.3%). The 5-year survival probability by age category was 0.83 (standard error [SE], 0.03), 0.88 (SE, 0.01), and 0.75 (SE, 0.04), respectively. CONCLUSIONS: The Nottingham Prognostic Index was the most effective prognostic factor. The model based on Bayesian methodology performed better with various sample sizes than the Cox model, which is the most widely used method of survival analysis.

Genetic parameters in female reproductive traits of Nile tilapia (Oreochromis niloticus)

ABSTRACT Genetic parameters for reproductive traits in female Nile tilapia were estimated in this study using Bayesian inference method. The data set presented information from 451 Nile tilapia females that were evaluated at two different places in Maringá - Paraná - Brazil (hapas of 1 and 10 m³) and at one location in Alfenas - Minas Gerais - Brazil. A spawning examination was conducted once a week from October 2012 to March 2013 for a total of 23 weeks of evaluation. Single-trait analyses for spawning success, multiple spawning, spawning frequency, and volume of eggs/female were performed by using the software MTGSAM Threshold. The heritability estimates were 0.14, 0.16, 0.53, and 0.08 for spawning success, multiple spawning, spawning frequency and volume of eggs/female, respectively, indicating it is possible to achieve a substantial genetic gain using these reproductive traits as selection criteria.