A multiscale agent-based in silico model of liver fibrosis progression

Chronic hepatic inflammation involves a complex interplay of inflammatory and mechanical influences, ultimately manifesting in a characteristic histopathology of liver fibrosis. We created an agent-based model (ABM) of liver tissue in order to computationally examine the consequence of liver inflammation. Our liver fibrosis ABM (LFABM) is comprised of literature-derived rules describing molecular and histopathological aspects of inflammation and fibrosis in a section of chemically injured liver. Hepatocytes are modeled as agents within hexagonal lobules. Injury triggers an inflammatory reaction, which leads to activation of local Kupffer cells and recruitment of monocytes from circulation. Portal fibroblasts and hepatic stellate cells are activated locally by the products of inflammation. The various agents in the simulation are regulated by above-threshold concentrations of pro- and anti-inflammatory cytokines and damage-associated molecular pattern molecules. The simulation progresses from chronic inflammation to collagen deposition, exhibiting periportal fibrosis followed by bridging fibrosis, and culminating in disruption of the regular lobular structure. The ABM exhibited key histopathological features observed in liver sections from rats treated with carbon tetrachloride (CCl4). An in silico "tension test" for the hepatic lobules predicted an overall increase in tissue stiffness, in line with clinical elastography literature and published studies in CCl4-treated rats. Therapy simulations suggested differential anti-fibrotic effects of neutralizing tumor necrosis factor alpha vs. enhancing M2 Kupffer cells. We conclude that a computational model of liver inflammation on a structural skeleton of physical forces can recapitulate key histopathological and macroscopic properties of CCl4-injured liver. This multiscale approach linking molecular and chemomechanical stimuli enables a model that could be used to gain translationally relevant insights into liver fibrosis

Museo Comunitario, propuesta de desarrollo ecoturístico para municipios del Estado de Oaxaca

El Estado de Oaxaca se encuentra dividido en ocho regiones geográficas las cuales comprenden 30 distritos, mismos que están formados por 570 municipios, las regiones son: la Costa, el Istmo, los Valles Centrales, la Cañada, la Mixteca, la Sierra Norte, Sierra Sur y el Papaloapan; cada uno de ellos tienen diversas costumbres y tradiciones, así como su tipo de gobierno. Para Montero (2004:147) “el patrimonio tangible, que lleva a los sitios que son sagrados en alguna cultura, obra y producto hecha por el hombre, como lo son los museos, monumentos, lugares y localidades de arte o de carácter, sitios arqueológicos, etc. y el patrimonio que es intangible, remite a expresiones y fiestas tradicionales y de saberes-hacer del pasado y del presente”. Dentro de los municipios del estado de Oaxaca, se encuentra una variedad de patrimonios culturales tangibles e intangibles, por lo que este trabajo de investigación tiene como objetivo general: Proponer el diseño de museos comunitarios en municipios con características de subdesarrollo o marcadas desigualdades económicas, que permitan el desarrollo del mismo; generándose un progreso del ecoturismo. El trabajo se divide en tres partes: la primera describe el área de estudio, la segunda, el estado del arte que permite comprender lo que es un museo comunitario, su importancia, así como sus características, y finalmente se desarrolla la propuesta. La metodología que se llevó a cabo es de gabinete, de consultas de trabajos realizados sobre el tema propuesto, por lo que la hipótesis que se esboza es la siguiente: Una estrategia de política pública del diseño de un museo comunitario permite el desarrollo local de municipios con marcadas desigualdades económicas. No obstante, dentro de la definición e importancia del museo comunitario; es conveniente señalar la definición de “museo”. Para Rivière (1993:70), es una institución al servicio de la sociedad que selecciona, adquiere, conserva, comunica y sobre todo expone con fines de acrecentamiento del saber, la salvaguarda y desarrollo del patrimonio, la realidad y la imagen de los bienes de la naturaleza del hombre. Así mismo, existen diversas iniciativas para la creación de museos con enfoques distintos; tal como, el museo que fomenta la conservación y preservación del patrimonio intangible de algunos territorios, fortaleciendo su identidad; en concreto, el museo comunitario o bien el ecomuseo forman parte de estas instituciones con dichas iniciativas. Dentro de los resultados obtenidos se encuentra el concepto de ecomuseo y su relación con el museo comunitario; de acuerdo a los trabajos científicos que se consultaron se aceptó la hipótesis de estudio. En conclusión, los autores consultados en el tema de ecomuseo y museos comunitarios, señalan que son una herramienta para el rescate y preservación del patrimonio de un territorio, que reactiva la memoria colectiva, y siendo una alternativa de política pública para el desarrollo local. Por último, Borghi (2017:45) menciona que, cada ecomuseo, adopta un modelo que hace de la participación un elemento constitutivo de su identidad, y debe dotarse de instrumentos que la estimulen y la faciliten, instrumentos capaces de convertir a los ciudadanos en protagonistas activos en la experiencia de salvaguardia de su propio patrimonio

Virulence behavior of uropathogenic Escherichia coli strains in the host model Caenorhabditis elegans

Urinary tract infections (UTIs) are among the most common bacterial infections in humans. Although a number of bacteria can cause UTIs, most cases are due to infection by uropathogenic Escherichia coli (UPEC). UPEC are a genetically heterogeneous group that exhibit several virulence factors associated with colonization and persistence of bacteria in the urinary tract. Caenorhabditis elegans is a tiny, free-living nematode found worldwide. Because many biological pathways are conserved in C. elegans and humans, the nematode has been increasingly used as a model organism to study virulence mechanisms of microbial infections and innate immunity. The virulence of UPEC strains, characterized for antimicrobial resistance, pathogenicity-related genes associated with virulence and phylogenetic group belonging was evaluated by measuring the survival of C. elegans exposed to pure cultures of these strains. Our results showed that urinary strains can kill the nematode and that the clinical isolate ECP110 was able to efficiently colonize the gut and to inhibit the host oxidative response to infection. Our data support that C. elegans, a free-living nematode found worldwide, could serve as an in vivo model to distinguish, among uropathogenic E. coli, different virulence behavior

Modulatory effects of α- and γ-tocopherols on 4-hydroxyestradiol induced oxidative stresses in MCF-10A breast epithelial cells

The elevated level of circulating estradiol increases the risk of breast tumor development. To gain further insight into mechanisms involved in their actions, we investigated the molecular mechanisms of 4-hydroxyestradiol (4-OHE2) to initiate and/or promote abnormal cell growth, and of α- or γ-tocopherol to inhibit this process. MCF-10A, human breast epithelial cells were incubated with 0.1 µM 4-OHE2, either with or without 30 µM tocopherols for 96 h. 4-OHE2 caused the accumulation of intracellular ROS, while cellular GSH/GSSG ratio and MnSOD protein levels were decreased, indicating that there was an oxidative burden. 4-OHE2 treatment also changed the levels of DNA repair proteins, BRCA1 and PARP-1. γ-Tocopherol suppressed the 4-OHE2-induced increases in ROS, GSH/GSSG ratio, and MnSOD protein expression, while α-tocopherol up-regulated BRCA1 and PARP-1 protein expression. In conclusion, 4-OHE2 increases oxidative stress reducing the level of proteins related to DNA repair. Tocopherols suppressed oxidative stress by scavenging ROS or up-regulating DNA repair elements

Thyrotropin-releasing hormone (TRH) promotes wound re-epithelialisation in frog and human skin

There remains a critical need for new therapeutics that promote wound healing in patients suffering from chronic skin wounds. This is, in part, due to a shortage of simple, physiologically and clinically relevant test systems for investigating candidate agents. The skin of amphibians possesses a remarkable regenerative capacity, which remains insufficiently explored for clinical purposes. Combining comparative biology with a translational medicine approach, we report the development and application of a simple ex vivo frog (Xenopus tropicalis) skin organ culture system that permits exploration of the effects of amphibian skin-derived agents on re-epithelialisation in both frog and human skin. Using this amphibian model, we identify thyrotropin-releasing hormone (TRH) as a novel stimulant of epidermal regeneration. Moving to a complementary human ex vivo wounded skin assay, we demonstrate that the effects of TRH are conserved across the amphibian-mammalian divide: TRH stimulates wound closure and formation of neo-epidermis in organ-cultured human skin, accompanied by increased keratinocyte proliferation and wound healing-associated differentiation (cytokeratin 6 expression). Thus, TRH represents a novel, clinically relevant neuroendocrine wound repair promoter that deserves further exploration. These complementary frog and human skin ex vivo assays encourage a comparative biology approach in future wound healing research so as to facilitate the rapid identification and preclinical testing of novel, evolutionarily conserved, and clinically relevant wound healing promoters

Spatially uninformative sounds increase sensitivity for visual motion change

It has recently been shown that spatially uninformative sounds can cause a visual stimulus to pop out from an array of similar distractor stimuli when that sound is presented in temporal proximity to a feature change in the visual stimulus. Until now, this effect has predominantly been demonstrated by using stationary stimuli. Here, we extended these results by showing that auditory stimuli can also improve the sensitivity of visual motion change detection. To accomplish this, we presented moving visual stimuli (small dots) on a computer screen. At a random moment during a trial, one of these stimuli could abruptly move in an orthogonal direction. Participants’ task was to indicate whether such an abrupt motion change occurred or not by making a corresponding button press. If a sound (a short 1,000 Hz tone pip) co-occurred with the abrupt motion change, participants were able to detect this motion change more frequently than when the sound was not present. Using measures derived from signal detection theory, we were able to demonstrate that the effect on accuracy was due to increased sensitivity rather than to changes in response bias

Has decentralisation affected child immunisation status in Indonesia?

Background: The past two decades have seen many countries, including a number in Southeast Asia, decentralising their health system with the expectation that this reform will improve their citizens’ health. However, the consequences of this reform remain largely unknown. Objective: This study analyses the effects of fiscal decentralisation on child immunisation status in Indonesia. Design: We used multilevel logistic regression analysis to estimate these effects, and multilevel multiple imputation to manage missing data. The 2011 publication of Indonesia's national socio-economic survey (Susenas) is the source of household data, while the Podes village census survey from the same year provides village-level data. We supplement these with local government fiscal data from the Ministry of Finance. Results: The findings show that decentralising the fiscal allocation of responsibilities to local governments has a lack of association with child immunisation status and the results are robust. The results also suggest that increasing the number of village health centres (posyandu) per 1,000 population improves probability of children to receive full immunisation significantly, while increasing that of hospitals and health centres (puskesmas) has no significant effect. Conclusion: These findings suggest that merely decentralising the health system does not guarantee improvement in a country's immunisation coverage. Any successful decentralisation demands good capacity and capability of local governments

Evolving Sensitivity Balances Boolean Networks

We investigate the sensitivity of Boolean Networks (BNs) to mutations. We are interested in Boolean Networks as a model of Gene Regulatory Networks (GRNs). We adopt Ribeiro and Kauffman’s Ergodic Set and use it to study the long term dynamics of a BN. We define the sensitivity of a BN to be the mean change in its Ergodic Set structure under all possible loss of interaction mutations. Insilico experiments were used to selectively evolve BNs for sensitivity to losing interactions. We find that maximum sensitivity was often achievable and resulted in the BNs becoming topologically balanced, i.e. they evolve towards network structures in which they have a similar number of inhibitory and excitatory interactions. In terms of the dynamics, the dominant sensitivity strategy that evolved was to build BNs with Ergodic Sets dominated by a single long limit cycle which is easily destabilised by mutations. We discuss the relevance of our findings in the context of Stem Cell Differentiation and propose a relationship between pluripotent stem cells and our evolved sensitive networks