Propagation of kinetic uncertainties through a canonical topology of the TLR4 signaling network in different regions of biochemical reaction space

<p>Abstract</p> <p>Background</p> <p>Signal transduction networks represent the information processing systems that dictate which dynamical regimes of biochemical activity can be accessible to a cell under certain circumstances. One of the major concerns in molecular systems biology is centered on the elucidation of the robustness properties and information processing capabilities of signal transduction networks. Achieving this goal requires the establishment of causal relations between the design principle of biochemical reaction systems and their emergent dynamical behaviors.</p> <p>Methods</p> <p>In this study, efforts were focused in the construction of a relatively well informed, deterministic, non-linear dynamic model, accounting for reaction mechanisms grounded on standard mass action and Hill saturation kinetics, of the canonical reaction topology underlying Toll-like receptor 4 (TLR4)-mediated signaling events. This signaling mechanism has been shown to be deployed in macrophages during a relatively short time window in response to lypopolysaccharyde (LPS) stimulation, which leads to a rapidly mounted innate immune response. An extensive computational exploration of the biochemical reaction space inhabited by this signal transduction network was performed via local and global perturbation strategies. Importantly, a broad spectrum of biologically plausible dynamical regimes accessible to the network in widely scattered regions of parameter space was reconstructed computationally. Additionally, experimentally reported transcriptional readouts of target pro-inflammatory genes, which are actively modulated by the network in response to LPS stimulation, were also simulated. This was done with the main goal of carrying out an unbiased statistical assessment of the intrinsic robustness properties of this canonical reaction topology.</p> <p>Results</p> <p>Our simulation results provide convincing numerical evidence supporting the idea that a canonical reaction mechanism of the TLR4 signaling network is capable of performing information processing in a robust manner, a functional property that is independent of the signaling task required to be executed. Nevertheless, it was found that the robust performance of the network is not solely determined by its design principle (topology), but this may be heavily dependent on the network's current position in biochemical reaction space. Ultimately, our results enabled us the identification of key rate limiting steps which most effectively control the performance of the system under diverse dynamical regimes.</p> <p>Conclusions</p> <p>Overall, our <it>in silico </it>study suggests that biologically relevant and non-intuitive aspects on the general behavior of a complex biomolecular network can be elucidated only when taking into account a wide spectrum of dynamical regimes attainable by the system. Most importantly, this strategy provides the means for a suitable assessment of the inherent variational constraints imposed by the structure of the system when systematically probing its parameter space.</p

No cumplimiento del esquema de vacunación nacional en niños menores de 5 años en la selva peruana en el año 2019: Non-compliance with the national vaccination scheme in children under 5 years old in the peruvian jungle in 2019

In the past decade, levels of coverage on children vaccination had been decreasing nationwide, even more in the Peruvian jungle, reason why is an important public health’s subject to attend. The purpose of this investigation was to analyze maternal and social factors that are associated with incomplete vaccination schedules on children under 5 years old on the Peruvian jungle. It is an observational, analytic investigation, using a secondary source from the Demographic and Family survey (ENDES) from 2019, where is found the information of all the under 5 years old with the healthcare card of oral information given by the mother. Then after selecting the chosen variables, we used the SPSS statistic program for the posterior analysis. Of the 4373 surveys studied; it was shown that 57.5% of children under 5 years have the incomplete vaccination schedule. The multivariate analysis found that non-compliance with the vaccination schedule associated with maternal and social factors such as not having health insurance (ORa 1.72; p&lt;0.01, IC95% 1.39-2,13), poverty (ORa-1,427, p&lt;0.01, IC95% 1.89-1.71), native mother tongue (ORa-1.50, p&lt;0.01, IC-1.13-2,0), problems attending the health center (ORa-1,213, p=0.02, IC95% 1.02-1.44), live outside the city (ORa-1.31, p&lt;0.01, IC95% 1.09- 1.58), age under the age of 24 as a mother/guardian (ORa-1.38, p&lt;0.01, IC95% 1,186-1,619). Not having health insurance, living in poverty, having trouble going to the health center, living outside the city, having a different mother tongue than Spanish and age under 24 are factors associated with non-compliance with the vaccination schedule.En los últimos años a nivel nacional se ha visto un decaimiento de la cobertura en niños menores de 5 años siendo la región selva la más afectada. El presente estudio tuvo como objetivo analizar los factores maternos y sociales asociados al no cumplimiento del esquema de vacunación nacional en niños de 1 a 5 años en la selva peruana en el año 2019, con diseño observacional, analítico empleando la base de datos de la Encuesta Demográfica y de Salud Familiar-(ENDES) 2019 comprendiendo los menores de 5 años en Perú en ese mismo año, se seleccionaron las variables de estudio y se utilizó el programa SPSS 26.0 para el análisis. Fueron 4373 encuestas seleccionadas; se evidenció que el 57.5% de 1 a 5 años tienen el esquema de vacunación incompleto, cuyos factores asociados fueron no tener seguro de salud (ORa 1.72; p&lt;0,01, IC95% 1,39-2,13), la pobreza (ORa=1,427, p&lt;0,01, IC95% 1,89-1,71), lengua materna nativa (ORa=1,50, p&lt;0,01, IC95% 1,13-2,0), problemas para acudir al centro de salud[1] (ORa=1,213, p=0,02, IC95% 1,02-1,44), vivir fuera de la ciudad (ORa= 1,31, p&lt;0,01, IC95% 1,09- 1,58), edad menor a 24 años de madre/apoderado (ORa=1,38, p&lt;0,01, IC95% 1,186-1,619).  Lo que indica una asociación estadísticamente significativa entre algunos de los factores maternos y sociales estudiados con el no cumplimiento del esquema nacional de vacunación

Obesity and the gut microbiota: does up-regulating colonic fermentation protect against obesity and metabolic disease?

Obesity is now considered a major public health concern globally as it predisposes to a number of chronic human diseases. Most developed countries have experienced a dramatic and significant rise in obesity since the 1980s, with obesity apparently accompanying, hand in hand, the adoption of “Western”-style diets and low-energy expenditure lifestyles around the world. Recent studies report an aberrant gut microbiota in obese subjects and that gut microbial metabolic activities, especially carbohydrate fermentation and bile acid metabolism, can impact on a number of mammalian physiological functions linked to obesity. The aim of this review is to present the evidence for a characteristic “obese-type” gut microbiota and to discuss studies linking microbial metabolic activities with mammalian regulation of lipid and glucose metabolism, thermogenesis, satiety, and chronic systemic inflammation. We focus in particular on short-chain fatty acids (SCFA) produced upon fiber fermentation in the colon. Although SCFA are reported to be elevated in the feces of obese individuals, they are also, in contradiction, identified as key metabolic regulators of the physiological checks and controls mammals rely upon to regulate energy metabolism. Most studies suggest that the gut microbiota differs in composition between lean and obese individuals and that diet, especially the high-fat low-fiber Western-style diet, dramatically impacts on the gut microbiota. There is currently no consensus as to whether the gut microbiota plays a causative role in obesity or is modulated in response to the obese state itself or the diet in obesity. Further studies, especially on the regulatory role of SCFA in human energy homeostasis, are needed to clarify the physiological consequences of an “obese-style” microbiota and any putative dietary modulation of associated disease risk