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

A novel ABCA4 mutation associated with a late-onset Stargardt disease phenotype: a hypomorphic allele?

Background: Stargardt disease (STGD) is the most common juvenile hereditary macular dystrophy. In the majority of cases, the diagnosis is made prior to 20 years of age and usually leads to loss of central vision. Late-onset STGD affects a smaller number of patients. Identifying genetic changes which could be associated with clinically important differences in severity or presentation of the disease is important for understanding the mechanisms of visual loss and for planning future therapeutic approaches. Methods: We report a patient with the classic phenotype of STGD with late-onset mild disease exhibiting a slow clinical progression over 14 months of follow-up. Results: A 37-year-old man presented with STGD and good vision of 6/24 in the right eye and of 6/6 in the left eye as well as typical electrophysiology findings. Objective and subjective visual deterioration was not noted over a period of 14 months. Macular genetic testing revealed a novel missense mutation in ABCA4 (Thr829Met) combined with Gly1961Glu, a classic STGD mutation usually associated with a moderately severe phenotype. Conclusions: It is suggested that the Thr829Met mutation could give rise to a hypomorphic allele of the ABC transporter with a resultant phenotype of comparatively mild STGD

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

Total knee replacement versus osteochondral allograft in proximal tibia bone tumours

Total knee modular megaprosthesis or osteochondral allograft are used to preserve joint movement in bone tumours of the proximal tibia. The aim of this study was to compare two groups of patients with total knee modular megaprosthesis and osteochondral allograft through an objective analysis. Eighteen patients, ten treated with prosthesis (TKR group) and eight with osteochondral allografts (AL group), were included in the study. X-ray, muscular strength measurements, and studies of gait analysis including electromyography (EMG) were used to compare functional results of patients. In the TKR group a higher incidence of knee extension lag was found. While the TKR group had a prevalent knee stiff/hyperextension pattern with reduced rectus femoris activity, the AL group had a higher percentage of normal knee pattern. Knee extensor muscular strength was reduced in the TKR group. TKR functional performance during gait is in most cases abnormal, consistent with the weakness of the extensor apparatus and knee extension lag. Although a greater rate of normal walking was found in the AL group, problems related to a short patellar tendon, knee instability, and joint mismatching were considered to be responsible for abnormal knee kinematics. An allograft, when optimal reconstruction is performed, gives better functional results

Bladder carcinoma: MDCT cystography and virtual cystoscopy

Bladder carcinoma is the most common tumor among the low urinary tract, accounting for 90% of cancer cases. Conventional cystoscopy represents the gold standard for diagnosis and local management of bladder carcinoma. As the prevalence of transitional cell carcinoma is four-fold greater in men than in women, the endoscopic procedure presents objective difficulties related to the length and bending of male urethra. The most important problems are represented by intense discomfort for the patient and bleeding; furthermore, the high cost, invasivity, and local complications such as infections and mechanical lesions are well-known drawbacks. Additionally, conventional cystoscopy does not provide information about extravescical extensions of the tumor. CT cystography, combined with virtual cystoscopy, is mandatory for TNM staging of the tumor and also is useful when conventional cystoscopy is inconclusive or cannot be performed. We presents the CT cystography combined with virtual endoscopy correlation and bladder carcinoma appearance. © Springer Science+Business Media, LLC 2009

Facial electroneurography in Bell's palsy: variability in the early stage and comparison between interpretation methods Eletroneurografia do nervo facial na paralisia de Bell: variabilidade na fase aguda e comparação entre técnicas

To determine the variability of the abnormalities found in the electroneurography (ENG) of the facial nerve in cases of Bell's palsy during the initial two week period was one of the objectives of the authors. A second one was to investigate the value of ENG as a tool to determine an early prognosis of recovery utilizing two different methods. In the first one the amplitude of the compound muscular action potential (CMAP) obtained on the paralyzed side was compared to this potential on the opposite (normal) side. The second method compared the CMAP on the paralyzed side to normal standardized data from normal individuals. A group of 33 patients with Bell's palsy was followed until total recovery or for at least 4 months, if the recovery was not achieved earlier. It was observed that amplitude of the CMAP become stable towards the sixth day of palsy and this is a good time to establish the prognosis. Another conclusion is that both methods were equivalent to determine the prognosis in Bell's palsy.<br>O objetivo deste trabalho é determinar a variabilidade da eletroneurografia (ENG) do nervo facial na paralisia de Bell durante as primeiras duas semanas e investigar o valor da ENG na determinação de um prognóstico precoce utilizando-se dois métodos diferentes. O primeiro método compara a amplitude do potencial de ação muscular composto obtido no lado paralisado com o lado normal e o segundo método compara o potencial de ação muscular composto obtido no lado paralisado com valores normativos. Um grupo de 33 pacientes com paralisia de Bell foi seguido até a recuperação total ou pelo menos por quatro meses nos casos em que não houve recuperação. Observou-se que a amplitude do potencial de ação muscular composto estabiliza-se em torno do sexto dia e que este é um bom momento para se realizar o exame e se estabelecer um prognóstico. Outra conclusão é que ambos os métodos são equivalentes para determinação prognóstica