Totally asymmetric simple exclusion process simulations of molecular motor transport on random networks with asymmetric exit rates

Using the totally asymmetric simple-exclusion-process and mean-field transport theory, we investigate the transport in closed random networks with simple crossing topology—two incoming, two outgoing segments, as a model for molecular motor motion along biopolymer networks. Inspired by in vitro observation of molecular motor motion, we model the motor behavior at the intersections by introducing different exit rates for the two outgoing segments. Our simulations of this simple network reveal surprisingly rich behavior of the transport current with respect to the global density and exit rate ratio. For asymmetric exit rates, we find a broad current plateau at intermediate motor densities resulting from the competition of two subnetwork populations. This current plateau leads to stabilization of transport properties within such networks

Unconditional positive self-regard, intrinsic aspirations and authenticity: pathways to psychological well-being

Unconditional positive self-regard (UPSR) is regarded by humanistic psychologists as an important determinant of well-being. However, until recently it has received little empirical attention. The current study aims to examine the association between unconditional positive self-regard and several key constructs consistent with the ideas of well-being within contemporary positive psychology. Study 1 is a confirmatory factor analysis of the UPSR scale. The statistically significant best fit for the data was a related two-factor model. Study 2 used the two-factors of the UPSR scale to explore the association with intrinsic aspirations. The study showed positive self-regard was statistically significantly positively correlated with the intrinsic aspirations total scale and with each of the separate scores for IA-importance and IA-chance. Unconditionality of regard was statistically significantly negatively correlated with IA-importance but was not statistically significantly correlated to either the IA-total or IA-chance scores. Study 3 considers the association between UPSR, intrinsic aspirations and authenticity. Unconditionality of regard was statistically significantly positively correlated with the authenticity scale score. Only IA-chance scores showed a statistically significant and positive correlation with authenticity. The remaining correlations between intrinsic aspirations and authenticity were not statistically significant. Results call for further empirical attention to UPSR within positive psychology research

Derivation of the method of characteristics for the fluid dynamic solution of flow advection along porous wall channels

This paper describes in detail a novel formulation of the method of characteristics for its application to solve one-dimensional compressible unsteady non-homentropic flow advected along porous wall channels. In particular, the method is implemented into a wall-flow monolith Diesel particulate filter model whose purpose is the pressure drop prediction. The flow inside the monolith channels is considered to be one-dimensional and the flow through the porous wall treated as a source term agree with the Darcy's law. The flow dynamic behaviour at internal nodes of the channels is solved by means of shock capturing methods, whereas the end nodes, or boundary conditions, are solved applying the method of characteristics. The derived solution in this study of the Riemann variables and the entropy level includes the variation along the space-time plane due to cross-section area changes, friction and heat transfer as traditionally stated, but also takes into account the key influence on every line of the flow leaving or entering to the channels through the porous walls. © 2011 Elsevier Inc.Desantes Fernández, JM.; Serrano Cruz, JR.; Arnau Martínez, FJ.; Piqueras Cabrera, P. (2012). Derivation of the method of characteristics for the fluid dynamic solution of flow advection along porous wall channels. Applied Mathematical Modelling. 36:3134-3152. doi:10.1016/j.apm.2011.09.090S313431523

Plasma proteome profiling identifies changes associated to AD but not to FTD

Background Frontotemporal dementia (FTD) is caused by frontotemporal lobar degeneration (FTLD), characterized mainly by inclusions of Tau (FTLD-Tau) or TAR DNA binding43 (FTLD-TDP) proteins. Plasma biomarkers are strongly needed for specific diagnosis and potential treatment monitoring of FTD. We aimed to identify specific FTD plasma biomarker profiles discriminating FTD from AD and controls, and between FTD pathological subtypes. In addition, we compared plasma results with results in post-mortem frontal cortex of FTD cases to understand the underlying process. Methods Plasma proteins (n = 1303) from pathologically and/or genetically confirmed FTD patients (n = 56; FTLD-Tau n = 16; age = 58.2 +/- 6.2; 44% female, FTLD-TDP n = 40; age = 59.8 +/- 7.9; 45% female), AD patients (n = 57; age = 65.5 +/- 8.0; 39% female), and non-demented controls (n = 148; 61.3 +/- 7.9; 41% female) were measured using an aptamer-based proteomic technology (SomaScan). In addition, exploratory analysis in post-mortem frontal brain cortex of FTD (n = 10; FTLD-Tau n = 5; age = 56.2 +/- 6.9, 60% female, and FTLD-TDP n = 5; age = 64.0 +/- 7.7, 60% female) and non-demented controls (n = 4; age = 61.3 +/- 8.1; 75% female) were also performed. Differentially regulated plasma and tissue proteins were identified by global testing adjusting for demographic variables and multiple testing. Logistic lasso regression was used to identify plasma protein panels discriminating FTD from non-demented controls and AD, or FTLD-Tau from FTLD-TDP. Performance of the discriminatory plasma protein panels was based on predictions obtained from bootstrapping with 1000 resampled analysis. Results Overall plasma protein expression profiles differed between FTD, AD and controls (6 proteins; p = 0.005), but none of the plasma proteins was specifically associated to FTD. The overall tissue protein expression profile differed between FTD and controls (7-proteins; p = 0.003). There was no difference in overall plasma or tissue expression profile between FTD subtypes. Regression analysis revealed a panel of 12-plasma proteins discriminating FTD from AD with high accuracy (AUC: 0.99). No plasma protein panels discriminating FTD from controls or FTD pathological subtypes were identified. Conclusions We identified a promising plasma protein panel as a minimally-invasive tool to aid in the differential diagnosis of FTD from AD, which was primarily associated to AD pathophysiology. The lack of plasma profiles specifically associated to FTD or its pathological subtypes might be explained by FTD heterogeneity, calling for FTD studies using large and well-characterize cohorts

The pediatric NAFLD fibrosis index: a predictor of liver fibrosis in children with non-alcoholic fatty liver disease

<p>Abstract</p> <p>Background</p> <p>Liver fibrosis is a stage of non-alcoholic fatty liver disease (NAFLD) which is responsible for liver-related morbidity and mortality in adults. Accordingly, the search for non-invasive markers of liver fibrosis has been the subject of intensive efforts in adults with NAFLD. Here, we developed a simple algorithm for the prediction of liver fibrosis in children with NAFLD followed at a tertiary care center.</p> <p>Methods</p> <p>The study included 136 male and 67 female children with NAFLD aged 3.3 to 18.0 years; 141 (69%) of them had fibrosis at liver biopsy. On the basis of biological plausibility, readily availability and evidence from adult studies, we evaluated the following potential predictors of liver fibrosis at bootstrapped stepwise logistic regression: gender, age, body mass index, waist circumference, alanine transaminase, aspartate transaminase, gamma-glutamyl-transferase, albumin, prothrombin time, glucose, insulin, triglycerides and cholesterol. A final model was developed using bootstrapped logistic regression with bias-correction. We used this model to develop the 'pediatric NAFLD fibrosis index' (PNFI), which varies between 0 and 10.</p> <p>Results</p> <p>The final model was based on age, waist circumference and triglycerides and had a area under the receiver operating characteristic curve of 0.85 (95% bootstrapped confidence interval (CI) with bias correction 0.80 to 0.90) for the prediction of liver fibrosis. A PNFI ≥ 9 (positive likelihood ratio = 28.6, 95% CI 4.0 to 201.0; positive predictive value = 98.5, 95% CI 91.8 to 100.0) could be used to rule in liver fibrosis without performing liver biopsy.</p> <p>Conclusion</p> <p>PNFI may help clinicians to predict liver fibrosis in children with NAFLD, but external validation is needed before it can be employed for this purpose.</p

Molecular Mechanics of the α-Actinin Rod Domain: Bending, Torsional, and Extensional Behavior

α-Actinin is an actin crosslinking molecule that can serve as a scaffold and maintain dynamic actin filament networks. As a crosslinker in the stressed cytoskeleton, α-actinin can retain conformation, function, and strength. α-Actinin has an actin binding domain and a calmodulin homology domain separated by a long rod domain. Using molecular dynamics and normal mode analysis, we suggest that the α-actinin rod domain has flexible terminal regions which can twist and extend under mechanical stress, yet has a highly rigid interior region stabilized by aromatic packing within each spectrin repeat, by electrostatic interactions between the spectrin repeats, and by strong salt bridges between its two anti-parallel monomers. By exploring the natural vibrations of the α-actinin rod domain and by conducting bending molecular dynamics simulations we also predict that bending of the rod domain is possible with minimal force. We introduce computational methods for analyzing the torsional strain of molecules using rotating constraints. Molecular dynamics extension of the α-actinin rod is also performed, demonstrating transduction of the unfolding forces across salt bridges to the associated monomer of the α-actinin rod domain

Diagnostic value of biochemical markers (FibroTest-FibroSURE) for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease

BACKGROUND: Liver biopsy is considered as the gold standard for assessing non-alcoholic fatty liver disease (NAFLD) histologic lesions. The aim of this study was to determine the diagnostic utility of non-invasive markers of fibrosis, validated in chronic viral hepatitis and alcoholic liver disease (FibroTest, FT), in patients with NAFLD. METHODS: 170 patients with suspected NAFLD were prospectively included in a reference center (Group 1), 97 in a multicenter study (Group 2) and 954 blood donors as controls. Fibrosis was assessed on a 5 stage histological scale validated by Kleiner et al from F0 = none, F1 = perisinusoidal or periportal, F2 = perisinusoidal and portal/periportal, F3 = bridging and F4 = cirrhosis. Histology and the biochemical measurements were blinded to any other characteristics. The area under the ROC curves (AUROC), sensitivity (Se), specificity (Sp), positive and negative predictive values (PPV, NPV) were assessed. RESULTS: In both groups FT has elevated and not different AUROCs for the diagnosis of advanced fibrosis (F2F3F4): 0.86 (95%CI 0.77–0.91) versus 0.75 (95%CI 0.61–0.83; P = 0.10), and for F3F4: 0.92 (95%CI 0.83–0.96) versus 0.81 (95%CI 0.64–0.91; P = 0.12) in Group1 and Group 2 respectively. When the 2 groups were pooled together a FT cutoff of 0.30 had a 90% NPV for advanced fibrosis (Se 77%); a FT cutoff of 0.70 had a 73% PPV for advanced fibrosis (Sp 98%). CONCLUSION: In patients with NAFLD, FibroTest, a simple and non-invasive quantitative estimate of liver fibrosis reliably predicts advanced fibrosis

Metabolic syndrome is linked to a mild elevation in liver aminotransferases in diabetic patients with undetectable non-alcoholic fatty liver disease by ultrasound

<p>Abstract</p> <p>Background</p> <p>Despite ongoing findings on the relationship between elevated levels of alanine and aspartate aminotransferases (ALT and AST) and metabolic syndrome (MetS), this association in diabetic patients without a known cause for liver enzymes elevation other than diabetes, per se, remains unclear. In this study, we aimed to assess the relationship between circulating liver enzymes and MetS in a relatively large sample of patients with diabetes.</p> <p>Methods</p> <p>A total of 670 diabetic patients, without known causes of hepatocellular injury, were enrolled. Patients with ultrasonographic signs of fatty liver disease were not included. Fasting blood samples were obtained and biochemical characteristics were measured. MetS was defined according to the international diabetes federation criteria.</p> <p>Results</p> <p>Serum ALT and AST were significantly higher in patients with MetS (p < 0.001). High waist circumference and low HDL-cholesterol were significantly associated with elevated ALT (OR = 2.56 and 2.0, respectively) and AST (OR = 2.23 and 2.21, respectively). ALT and AST were significantly associated with MetS (OR = 2.17 and 2.31, respectively). These associations remained significant after multiple adjustments for age, sex, BMI, diabetes duration, HbA1c and medications. There was a significant (p < 0.01) positive association between the number of the MetS features and the level of ALT or AST.</p> <p>Conclusion</p> <p>In diabetic patients without ultrasonographic evidence of fatty liver, elevated aminotransferases are independently associated with MetS. Despite negative ultrasound results in diabetic patients with MetS, the serum level of liver aminotransferases may be elevated and should be more thoroughly monitored.</p

Fibroblast growth factor 21 reflects liver fat accumulation and dysregulation of signalling pathways in the liver of C57BL/6J mice

Fibroblast growth factor 21 (Fgf21) has emerged as a potential plasma marker to diagnose non-alcoholic fatty liver disease (NAFLD). To study the molecular processes underlying the association of plasma Fgf21 with NAFLD, we explored the liver transcriptome data of a mild NAFLD model of aging C57BL/6J mice at 12, 24, and 28 months of age. The plasma Fgf21 level significantly correlated with intrahepatic triglyceride content. At the molecular level, elevated plasma Fgf21 levels were associated with dysregulated metabolic and cancerrelated pathways. The up-regulated Fgf21 levels in NAFLD were implied to be a protective response against the NAFLD-induced adverse effects, e.g. lipotoxicity, oxidative stress and endoplasmic reticulum stress. An in vivo PPARα challenge demonstrated the dysregulation of PPARα signalling in the presence of NAFLD, which resulted in a stochastically increasing hepatic expression of Fgf21. Notably, elevated plasma Fgf21 was associated with declining expression of Klb, Fgf21’s crucial co-receptor, which suggests a resistance to Fgf21. Therefore, although liver fat accumulation is a benign stage of NAFLD, the elevated plasma Fgf21 likely indicated vulnerability to metabolic stressors that may contribute towards progression to end-stage NAFLD. In conclusion, plasma levels of Fgf21 reflect liver fat accumulation and dysregulation of metabolic pathways in the liver

Accounting for Diffusion in Agent Based Models of Reaction-Diffusion Systems with Application to Cytoskeletal Diffusion

Diffusion plays a key role in many biochemical reaction systems seen in nature. Scenarios where diffusion behavior is critical can be seen in the cell and subcellular compartments where molecular crowding limits the interaction between particles. We investigate the application of a computational method for modeling the diffusion of molecules and macromolecules in three-dimensional solutions using agent based modeling. This method allows for realistic modeling of a system of particles with different properties such as size, diffusion coefficients, and affinity as well as the environment properties such as viscosity and geometry. Simulations using these movement probabilities yield behavior that mimics natural diffusion. Using this modeling framework, we simulate the effects of molecular crowding on effective diffusion and have validated the results of our model using Langevin dynamics simulations and note that they are in good agreement with previous experimental data. Furthermore, we investigate an extension of this framework where single discrete cells can contain multiple particles of varying size in an effort to highlight errors that can arise from discretization that lead to the unnatural behavior of particles undergoing diffusion. Subsequently, we explore various algorithms that differ in how they handle the movement of multiple particles per cell and suggest an algorithm that properly accommodates multiple particles of various sizes per cell that can replicate the natural behavior of these particles diffusing. Finally, we use the present modeling framework to investigate the effect of structural geometry on the directionality of diffusion in the cell cytoskeleton with the observation that parallel orientation in the structural geometry of actin filaments of filopodia and the branched structure of lamellipodia can give directionality to diffusion at the filopodia-lamellipodia interface