Structural and molecular pathology of the atrium in boxer arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy (AC), also known as arrhythmogenic right ventricular cardiomyopathy (ARVC), is a disease characterized by fatty or fibro-fatty myocardial replacement, predominantly in the right ventricle and to a lower extent the left ventricle. It is recognized as a disease affecting the cardiac intercalated disc. Clinically, it is associated with ventricular arrhythmias, although atrial arrhythmias and atrial histopathological changes characteristic of AC have occasionally been reported. The full extent of atrial involvement in AC has not been investigated. Therefore, we aimed to apply histopathology, immunochemical detection, immunolocalization and transmission electron microscopy (TEM) techniques to characterize the distribution of desmosomal and gap junction proteins at the intercalated disc in the atria of boxers with AC. We hypothesized that histological changes consistent with AC and alterations to the intercalated disc proteins are present in the atria of boxer dogs with AC. The hearts from 14 control and 13 boxers with confirmed AC were studied. Right and left atrial sections from 11 boxers were examined by immunofluorescence. Samples from 10 boxers were used for Western blot analysis. The intercalated disc proteins investigated were connexin 43 (Cx43), connexin 45, connexin 40, plakoglobin, plakophilin-2, desmoplakin, and cadherin. Transmission electron microscopy was performed on the right and left atrial sections of 2 boxers and 2 controls. Western blot band relative density indicated a significant decrease of Cx43 in the right atrium of affected boxers compared to controls. There was no difference between controls and boxers for the other proteins investigated. Immunofluorescence analysis showed that the number of Cx43 signals and the signal intensity for plakoglobin was decreased in the left and right atrium of affected boxers. Transmission electron microscopy suggested disruption of the intercalated disc in affected boxers. In conclusion, these results indicate the alteration of intercalated disc proteins in the atrial myocardium of boxers, showing atrial involvement in addition to the ventricles. These findings support the use of the broader term of AC rather than ARVC to describe this disease. The decrease in the amount of Cx43 in conjunction with the histological changes could represent the substrate for the atrial arrhythmias associated with AC

Thoughts on the Proteins Native State

The presence of metamorphism in the protein's native state is not yet fully understood. In an attempt to throw light on this issue here we present an assessment, in terms of the amide hydrogen exchange protection factor, that aims to determine the likely existence of structural fluctuations in the native-state consistent with both the upper bound marginal stability of proteins and the metamorphism presence. The preliminary results enable us to conclude that the native-state metamorphism is, indeed, more probable than thought.Comment: 10 pages, 1 figur

Analysis of proteins in the light of mutations

Proteins have evolved through mutations, amino acid substitutions, since life appeared on Earth, some 109 years ago. The study of these phenomena has been of particular significance because of their impact on protein stability, function, and structure. Three of the most recent findings in these areas deserve to be highlighted. First, an innovative method has made it feasible to massively determine the impact of mutations on protein stability. Second, a theoretical analysis showed how mutations impact the evolution of protein folding rates. Lastly, it has been shown that native-state structural changes brought on by mutations can be explained in detail by the amide hydrogen exchange protection factors. This study offers a new perspective on how those findings can be used to analyze proteins in the light of mutations. The preliminary results indicate that: (i) mutations can be viewed as sensitive probes to identify "typos" in the amino-acid sequence and also to assess the resistance of naturally occurring proteins to unwanted sequence alterations; (ii) the presence of "typos" in the amino acid sequence, rather than being an evolutionary obstacle, could promote faster evolvability and, in turn, increase the likelihood of higher protein stability; (iii) the mutation site is far more important than the substituted amino acid in terms of the protein's marginal stability changes, and (iv) the protein evolution unpredictability at the molecular level by mutations exists even in the absence of epistasis effects. Finally, the study results support the Darwinian concept of evolution as "descent with modification" by demonstrating that some regions of any protein sequence are susceptible to mutations while others are not.Comment: Manuscript of 10 pages and 5 figure

Finite Dimension: A Mathematical Tool to Analise Glycans

There is a need to develop widely applicable tools to understand glycan organization, diversity and structure. We present a graph-theoretical study of a large sample of glycans in terms of finite dimension, a new metric which is an adaptation to finite sets of the classical Hausdorff "fractal" dimension. Every glycan in the sample is encoded, via finite dimension, as a point of Glycan Space, a new notion introduced in this paper. Two major outcomes were found: (a) the existence of universal bounds that restrict the universe of possible glycans and show, for instance, that the graphs of glycans are a very special type of chemical graph, and (b) how Glycan Space is related to biological domains associated to the analysed glycans. In addition, we discuss briefly how this encoding may help to improve search in glycan databases.Fil: Alonso, Juan Manuel. Universidad Nacional de Cuyo; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi". Universidad Nacional de San Luis. Facultad de Ciencias Físico, Matemáticas y Naturales. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi"; ArgentinaFil: Arroyuelo, Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi". Universidad Nacional de San Luis. Facultad de Ciencias Físico, Matemáticas y Naturales. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi"; ArgentinaFil: Garay, Pablo Germán. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi". Universidad Nacional de San Luis. Facultad de Ciencias Físico, Matemáticas y Naturales. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi"; ArgentinaFil: Martín, Osvaldo Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi". Universidad Nacional de San Luis. Facultad de Ciencias Físico, Matemáticas y Naturales. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi"; ArgentinaFil: Vila, Jorge Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi". Universidad Nacional de San Luis. Facultad de Ciencias Físico, Matemáticas y Naturales. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi"; Argentin

Scale effects in transmissivity

Heterogeneity accounts for several paradoxes in groundwater flow and solute transport. One of the most striking observations is the emergence of scale effects in transmissivity, that is, the increase in effective transmissivity (or hydraulic conductivity, for that matter) with increasing scale of observation. Traditional stochastic approaches, where transmissivity is treated as a multilog-normal random function, lead to a large-scale effective transmissivity equal to the geometric average of local measurements. We present several field cases in which large-scale transmissivities are indeed larger than the geometric average of local tests. This suggests that the assumption of multilog-normality may not be valid in many cases, even if point T values display a log-normal distribution. We conjecture that scale dependence of T may, in part, be a consequence of high T zones being better connected than average or low T zones, a feature which may occur in many geological environments, but which is not consistent with multinormal log-T fields. We go on to generate a suite of log-T fields with a normal distribution for point values but non-multinormal spatial correlation. In all our fields, high T zones show longer correlations than average of low T zones. By simulating flow through these synthetic fields under simple boundary conditions, and estimating their effective transmissivity values, we conclude that these types of departures from the multilog-normality assumption lead consistently to scale effects