Remodelling of gap junctions and connexin expression in diseased myocardium

Gap junctions form the cell-to-cell pathways for propagation of the precisely orchestrated patterns of current flow that govern the regular rhythm of the healthy heart. As in most tissues and organs, multiple connexin types are expressed in the heart: connexin43 (Cx43), Cx40 and Cx45 are found in distinctive combinations and relative quantities in different, functionally-specialized subsets of cardiac myocyte. Mutations in genes that encode connexins have only rarely been identified as being a cause of human cardiac disease, but remodelling of connexin expression and gap junction organization are well documented in acquired adult heart disease, notably ischaemic heart disease and heart failure. Remodelling may take the form of alterations in (i) the distribution of gap junctions and (ii) the amount and type of connexins expressed. Heterogeneous reduction in Cx43 expression and disordering in gap junction distribution feature in human ventricular disease and correlate with electrophysiologically identified arrhythmic changes and contractile dysfunction in animal models. Disease-related alterations in Cx45 and Cx40 expression have also been reported, and some of the functional implications of these are beginning to emerge. Apart from ventricular disease, various features of gap junction organization and connexin expression have been implicated in the initiation and persistence of the most common form of atrial arrhythmia, atrial fibrillation, though the disparate findings in this area remain to be clarified. Other major tasks ahead focus on the Purkinje/working ventricular myocyte interface and its role in normal and abnormal impulse propagation, connexin-interacting proteins and their regulatory functions, and on defining the precise functional properties conferred by the distinctive connexin co-expression patterns of different myocyte types in health and disease

Evolution of costs of inflammatory bowel disease over two years of follow-up

Background: With the increasing use of anti-TNF therapy in inflammatory bowel disease (IBD), a shift of costs has been observed with medication costs replacing hospitalization and surgery as major cost driver. We aimed to explore the evolution of IBD-related costs over two years of follow-up. Methods and Findings: In total 1,307 Crohn's disease (CD) patients and 915 ulcerative colitis (UC) patients were prospectively followed for two years by three-monthly web-based questionnaires. Changes of healthcare costs, productivity costs and out-of-pocket costs over time were assessed using mixed model analysis. Multivariable logistic regression analysis was used to identify costs drivers. In total 737 CD patients and 566 UC were included. Total costs were stable over two years of follow-up, with annual total costs of € 7,835 in CD and € 3,600 in UC. However, within healthcare costs, the proportion of anti-TNF therapy-related costs increased from 64% to 72% in CD (p<0.01) and from 31% to 39% in UC (p < 0.01). In contrast, the proportion of hospitalization costs decreased from 19% to 13% in CD (p<0.01), and 22% to 15% in UC (p < 0.01). Penetrating disease course predicted an increase of healthcare costs (adjusted odds ratio (adj. OR) 1.95 (95% CI 1.02-3.37) in CD and age <40 years in UC (adj. OR 4.72 (95% CI 1.61-13.86)). Conclusions: BD-related costs remained stable over two years. However, the proportion of anti-TNFrelated healthcare costs increased, while hospitalization costs decreased. Factors associated with increased costs were penetrating disease course in CD and age <40 in UC

The effect of materials' rheology on process energy consumption and melt thermal quality in polymer extrusion

YesPolymer extrusion is an important but an energy intensive method of processing polymeric materials. The rapid increase in demand of polymeric products has forced manufactures to rethink their processing efficiencies to manufacture good quality products with low-unit-cost. Here, analyzing the operational conditions has become a key strategy to achieve both energy and thermal efficiencies simultaneously. This study aims to explore the effects of polymers' rheology on the energy consumption and melt thermal quality (ie, a thermally homogeneous melt flow in both radial and axil directions) of extruders. Six commodity grades of polymers (LDPE, LLDPE, PP, PET, PS, and PMMA) were processed at different conditions in two types of continuous screw extruders. Total power, motor power, and melt temperature profiles were analyzed in an industrial scale single-screw extruder. Moreover, the active power (AP), mass throughput, torque, and power factor were measured in a laboratory scale twin-screw extruder. The results confirmed that the specific energy consumption for both single and twin screw extruders tends to decrease with the processing speed. However, this action deteriorates the thermal stability of the melt regardless the nature of the polymer. Rheological characterization results showed that the viscosity of LDPE and PS exhibited a normal shear thinning behavior. However, PMMA presented a shear thickening behavior at moderate-to-high shear rates, indicating the possible formation of entanglements. Overall, the findings of this work confirm that the materials' rheology has an appreciable correlation with the energy consumption in polymer extrusion and also most of the findings are in agreement with the previously reported investigations. Therefore, further research should be useful for identifying possible correlations between key process parameters and hence to further understand the processing behavior for wide range of machines, polymers, and operating conditions

Synergy Between Intercellular Communication and Intracellular Ca2+ Handling in Arrhythmogenesis

Calcium is the primary signalling component of excitation-contraction coupling, the process linking electrical excitability of cardiac muscle cells to coordinated contraction of the heart. Understanding Ca2þ handling processes at the cellular level and the role of intercellular communication in the emergence of multicellular synchronization are key aspects in the study of arrhythmias. To probe these mechanisms, we have simulated cellular interactions on large scale arrays that mimic cardiac tissue, and where individual cells are represented by a mathematical model of intracellular Ca2þ dynamics. Theoretical predictions successfully reproduced experimental findings and provide novel insights on the action of two pharmacological agents (ionomycin and verapamil) that modulate Ca2þ signalling pathways via distinct mechanisms. Computational results have demonstrated how transitions between local synchronisation events and large scale wave formation are affected by these agents. Entrainment phenomena are shown to be linked to both ntracellular Ca2þ and coupling-specific dynamics in a synergistic manner. The intrinsic variability of the cellular matrix is also shown to affect emergent patterns of rhythmicity, providing insights into the origins of arrhythmogenic Ca2þ perturbations in cardiac tissue in situ

Two novel connexin32 mutations cause early onset X-linked Charcot-Marie-Tooth disease

<p>Abstract</p> <p>Background</p> <p>X-linked Charcot-Marie Tooth (CMT) is caused by mutations in the connexin32 gene that encodes a polypeptide which is arranged in hexameric array and form gap junctions.</p> <p>Methods</p> <p>We describe two novel mutations in the connexin32 gene in two Norwegian families.</p> <p>Results</p> <p>Family 1 had a c.225delG (R75fsX83) which causes a frameshift and premature stop codon at position 247. This probably results in a shorter non-functional protein structure. Affected individuals had an early age at onset usually in the first decade. The symptoms were more severe in men than women. All had severe muscle weakness in the legs. Several abortions were observed in this family. Family 2 had a c.536 G>A (C179Y) transition which causes a change of the highly conserved cysteine residue, i.e. disruption of at least one of three disulfide bridges. The mean age at onset was in the first decade. Muscle wasting was severe and correlated with muscle weakness in legs. The men and one woman also had symptom from their hands.</p> <p>The neuropathy is demyelinating and the nerve conduction velocities were in the intermediate range (25–49 m/s). Affected individuals had symmetrical clinical findings, while the neurophysiology revealed minor asymmetrical findings in nerve conduction velocity in 6 of 10 affected individuals.</p> <p>Conclusion</p> <p>The two novel mutations in the connexin32 gene are more severe than the majority of previously described mutations possibly due to the severe structural change of the gap junction they encode.</p

Microautophagy of the Nucleus Coincides with a Vacuolar Diffusion Barrier at Nuclear–Vacuolar Junctions

Nuclear-vacuolar (NV) junctions are organelle contact sites in yeast. They exclude nuclear pores from the organelle interface. On the vacuolar side, a lipid-dependent process excludes specific membrane proteins, such as V-ATPase, from the contact site. This suggests that NV junctions establish selective diffusion barriers

Biogenesis and functions of bacterial S-layers.

The outer surface of many archaea and bacteria is coated with a proteinaceous surface layer (known as an S-layer), which is formed by the self-assembly of monomeric proteins into a regularly spaced, two-dimensional array. Bacteria possess dedicated pathways for the secretion and anchoring of the S-layer to the cell wall, and some Gram-positive species have large S-layer-associated gene families. S-layers have important roles in growth and survival, and their many functions include the maintenance of cell integrity, enzyme display and, in pathogens and commensals, interaction with the host and its immune system. In this Review, we discuss our current knowledge of S-layer and related proteins, including their structures, mechanisms of secretion and anchoring and their diverse functions