On the Role of Mechanics in Chronic Lung Disease.

Progressive airflow obstruction is a classical hallmark of chronic lung disease, affecting more than one fourth of the adult population. As the disease progresses, the inner layer of the airway wall grows, folds inwards, and narrows the lumen. The critical failure conditions for airway folding have been studied intensely for idealized circular cross-sections. However, the role of airway branching during this process is unknown. Here, we show that the geometry of the bronchial tree plays a crucial role in chronic airway obstruction and that critical failure conditions vary significantly along a branching airway segment. We perform systematic parametric studies for varying airway cross-sections using a computational model for mucosal thickening based on the theory of finite growth. Our simulations indicate that smaller airways are at a higher risk of narrowing than larger airways and that regions away from a branch narrow more drastically than regions close to a branch. These results agree with clinical observations and could help explain the underlying mechanisms of progressive airway obstruction. Understanding growth-induced instabilities in constrained geometries has immediate biomedical applications beyond asthma and chronic bronchitis in the diagnostics and treatment of chronic gastritis, obstructive sleep apnea and breast cancer

Subgap features due to quasiparticle tunneling in quantum dots coupled to superconducting leads

We present a microscopic theory of transport through quantum dot set-ups coupled to superconducting leads. We derive a master equation for the reduced density matrix to lowest order in the tunneling Hamiltonian and focus on quasiparticle tunneling. For high enough temperatures transport occurs in the subgap region due to thermally excited quasiparticles, which can be used to observe excited states of the system for low bias voltages. On the example of a double quantum dot we show how subgap transport spectroscopy can be done. Moreover, we use the single level quantum dot coupled to a normal and a superconducting lead to give a possible explanation for the subgap features observed in the experiments published in Appl. Phys. Lett. 95, 192103 (2009).Comment: 18 pages, 20 figures, revised according to published versio

Biogenesis of mitochondrial porin

We review here the present knowledge about the pathway of import and assembly of porin into mitochondria and compare it to those of other mitochondrial proteins. Porin, like all outer mitochondrial membrane proteins studied so far is made as a precursor without a cleavble lsquosignalrsquo sequence; thus targeting information must reside in the mature sequence. At least part of this information appears to be located at the amino-terminal end of the molecule. Transport into mitochondria can occur post-translationally. In a first step, the porin precursor is specifically recognized on the mitochondrial surface by a protease sensitive receptor. In a second step, porin precursor inserts partially into the outer membrane. This step is mediated by a component of the import machinery common to the import pathways of precursor proteins destined for other mitochondrial subcompartments. Finally, porin is assembled to produce the functional oligomeric form of an integral membrane protein wich is characterized by its extreme protease resistance

Automatic Mapping of Atrial Fiber Orientations for Patient-Specific Modeling of Cardiac Electromechanics using Image-Registration

Knowledge of appropriate local fiber architecture is necessary to simulate patient-specific electromechanics in the human heart. However, it is not yet possible to reliably measure in-vivo fiber directions, especially in human atria. Thus, we present a method which defines the fiber architecture in arbitrarily shaped atria using image registration and reorientation methods based on atlas atria with fibers predefined from detailed histological observations. Thereby, it is possible to generate detailed fiber families in every new patient-specific geometry in an automated, time-efficient process. We demonstrate the good performance of the image registration and fiber definition on ten differently shaped human atria. Additionally, we show that characteristics of the electrophysiological activation pattern which appear in the atlas atria also appear in the patients' atria. We arrive at analogous conclusions for coupled electro-mechano-hemodynamical computations

A homogenized constrained mixture model of cardiac growth and remodeling: Analyzing mechanobiological stability and reversal

Cardiac growth and remodeling (G&R) patterns change ventricular size, shape, and function both globally and locally. Biomechanical, neurohormonal, and genetic stimuli drive these patterns through changes in myocyte dimension and fibrosis. We propose a novel microstructure-motivated model that predicts organ-scale G&R in the heart based on the homogenized constrained mixture theory. Previous models, based on the kinematic growth theory, reproduced consequences of G&R in bulk myocardial tissue by prescribing the direction and extent of growth but neglected underlying cellular mechanisms. In our model, the direction and extent of G&R emerge naturally from intra- and extra cellular turnover processes in myocardial tissue constituents and their preferred homeostatic stretch state. We additionally propose a method to obtain a mechanobiologically equilibrated reference configuration. We test our model on an idealized 3D left ventricular geometry and demonstrate that our model aims to maintain tensional homeostasis in hypertension conditions. In a stability map, we identify regions of stable and unstable G&R from an identical parameter set with varying systolic pressures and growth factors. Furthermore, we show the extent of G&R reversal after returning the systolic pressure to baseline following stage 1 and 2 hypertension. A realistic model of organ-scale cardiac G&R has the potential to identify patients at risk of heart failure, enable personalized cardiac therapies, and facilitate the optimal design of medical devices

Mitochondrial precursor proteins are imported through a hydrophilic membrane environment

We have analyzed how translocation intermediates of imported mitochondrial precursor proteins, which span contact sites, interact with the mitochondrial membranes. F1-ATPase subunit β(F1β) was trapped at contact sites by importing it into Neurospora mitochondria in the presence of low levels of nucleoside triphosphates. This F1β translocation intermediate could be extracted from the membranes by treatment with protein denaturants such as alkaline pH or urea. By performing import at low temperatures, the ADP/ATP carrier was accumulated in contact sites of Neurospora mitochondria and cytochrome b2 in contact sites of yeast mitochondria. These translocation intermediates were also extractable from the membranes at alkaline pH. Thus, translocation of precursor proteins across mitochondrial membranes seems to occur through an environment which is accessible to aqueous perturbants. We propose that proteinaceous structures are essential components of a translocation apparatus present in contact sites

The role of Isocitrate Lyase (ICL1) in the metabolic adaptation of Candida albicans biofilms

Background A major characteristic of Candida biofilm cells that differentiates them from free-floating cells is their high tolerance to antifungal drugs. This high resistance is attributed to particular biofilm properties, including the accumulation of extrapolymeric substances, morphogenetic switching, and metabolic flexibility. Objectives This study evaluated the roles of metabolic processes (in particular the glyoxylate cycle) on biofilm formation, antifungal drug resistance, morphology, and cell wall components. Methods Growth, adhesion, biofilm formation, and cell wall carbohydrate composition were quantified for isogenic Candida albicans ICL1/ICL1, ICL1/icl1, and icl1/icl1 strains. The morphology and topography of these strains were compared by light microscopy and scanning electron microscopy. FKS1 (glucan synthase), ERG11 (14-α-demethylase), and CDR2 (efflux pump) mRNA levels were quantified using qRT-PCR. Results The ICL1/icl1 and icl1/icl1 strains formed similar biofilms and exhibited analogous drug-tolerance levels to the control ICL1/ICL1 strains. Furthermore, the drug sequestration ability of β-1, 3-glucan, a major carbohydrate component of the extracellular matrix, was not impaired. However, the inactivation of ICL1 did impair morphogenesis. ICL1 deletion also had a considerable effect on the expression of the FKS1, ERG11, and CDR2 genes. FKS1 and ERG11 were upregulated in ICL1/icl1 and icl1/icl1 cells throughout the biofilm developmental stages, and CDR2 was upregulated at the early phase. However, their expression was downregulated compared to the control ICL1/ICL1 strain. Conclusions We conclude that the glyoxylate cycle is not a specific determinant of biofilm drug resistance