Information-Theoretic Analysis of Neural Coding

We describe an approach to analyzing single- and multiunit (ensemble) discharge patterns based on information-theoretic distance measures and on empirical theories derived from work in universal signal processing. In this approach, we quantify the difference between response patterns, whether time-varying or not, using information-theoretic distance measures. We apply these techniques to single- and multiple-unit processing of sound amplitude and sound location. These examples illustrate that neurons can simultaneously represent at least two kinds of information with different levels of fidelity. The fidelity can persist through a transient and a subsequent steady-state response, indicating that it is possible for an evolving neural code to represent information with constant fidelity.     

Effect of systolic flow rate on the prediction of effective prosthetic valve orifice area

The Gorlin equation for the hemodynamic assessment of valve area is commonly used in cardiac catheterization laboratories. A study was performed to test the prediction capabilities of the Gorlin formula as well as the Aaslid and Gabbay formula for the effective orifice area of prosthetic heart valves. Pressure gradient, flow, and valve opening area measurements were performed on four 27 mm valve prostheses (two mechanical bileaflet designs, St. Jude and Edwards-Duromedics, an Edwards pericardial tissue valve, and a trileaflet polyurethane valve) each mounted in the aortic position of an in vitro pulse duplicator. With the known valve orifice area, a different discharge coefficient was computed for each of the four valves and three orifice area formulas. After some theoretical considerations, it was proposed that the discharge coefficient would be a function of the flow rate through the valve. All discharge coefficients were observed to increase with increasing systolic flow rate. An empirical relationship of discharge coefficient as a linear function of systolic flow rate was determined through a regression analysis, with a different relationship for each valve and each orifice area formula. Using this relationship in the orifice area formulas improved the accuracy of the prediction of the effective orifice area with all three formulas performing equally well.     

Increasing autophagy and blocking Nrf2 suppress laminopathy‐induced age‐dependent cardiac dysfunction and shortened lifespan

Mutations in the human LMNA gene cause a collection of diseases known as laminopathies. These include myocardial diseases that exhibit age‐dependent penetrance of dysrhythmias and heart failure. The LMNA gene encodes A‐type lamins, intermediate filaments that support nuclear structure and organize the genome. Mechanisms by which mutant lamins cause age‐dependent heart defects are not well understood. To address this issue, we modeled human disease‐causing mutations in the Drosophila melanogaster Lamin C gene and expressed mutant Lamin C exclusively in the heart. This resulted in progressive cardiac dysfunction, loss of adipose tissue homeostasis, and a shortened adult lifespan. Within cardiac cells, mutant Lamin C aggregated in the cytoplasm, the CncC(Nrf2)/Keap1 redox sensing pathway was activated, mitochondria exhibited abnormal morphology, and the autophagy cargo receptor Ref2(P)/p62 was upregulated. Genetic analyses demonstrated that simultaneous over‐expression of the autophagy kinase Atg1 gene and an RNAi against CncC eliminated the cytoplasmic protein aggregates, restored cardiac function, and lengthened lifespan. These data suggest that simultaneously increasing rates of autophagy and blocking the Nrf2/Keap1 pathway are a potential therapeutic strategy for cardiac laminopathies.     

Structure of the reovirus membrane-penetration protein, Mu1, in a complex with is protector protein, Sigma3

Cell entry by nonenveloped animal viruses requires membrane penetration without membrane fusion. The reovirus penetration agent is the outer-capsid protein, Mu1. The structure of Mu1, complexed with its "protector" protein, Sigma3, and the fit of this Mu1(3)Sigma3(3) heterohexameric complex into the cryoEM image of an intact virion, reveal molecular events essential for viral penetration. Autolytic cleavage divides Mu1 into myristoylated Mu1N and Mu1C. A long hydrophobic pocket can receive the myristoyl group. Dissociation of Mu1N, linked to a major conformational change of the entire Mu1 trimer, must precede myristoyl-group insertion into the cellular membrane. A myristoyl switch, coupling exposure of the fatty acid chain, autolytic cleavage of Mu1N, and long-range molecular rearrangement of Mu1C, thus appears to be part of the penetration mechanism.     

Dynamic simulation pericardial bioprosthetic heart valve function

While providing nearly trouble-free function for 10-12 years, current bioprosthetic heart valves (BHV) continue to suffer from limited long-term durability. This is usually a result of leaflet calcification and/or structural degeneration, which may be related to regions of stress concentration associated with complex leaflet deformations. In the current work, a dynamic three-dimensional finite element analysis of a pericardial BHV was performed with a recently developed FE implementation of the generalized nonlinear anisotropic Fung-type elastic constitutive model for pericardial BHV tissues (W. Sun and M.S. Sacks, 2005, [Biomech. Model. Mechanobiol., 4(2-3), pp. 190-199]). The pericardial BHV was subjected to time-varying physiological pressure loading to compute the deformation and stress distribution during the opening phase of the valve function. A dynamic sequence of the displacements revealed that the free edge of the leaflet reached the fully open position earlier and the belly region followed. Asymmetry was observed in the resulting displacement and stress distribution due to the fiber direction and the anisotropic characteristics of the Fung-type elastic constitutive material model. The computed stress distribution indicated relatively high magnitudes near the free edge of the leaflet with local bending deformation and subsequently at the leaflet attachment boundary. The maximum computed von Mises stress during the opening phase was 33.8 kPa. The dynamic analysis indicated that the free edge regions of the leaflets were subjected to significant flexural deformation that may potentially lead to structural degeneration after millions of cycles of valve function. The regions subjected to time varying flexural deformation and high stresses of the present study also correspond to regions of tissue valve calcification and structural failure reported from explanted valves. In addition, the present simulation also demonstrated the importance of including the bending component together with the in-plane material behavior of the leaflets towards physiologically realistic deformation of the leaflets. Dynamic simulations with experimentally determined leaflet material specification can be potentially used to modify the valve towards an optimal design to minimize regions of stress concentration and structural failure.     

FGF-dependent generation of oligodendrocytes by a hedgehog-independent pathway

During development, spinal cord oligodendrocyte precursors (OPCs) originate from the ventral, but not dorsal, neuroepithelium. Sonic hedgehog (SHH) has crucial effects on oligodendrocyte production in the ventral region of the spinal cord; however, less is known regarding SHH signalling and oligodendrocyte generation from neural stem cells (NSCs). We show that NSCs isolated from the dorsal spinal cord can generate oligodendrocytes following FGF2 treatment, a MAP kinase dependent phenomenon that is associated with induction of the obligate oligogenic gene Olig2. Cyclopamine, a potent inhibitor of hedgehog signalling, did not block the formation of oligodendrocytes from FGF2-treated neurosphere cultures. Furthermore, neurospheres generated from SHH null mice also produced oligodendrocytes, even in the presence of cyclopamine. These findings are compatible with the idea of a hedgehog independent pathway for oligodendrocyte generation from neural stem cells.     

Structure of the mouth tube of a parasitic copepod,Isobranchia appendiculata Heegaard, 1947 (Siphonostomatoida:Lernaeopodidae)

The structure and musculature of the mouth tube of the lernaeopodidIsobranchia appendiculata Heegaard is described in detail. Situated on the median eminence, the mouth tube appears to be lodged inside a median longitudinal groove on the ventral wall of the cephalothorax. The components of the mouth tube, the labrum and the labium are loosely held together along their lateral edges. The thin, transparent walls of both the labrum and the labium are reinforced by chitinous rods. The musculature of the mouth tube consists of two pairs ofretractores oris, four pairs ofcompressores labri and two pairs oflevatores labii. The mandibles are operated by a pair of antagonistic muscles, theroto adductor mandibulae androto abductor mandibulae. Like other lernaeopodids,I. appendiculata resorts to a browsing type of feeding.     

Exploration of the conformational landscape in pregnane X receptor reveals a new binding pocket

Ligand‐regulated pregnane X receptor (PXR), a member of the nuclear receptor superfamily, plays a central role in xenobiotic metabolism. Despite its critical role in drug metabolism, PXR activation can lead to adverse drug‐drug interactions and early stage metabolism of drugs. Activated PXR can induce cancer drug resistance and enhance the onset of malignancy. Since promiscuity in ligand binding makes it difficult to develop competitive inhibitors targeting PXR ligand binding pocket (LBP), it is essential to identify allosteric sites for effective PXR antagonism. Here, molecular dynamics (MD) simulation studies unravelled the existence of two different conformational states, namely “expanded” and “contracted”, in apo PXR ligand binding domain (LBD). Ligand binding events shifted this conformational equilibrium and locked the LBD in a single “ligand‐adaptable” conformational state. Ensemble‐based computational solvent mapping identified a transiently open potential small molecule binding pocket between α5 and α8 helices, named “α8 pocket”, whose opening‐closing mechanism directly correlated with the conformational shift in LBD. A virtual hit identified through structure‐based virtual screening against α8 pocket locks the pocket in its open conformation. MD simulations further revealed that the presence of small molecule at allosteric site disrupts the LBD dynamics and locks the LBD in a “tightly‐contracted” conformation. The molecular details provided here could guide new structural studies to understand PXR activation and antagonism.     

Affine versus non-affine fibril kinematics in collagen networks: theoretical studies of network behavior

The microstructure of tissues and tissue equivalents (TEs) plays a critical role in determining the mechanical properties thereof. One of the key challenges in constitutive modeling of TEs is incorporating the kinematics at both the macroscopic and the microscopic scale. Models of fibrous microstructure commonly assume fibrils to move homogeneously, that is affine with the macroscopic deformation. While intuitive for situations of fibril-matrix load transfer, the relevance of the affine assumption is less clear when primary load transfer is from fibril to fibril. The microstructure of TEs is a hydrated network of collagen fibrils, making its microstructural kinematics an open question. Numerical simulation of uniaxial extensile behavior in planar TE networks was performed with fibril kinematics dictated by the network model and by the affine model. The average fibril orientation evolved similarly with strain for both models. The individual fibril kinematics, however, were markedly different. There was no correlation between fibril strain and orientation in the network model, and fibril strains were contained by extensive reorientation. As a result, the macroscopic stress given by the network model was roughly threefold lower than the affine model. Also, the network model showed a toe region, where fibril reorientation precluded the development of significant fibril strain. We conclude that network fibril kinematics are not governed by affine principles, an important consideration in the understanding of tissue and TE mechanics, especially when load bearing is primarily by an interconnected fibril network.