Crustacean cardiac ganglion model reveals constraints on morphology and conductances

The crustacean cardiac ganglion (CG) network coordinates the rhythmic contractions of the heart muscle to control the circulation of blood. The network consists of 9 cells, 5 large motor cells (LC1-5) and 4 small endogenous pacemaker cells (SCs). We report a new three-compartmental biophysical model of an LC that is morphologically realistic and includes provision for inputs from the SCs via a gap-junction coupled spike-initiation-zone (SIZ) compartments. To determine physiologically viable LC models in this realistic configuration, maximal conductances in three compartments of an LC are determined by random sampling from a biologically-characterized 9D-parameter space, followed by a three stage rejection protocol that checks for conformity with electrophysiological features from single cell traces. LC models that pass the single cell rejection protocol are then incorporated into a network model which is then used in a final rejection protocol stage. Using disparate experimental data, the study provides hitherto unknown structure-function insights related to the crustacean cardiac ganglion large cell, including predictions about morphology including the role of its SIZ, and the differential roles of active conductances in the three compartments. Further, we extend analyses of emergent conductance relationships and correlations in model neurons relative to their biological counterparts, allowing us to make inferences both with respect to the biological system as well as the implications of the ability to detect such relationships in populations of model neurons going forward.

Control Points Selection Based on Maximum External Reliability for Designing Geodetic Networks

A set of stable and identifiable points—known as control points—are interconnected by direction, distance or height differences measurements form a geodetic network. Geodetic networks are used in various branches of modern science, such as monitoring the man-made structures, analysing the crustal deformation of the Earth, establishing and maintaining a geospatial reference frame, mapping, civil engineering projects and others. One of the most crucial components for ensuring the network quality is Geodetic Network Design. The design of a geodetic network depends on its purpose. In this paper, an automatic procedure for selection of control points is proposed. The goal is to find the optimum control points location so that the maximum influence of an anomaly measurement (outlier) on the coordinates of the network is minimum. Here, the concept of Minimal Detectable Bias defines the size of the outlier and its propagation on the network coordinates is used to describe the external reliability. The proposed procedure was applied to design a levelling network. Two scenarios were investigated: design of a network with one control point (minimally constrained levelling network) and another with two control points (over-constrained levelling network). The centre of the network was the optimum position to set the control point. Results for that network reveal that the centre of the network was the optimum position to set the control point for the minimal constraint case, whereas the over-constraint case were those with less line connections. We highlight that the procedure is a generally applicable method.

A Rho signaling network links microtubules to PKD controlled carrier transport to focal adhesions

Protein kinase D (PKD) is a family of serine/threonine kinases that is required for the structural integrity and function of the Golgi complex. Despite its importance in the regulation of Golgi function, the molecular mechanisms regulating PKD activity are still incompletely understood. Using the genetically encoded PKD activity reporter G-PKDrep we now uncover a Rho signaling network comprising GEF-H1, the RhoGAP DLC3, and the Rho effector PLCε that regulate the activation of PKD at trans-Golgi membranes. We further show that this molecular network coordinates the formation of TGN-derived Rab6-positive transport carriers delivering cargo for localized exocytosis at focal adhesions.

Pathways of cellular proteostasis in aging and disease

Ensuring cellular protein homeostasis, or proteostasis, requires precise control of protein synthesis, folding, conformational maintenance, and degradation. A complex and adaptive proteostasis network coordinates these processes with molecular chaperones of different classes and their regulators functioning as major players. This network serves to ensure that cells have the proteins they need while minimizing misfolding or aggregation events that are hallmarks of age-associated proteinopathies, including neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. It is now clear that the capacity of cells to maintain proteostasis undergoes a decline during aging, rendering the organism susceptible to these pathologies. Here we discuss the major proteostasis pathways in light of recent research suggesting that their age-dependent failure can both contribute to and result from disease. We consider different strategies to modulate proteostasis capacity, which may help develop urgently needed therapies for neurodegeneration and other age-dependent pathologies.