Critical Communication Links Research Articles

Myosin Transducer Inter-Strand Communication Is Critical for Normal ATPase Activity and Myofibril Structure.

Simple SummaryMyosin is a molecular motor protein that is critical for using stored energy to yield contraction in both skeletal muscle and in the heart. Mutations in myosin can result in inherited human hypertrophic cardiomyopathy, wherein the heart walls become thickened. This results in inability to adequately pump enough oxygenated blood to meet bodily demands, and can lead to abnormal heart beating patterns and the possibility of sudden death. Typically, over-active myosin can be causative for this disease. Here, we used the common fruit fly to study one of these cardiomyopathy-causing mutations by expressing the mutant protein in the indirect flight muscle of the fly. Surprisingly, we found that the mutation and associated mutations decrease myosin and muscle function instead of enhancing it. We show that at least some of these defects result from improper interactions within the myosin protein. This suggests that appropriate communications within myosin are critical for its function and further indicates that certain aspects of indirect flight muscle myosin are functionally distinct from those of myosin in the human heart. By understanding the intricate interactions within the myosin motor protein that are important for its normal role, therapeutics for improving mutant myosin function can be developed.The R249Q mutation in human β-cardiac myosin results in hypertrophic cardiomyopathy. We previously showed that inserting this mutation into Drosophila melanogaster indirect flight muscle myosin yields mechanical and locomotory defects. Here, we use transgenic Drosophila mutants to demonstrate that residue R249 serves as a critical communication link within myosin that controls both ATPase activity and myofibril integrity. R249 is located on a β-strand of the central transducer of myosin, and our molecular modeling shows that it interacts via a salt bridge with D262 on the adjacent β-strand. We find that disrupting this interaction via R249Q, R249D or D262R mutations reduces basal and actin-activated ATPase activity, actin in vitro motility and flight muscle function. Further, the R249D mutation dramatically affects myofibril assembly, yielding abnormalities in sarcomere lengths, increased Z-line thickness and split myofibrils. These defects are exacerbated during aging. Re-establishing the β-strand interaction via a R249D/D262R double mutation restores both basal ATPase activity and myofibril assembly, indicating that these properties are dependent upon transducer inter-strand communication. Thus, the transducer plays an important role in myosin function and myofibril architecture.

Intelligent Power Sharing of DC Isolated Microgrid Based on Fuzzy Sliding Mode Droop Control

Linear droop control can realize power sharing among generators in dc microgrid (MG) without relying on critical communication links. However, the droop relationship between output power and voltage magnitude of renewable power generate system is nonlinear with uncertainties and disturbances from renewable sources and loads in practical dc MG. A novel droop scheme is proposed for an isolated dc MG to solve the nonlinear problem. The control strategy is proposed by using the Takagi–Sugeno (T–S) fuzzy model and sliding mode algorithm. The nonlinear droop characteristics can be represented by T–S model through taking advantage of locally measured output variables. The sliding mode droop controller is designed for compensating the uncertainties and disturbances to derive accurate power sharing based on T–S fuzzy model. The proposed scheme is proved to be effective under variable operating conditions through PSIM/MATLAB simulation.

Conditioned media from AICAR-treated skeletal muscle cells increases neuronal differentiation of adult neural progenitor cells

Exercise has profound benefits for brain function in animals and humans. In rodents, voluntary wheel running increases the production of new neurons and upregulates neurotrophin levels in the hippocampus, as well as improving synaptic plasticity, memory function and mood. The underlying cellular mechanisms, however, remain unresolved. Recent research indicates that peripheral organs such as skeletal muscle, liver and adipose tissue secrete factors during physical activity that may influence neuronal function. Here we used an in vitro cell assay and proteomic analysis to investigate the effects of proteins secreted from skeletal muscle cells on adult hippocampal neural progenitor cell (aNPC) differentiation. We also sought to identify the relevant molecules driving these effects. Specifically, we treated rat L6 skeletal muscle cells with the AMP-kinase (AMPK) agonist 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) or vehicle (distilled water). We then collected the conditioned media (CM) and fractionated it using high-performance liquid chromatography (HPLC). Treatment of aNPCs with a specific fraction of the AICAR-CM upregulated expression of doublecortin (DCX) and Tuj1, markers of immature neurons. Proteomic analysis of this fraction identified proteins known to be involved in energy metabolism, cell migration, adhesion and neurogenesis. Culturing differentiating aNPCs in the presence of one of the factors, glycolytic enzyme glucose-6-phosphate isomerase (GPI), or AICAR-CM, increased the proportion of neuronal (Tuj1+) and astrocytic, glial fibrillary acidic protein (GFAP+) cells. Our study provides further evidence that proteins secreted from skeletal muscle cells may serve as a critical communication link to the brain through factors that enhance neural differentiation.

Enhanced droop controller for operating parallel-connected distributed-generation inverters in a microgrid

Distributed generation (DG) is gaining popularity because of prevalent environmental issues and the need for better power quality. To address these concerns, the microgrid was introduced to utilize DG. Inverter controls are essential for improving power quality because DG units are connected to a grid through an inverter. In this paper, an enhanced droop control technique is proposed to properly operate parallel-connected inverters in an AC microgrid. The proposed control strategy is based on the droop control technique, which utilizes locally measurable feedback signals. The droop control method is used for power sharing because of the absence of critical communication links among parallel-connected inverters. The transient response of the conventional droop control of power sharing is slow, and its frequency and voltage deviations are high. These factors limit accurate power sharing among parallel-connected inverters. The enhanced droop control is introduced to mitigate this problem, through which the trade-off between voltage regulation and reactive power sharing decreases significantly. In addition, the proposed method improves the transient response and achieves higher output power without voltage and frequency deviations. The results indicate that the desired transient response and accurate reactive power sharing with the line impedance mismatch are achieved. The simulation results are analyzed using MATLAB/Simlink to verify the effectiveness of the proposed control strategy.

Process-waste reduction in the construction supply chain using proactive information network

Construction projects require the generation and communication of an ever-larger amount of information. Unfortunately, present project organisations do not foster proactive approaches to preventing costly production waste derived from communication problems. To address this, the effective exchange of information needs to be performed across all different parties, as the construction project commonly includes concurrent progresses along its supply chain. This article proposes a new concept that integrates feed-forward control with the principle of network science. Referred to as supply-chain information network, it aims to comprehend the correlations within a sequenced supply chain network, in order to identify the critical communication links supporting a preventive control. Its effectiveness was verified by applying the model to an actual case: the rebar supply chain from a multi-story building in Sydney, NSW, Australia. The analysis recognised four problematical players in the supply chain: (1) rebar factory linemen, (2) radio crew, (3) senior steel fixers and (4) steel fixers, based on four centrality measurements. Consequently, the experimental data confirm the hypothesis that proactive management of the supply chain will produce drastic improvements, achieving up to 23.3% reduction in waste time during placement. The relevance of this research lies in the operational introduction of network science to the construction supply chain, and its proactive culture resulted in significant improvements of process performance. In addition, the developed communication backbone suggests an actualised test bed of concurrent information exchanges that tried to escape the spatiotemporal limitation in a chained attribute in the construction industry.

Evolutionarily conserved network properties of intrinsically disordered proteins.

BackgroundIntrinsically disordered proteins (IDPs) lack a stable tertiary structure in isolation. Remarkably, however, a substantial portion of IDPs undergo disorder-to-order transitions upon binding to their cognate partners. Structural flexibility and binding plasticity enable IDPs to interact with a broad range of partners. However, the broader network properties that could provide additional insights into the functional role of IDPs are not known.ResultsHere, we report the first comprehensive survey of network properties of IDP-induced sub-networks in multiple species from yeast to human. Our results show that IDPs exhibit greater-than-expected modularity and are connected to the rest of the protein interaction network (PIN) via proteins that exhibit the highest betweenness centrality and connect to fewer-than-expected IDP communities, suggesting that they form critical communication links from IDP modules to the rest of the PIN. Moreover, we found that IDPs are enriched at the top level of regulatory hierarchy.ConclusionOverall, our analyses reveal coherent and remarkably conserved IDP-centric network properties, namely, modularity in IDP-induced network and a layer of critical nodes connecting IDPs with the rest of the PIN.

P2X7 Receptors: Channels, Pores and More

Purine nucleotides are well established as extracellular signaling molecules. P2X7 receptors (P2X7Rs) are members of the family of ionotropic ATP-gated receptors. Their activity can be found in a limited number of cell types, but is readily detectable in cells of hemopoietic lineage including macrophages, microglia, and certain lymphocytes, and mediates the influx of Ca2+ and Na+ as well as the release of pro-inflammatory cytokines. Amongst P2X receptors, P2X7Rs behave as a bifunctional molecule. The binding of ATP induces within milliseconds the opening of a channel selective for small cations, and within seconds a larger pore opens which allows permeation by molecules with a mass of up to 900 Da. In humans at least, the P2RX7 gene is highly polymorphic, and genetic differences within P2X7R affect receptor pore formation and channel function. ATP can act as a neurotransmitter, while the presence of P2X7Rs on immune cells suggests that they also regulate immune function and inflammatory responses. In addition, activation of the P2X7R has dramatic cytotoxic properties. The role of extracellular ATP and purinoceptors in cytokine regulation and neurological disorders is, in fact, the focus of a rapidly expanding area of research. P2X7Rs may affect neuronal cell death by regulating the processing and release of interleukin-1β, a key mediator in neurodegeneration, chronic inflammation, and chronic pain. Activation of P2X7Rs provides an inflammatory stimulus, and P2X7R-deficient mice display a marked attenuation of inflammatory responses, including models of neuropathic and chronic inflammatory pain. Moreover, P2X7R activity, by regulating the release of pro-inflammatory cytokines, may be involved in the pathophysiology of neuropsychiatric disorders. The P2X7R may thus represent a critical communication link between the nervous and immune systems, while providing a target for therapeutic exploitation. In this review we discuss current biology and pharmacology of the P2X7R, as well as insights into the role for this receptor in neurological/psychiatric diseases.

The P2X7purinergic receptor: from physiology to neurological disorders

Purine nucleotides are well established as extracellular signaling molecules. P2X receptors are ATP-gated cation channels that mediate fast excitatory transmission in diverse regions of the brain and spinal cord. Several P2X receptor subtypes, including P2X(7), have the unusual property of changing their ion selectivity during prolonged exposure to ATP, which results in progressive dilation of the channel pore and the development of permeability to molecules as large as 900 Da. The P2X(7) receptor was originally described in cells of hematopoietic origin, including macrophages, microglia, and certain lymphocytes, and mediates the influx of Ca(2+) and Na(+) ions, as well as the release of proinflammatory cytokines. P2X(7) receptors may affect neuronal cell death through their ability to regulate the processing and release of interleukin-1beta, a key mediator in neurodegeneration, chronic inflammation, and chronic pain. Activation of P2X(7) receptors provides an inflammatory stimulus, and P2X(7) receptor-deficient mice have substantially attenuated inflammatory responses, including models of neuropathic and chronic inflammatory pain. Moreover, P2X(7) receptor activity, by regulating the release of proinflammatory cytokines, may be involved in the pathophysiology of depression. The P2X(7) receptor may thus represent a critical communication link between the nervous and immune systems, while providing a target for therapeutic exploitation. This review discusses the current biology and cellular signaling pathways of P2X(7) receptor function, as well as insights into the role for this receptor in neurological/psychiatric diseases, outstanding questions, and the therapeutic potential of P2X(7) receptor antagonism.

Heterophilic Interactions of Sodium Channel β1 Subunits with Axonal and Glial Cell Adhesion Molecules

Voltage-gated sodium channels localize at high density in axon initial segments and nodes of Ranvier in myelinated axons. Sodium channels consist of a pore-forming alpha subunit and at least one beta subunit. beta1 is a member of the immunoglobulin superfamily of cell adhesion molecules and interacts homophilically and heterophilically with contactin and Nf186. In this study, we characterized beta1 interactions with contactin and Nf186 in greater detail and investigated interactions of beta1 with NrCAM, Nf155, and sodium channel beta2 and beta3 subunits. Using Fc fusion proteins and immunocytochemical techniques, we show that beta1 interacts with the fibronectin-like domains of contactin. beta1 also interacts with NrCAM, Nf155, sodium channel beta2, and Nf186 but not with sodium channel beta3. The interaction of the extracellular domains of beta1 and beta2 requires the region 169TEEEGKTDGEGNA181 located in the intracellular domain of beta2. Interaction of beta1 with Nf186 results in increased Nav).2 cell surface density over alpha alone, similar to that shown previously for contactin and beta2. We propose that beta1 is the critical communication link between sodium channels, nodal cell adhesion molecules, and ankyrinG.

Wisdom from ASCE Construction Congress VI

This article is the third in a series on wisdom in construction management. The goal of this paper is to identify the wisdom observed at the Construction Congress VI Conference in Orlando, Florida, whose theme was Building Together for a Better Tomorrow in an Increasingly Complex World. It was made clear that if researchers to not keep their work simple, it will not be used by industry. Some authors addressed the capabilities of the World Wide Web as the critical communication link with the players on construction projects. Faculties are developing Web-based simulation models that students may use to manage construction and make decisions. Four-dimensional computer-aided design was discussed in many papers, while many others discussed computer and new software uses. Twenty tables present the following topic groupings: construction modeling, construction simulation, electronic communications, construction education, quality of design and construction, sustainable development, business and management strategies, design-build delivery, safety in construction, lean construction, construction of advanced technology facilities, construction of foundations and earthwork, productivity, build-operate-transfer, residential construction, engineering performance, invited papers, specialty construction, additional papers, and practice-oriented papers.

Sodium Channel β Subunits Mediate Homophilic Cell Adhesion and Recruit Ankyrin to Points of Cell-Cell Contact

Sodium channels isolated from mammalian brain are composed of alpha, beta1, and beta2 subunits. The auxiliary beta subunits do not form the ion conducting pore, yet play important roles in channel modulation and plasma membrane expression. beta1 and beta2 are transmembrane proteins with one extracellular V-set immunoglobulin (Ig) protein domain. It has been shown recently that beta1 and beta2 interact with the extracellular matrix proteins tenascin-C and tenascin-R. In the present study we show that rat brain beta1 and beta2, but not alphaIIA, subunits interact in a trans-homophilic fashion, resulting in recruitment of the cytoskeletal protein ankyrin to sites of cell-cell contact in transfected Drosophila S2 cells. Whereas alphaIIA subunits expressed alone do not cause cellular aggregation, beta subunits co-expressed with alphaIIA retain the ability to adhere and recruit ankyrin. Truncated beta subunits lacking cytoplasmic domains interact homophilically to produce cell aggregation but do not recruit ankyrin. Thus, the cytoplasmic domains of beta1 and beta2 are required for cytoskeletal interactions. It is hypothesized that sodium channel beta subunits serve as a critical communication link between the extracellular and intracellular environments of the neuron and may play a role in sodium channel placement at nodes of Ranvier.