From signal transduction to signal interpretation: an alternative model for the molecular function of insulin receptor substrates

The insulin receptor (IR) recruits adaptor proteins, so-called insulin receptor substrates (IRS), to connect with downstream signalling pathways. A family of IRS proteins was defined based on three major common structural elements: Amino-terminal PH and PTB domains that mediate protein-lipid or protein-protein interactions, mostly carboxy-terminal multiple tyrosine residues that serve as binding sites for proteins that contain one or more SH2 domains and serine/threonine-rich regions which may be recognized by negative regulators of insulin action. The current model for the role of IRS proteins therefore combines an adaptor function with the integration of mostly negative input from other signal transduction cascades allowing for modulation of signalling amplitude. In this review we propose an extended version of the adaptor model that can explain how signalling specificity could be implemented at the level of IRS proteins.     

From coarse-grain to all-atom: toward multiscale analysis of protein landscapes

Multiscale methods are becoming increasingly promising as a way to characterize the dynamics of large protein systems on biologically relevant time-scales. The underlying assumption in multiscale simulations is that it is possible to move reliably between different resolutions. We present a method that efficiently generates realistic all-atom protein structures starting from the C(alpha) atom positions, as obtained for instance from extensive coarse-grain simulations. The method, a reconstruction algorithm for coarse-grain structures (RACOGS), is validated by reconstructing ensembles of coarse-grain structures obtained during folding simulations of the proteins src-SH3 and S6. The results show that RACOGS consistently produces low energy, all-atom structures. A comparison of the free energy landscapes calculated using the coarse-grain structures versus the all-atom structures shows good correspondence and little distortion in the protein folding landscape.     

A multiscale analysis of early flower development in Arabidopsis provides an integrated view of molecular regulation and growth control

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Mechanistics of amoeboid locomotion: signal to forces

Dictyostelium serves as an ideal model system for studying the molecular and structural properties of the actomyosin and microtubule systems. This organism also has been the vehicle on which the gene-targeting technique was pioneered. Dictyostelium also represents a small number of organisms whose chemotactic ligand-receptor mechanism has been well characterized. This article reviews recent advances in studies of the actin-based cytoskeletal system in Dictyostelium, focusing on the mechanistic aspects of the amoeboid motion. Special emphasis is placed on the recently identified cell-substrate-anchoring structures 'eupodia', and the measurement of single-cell migration forces. The recent advances in signal transduction cascade is also discussed with relevance to the mechanistics in amoeboid locomotion.     

Analysis of endothelial cell locomotion: Differential effects of motility and contact inhibition

Video microscopy and digital time-lapse recording were used to monitor locomotion and proliferation of bovine pulmonary artery endothelial (BPAE) cells cultured with varying concentrations of basic fibroblast growth factor (bFGF). Cell trajectories were reconstructed using a generalized nearest-neighbor algorithm and analyzed to determine how cell motility is affected by cell-cell collisions, cell divisions, and increasing cell density. The temporal evolution patterns of the average speed of locomotion for all cells in a culture were computed and the effects of varying bFGF concentrations were analyzed. Intermediate concentrations of bFGF (30 and 50 ng/mL) significantly increased the speed of locomotion above the levels we observed with 0 and 100 ng/mL concentrations of bFGF. Increases in cell density due to proliferation were immediately accompanied by a decrease in the average speed of locomotion of the cell population. Finally, the effect of bFGF concentration on the overall cell proliferation rates was assessed. With the addition of 30 or 50 ng/mL of bFGF to the culture media, the observed cell proliferation rates increased significantly. The proliferation rates decreased when the bFGF concentration increased to 100 ng/mL. These results show that bFGF concentrations that increase the motility of BPAE cells also increase the observed cell proliferation rates. (c) 1994 John Wiley & Sons, Inc.     

From neuromuscular activation to end-point locomotion: An artificial neural network-based technique for neural prostheses

Neuroprostheses, implantable or non-invasive ones, are promising techniques to enable paralyzed individuals with conditions, such as spinal cord injury or spina bifida (SB), to control their limbs voluntarily. Direct cortical control of invasive neuroprosthetic devices and robotic arms have recently become feasible for primates. However, little is known about designing non-invasive, closed-loop neuromuscular control strategies for neural prostheses. Our goal was to investigate if an artificial neural network-based (ANN-based) model for closed-loop-controlled neural prostheses could use neuromuscular activation recorded from individuals with impaired spinal cord to predict their end-point gait parameters (such as stride length and step width). We recruited 12 persons with SB (5 females and 7 males) and collected their neuromuscular activation and end-point gait parameters during overground walking. Our results show that the proposed ANN-based technique can achieve a highly accurate prediction (e.g., R-values of 0.92–0.97, ANN (tansig+tansig) for single composition of data sets) for altered end-point locomotion. Compared to traditional robust regression, this technique can provide up to 80% more accurate prediction. Our results suggest that more precise control of complex neural prostheses during locomotion can be achieved by engaging neuromuscular activity as intrinsic feedback to generate end-point leg movement. This ANN-based model allows a seamless incorporation of neuromuscular activity, detected from paralyzed individuals, to adaptively predict their altered gait patterns, which can be employed to provide closed-loop feedback information for neural prostheses.     

Frank-Starling mechanism,fluid responsiveness,and length-dependent activation: Unravelling the multiscale behaviors with an in silico analysis

The Frank-Starling mechanism is a fundamental regulatory property which underlies the cardiac output adaptation to venous filling. Length-dependent activation is generally assumed to be the cellular origin of this mechanism. At the heart scale, it is commonly admitted that an increase in preload (ventricular filling) leads to an increased cellular force and an increased volume of ejected blood. This explanation also forms the basis for vascular filling therapy. It is actually difficult to unravel the exact nature of the relationship between length-dependent activation and the Frank-Starling mechanism, as three different scales (cellular, ventricular and cardiovascular) are involved. Mathematical models are powerful tools to overcome these limitations. In this study, we use a multiscale model of the cardiovascular system to untangle the three concepts (length-dependent activation, Frank-Starling, and vascular filling). We first show that length-dependent activation is required to observe both the Frank-Starling mechanism and a positive response to high vascular fillings. Our results reveal a dynamical length dependent activation-driven response to changes in preload, which involves interactions between the cellular, ventricular and cardiovascular levels and thus highlights fundamentally multiscale behaviors. We show however that the cellular force increase is not enough to explain the cardiac response to rapid changes in preload. We also show that the absence of fluid responsiveness is not related to a saturating Frank-Starling effect. As it is challenging to study those multiscale phenomena experimentally, this computational approach contributes to a more comprehensive knowledge of the sophisticated length-dependent properties of cardiac muscle.     

From individual cell motility to collective behaviors: insights from a prokaryote, Myxococcus xanthus

In bird flocks, fish schools, and many other living organisms, regrouping among individuals of the same kin is frequently an advantageous strategy to survive, forage, and face predators. However, these behaviors are costly because the community must develop regulatory mechanisms to coordinate and adapt its response to rapid environmental changes. In principle, these regulatory mechanisms, involving communication between individuals, may also apply to cellular systems which must respond collectively during multicellular development. Dissecting the mechanisms at work requires amenable experimental systems, for example, developing bacteria. Myxococcus xanthus, a Gram-negative delatproteobacterium, is able to coordinate its motility in space and time to swarm, predate, and grow millimeter-size spore-filled fruiting bodies. A thorough understanding of the regulatory mechanisms first requires studying how individual cells move across solid surfaces and control their direction of movement, which was recently boosted by new cell biology techniques. In this review, we describe current molecular knowledge of the motility mechanism and its regulation as a lead-in to discuss how multicellular cooperation may have emerged from several layers of regulation: chemotaxis, cell-cell signaling, and the extracellular matrix. We suggest that Myxococcus is a powerful system to investigate collective principles that may also be relevant to other cellular systems.     

From mechanisms to function: an integrated framework of animal innovation

Animal innovations range from the discovery of novel food types to the invention of completely novel behaviours. Innovations can give access to new opportunities, and thus enable innovating agents to invade and create novel niches. This in turn can pave the way for morphological adaptation and adaptive radiation. The mechanisms that make innovations possible are probably as diverse as the innovations themselves. So too are their evolutionary consequences. Perhaps because of this diversity, we lack a unifying framework that links mechanism to function. We propose a framework for animal innovation that describes the interactions between mechanism, fitness benefit and evolutionary significance, and which suggests an expanded range of experimental approaches. In doing so, we split innovation into factors (components and phases) that can be manipulated systematically, and which can be investigated both experimentally and with correlational studies. We apply this framework to a selection of cases, showing how it helps us ask more precise questions and design more revealing experiments.     

Innovative strategies for intervertebral disc regenerative medicine: From cell therapies to multiscale delivery systems

As our understanding of the physiopathology of intervertebral disc (IVD) degeneration has improved, novel therapeutic strategies have emerged, based on the local injection of cells, bioactive molecules, and nucleic acids. However, with regard to the harsh environment constituted by degenerated IVDs, protecting biologics from in situ degradation while allowing their long-term delivery is a major challenge. Yet, the design of the optimal approach for IVD regeneration is still under debate and only a few papers provide a critical assessment of IVD-specific carriers for local and sustained delivery of biologics. In this review, we highlight the IVD-relevant polymers as well as their design as macro-, micro-, and nano-sized particles to promote endogenous repair. Finally, we illustrate how multiscale systems, combining in situ-forming hydrogels with ready-to-use particles, might drive IVD regenerative medicine strategies toward innovation.     

DnaSP version 3: an integrated program for molecular population genetics and molecular evolution analysis

SUMMARY: DnaSP is a Windows integrated software package for the analysis of the DNA polymorphism from nucleotide sequence data. DnaSP version 3 incorporates several methods for estimating the amount and pattern of DNA polymorphism and divergence, and for conducting neutrality tests. AVAILABILITY: For academic uses, DnaSP is available free of charge from: http://www.bio.ub.es/julio/DnaSP.html CONTACT: julio@porthos.bio.ub.es     

An integrated analysis of molecular aberrations in NCI-60 cell lines

Background  

Cancer is a complex disease where various types of molecular aberrations drive the development and progression of malignancies. Large-scale screenings of multiple types of molecular aberrations (e.g., mutations, copy number variations, DNA methylations, gene expressions) become increasingly important in the prognosis and study of cancer. Consequently, a computational model integrating multiple types of information is essential for the analysis of the comprehensive data.     

The effects of sloped surfaces on locomotion: an electromyographic analysis

Investigations using quadrupeds have suggested that the motor programs used for slope walking differ from that used for level walking. This idea has not yet been explored in humans. The aim of this study was to use electromyographic (EMG) signals obtained during level and slope walking to complement previously published joint angle and joint moment data in elucidating such control strategies. Nine healthy volunteers walked on an instrumented ramp at each of five grades (-39%, -15%, 0%, +15%, +39%). EMG activity was recorded unilaterally from eight lower limb muscles (gluteus maximus (GM), rectus femoris (RF), vastus medialis (VM), biceps femoris (BF), semimembranosus (SM), soleus (Sol), medial gastrocnemius (MG), and tibialis anterior (TA)). The burst onset, duration, and mean activity were calculated for each burst in every trial. The burst characteristics were then averaged within each grade and subject and submitted to repeated measures ANOVAs to assess the effect of grade (alpha=0.05, a priori). Power production increased during upslope walking, as did the mean activity and burst durations of most muscles. In this case, the changes in muscle activity patterns were not predictable based on the changes in joint moments because of the activation of biarticular muscles as antagonists. During downslope walking power absorption increased, as did knee extensor activity (mean and duration) and the duration of the ankle plantarflexor activity. The changes in muscle activity during this task were directly related to the changes in joint moments. Collectively these data suggest that the nervous system uses different control strategies to successfully locomote on slopes, and that joint power requirements are an important factor in determining these control strategies.     

Thy-1: a lymphoid cell subset marker capable of delivering an activation signal to mouse T lymphocytes

Monoclonal anti-Thy-1 antibodies are capable of activating mouse T cells in the absence of an antigen-specific signal. Therefore, Thy-1 appears to be connected to an alternative signal transduction pathway, operative in thymocytes as well as in neuronal cells, since this molecule is also present on brain. Biochemical data have shown that this molecule is differentially glycosylated with respect to its cellular distribution. Structure and sequence comparisons revealed a strong homology with the immunoglobulin primordial domain. In addition, the Thy-1 glycoprotein has the particularity of being anchored to the membrane via a glycophospholipid tail. Gene transfer experiments in different cell types have been performed to analyze the mechanism of the Thy-1 pathway of activation.