NETGEM: Network Embedded Temporal GEnerative Model for gene expression data

Background: Temporal analysis of gene expression data has been limited to identifying genes whose expression varies with time and/or correlation between genes that have similar temporal profiles. Often, the methods do not consider the underlying network constraints that connect the genes. It is becoming increasingly evident that interactions change substantially with time. Thus far, there is no systematic method to relate the temporal changes in gene expression to the dynamics of interactions between them. Information on interaction dynamics would open up possibilities for discovering new mechanisms of regulation by providing valuable insight into identifying time-sensitive interactions as well as permit studies on the effect of a genetic perturbation. Results: We present NETGEM, a tractable model rooted in Markov dynamics, for analyzing the dynamics of the interactions between proteins based on the dynamics of the expression changes of the genes that encode them. The model treats the interaction strengths as random variables which are modulated by suitable priors. This approach is necessitated by the extremely small sample size of the datasets, relative to the number of interactions. The model is amenable to a linear time algorithm for efficient inference. Using temporal gene expression data, NETGEM was successful in identifying (i) temporal interactions and determining their strength, (ii) functional categories of the actively interacting partners and (iii) dynamics of interactions in perturbed networks. Conclusions: NETGEM represents an optimal trade-off between model complexity and data requirement. It was able to deduce actively interacting genes and functional categories from temporal gene expression data. It permits inference by incorporating the information available in perturbed networks. Given that the inputs to NETGEM are only the network and the temporal variation of the nodes, this algorithm promises to have widespread applications, beyond biological systems. The source code for NETGEM is available from https://github.com/vjethava/NETGEM

Flocking at a distance in active granular matter

The self-organized motion of vast numbers of creatures in a single direction is a spectacular example of emergent order. Here, we recreate this phenomenon using actuated nonliving components. We report here that millimetre-sized tapered rods, rendered motile by contact with an underlying vibrated surface and interacting through a medium of spherical beads, undergo a phase transition to a state of spontaneous alignment of velocities and orientations above a threshold bead area fraction. Guided by a detailed simulation model, we construct an analytical theory of this flocking transition, with two ingredients: a moving rod drags beads; neighbouring rods reorient in the resulting flow like a weathercock in the wind. Theory and experiment agree on the structure of our phase diagram in the plane of rod and bead concentrations and power-law spatial correlations near the phase boundary. Our discovery suggests possible new mechanisms for the collective transport of particulate or cellular matter.

A Global Constraint On Relative Rotation To Avoid Lumped Compliant Mechanisms In Topology Optimization

Some of the well known formulations for topology optimization of compliant mechanisms could lead to lumped compliant mechanisms. In lumped compliance, most of the elastic deformation in a mechanism occurs at few points, while rest of the mechanism remains more or less rigid. Such points are referred to as point-flexures. It has been noted in literature that high relative rotation is associated with point-flexures. In literature we also find a formulation of local constraint on relative rotations to avoid lumped compliance. However it is well known that a global constraint is easier to handle than a local constraint, by a numerical optimization algorithm. The current work presents a way of putting global constraint on relative rotations. This constraint is also simpler to implement since it uses linearized rotation at the center of finite-elements, to compute relative rotations. I show the results obtained by using this constraint oil the following benchmark problems - displacement inverter and gripper.

A computerized methodology for structural synthesis of kinematic chains: Part 3 - application to the new case of 10-link, three- freedom chains

The unified computer program for structural synthesis and analysis developed in Part 1 has been employed to derive the new and complete collection of 97 10-link, three-freedom simple-jointed kinematic chains. The program shows that of these chains, 3 have total freedom, 70 have partial freedom and the remaining 24 have fractionated freedom and that the 97 chains yield a total of 676 distinct mechanisms.

Contributions to organic synthesis and reaction mechanisms

Development of new methods, leading to the first stereo-specific total synthesis of a steroid,viz equilenin, and of estrone and their derivatives and of several important synthones, useful for the preparation of physiologically active steroids, and the first conversion of an equilenane to estrane have been described. An account of the achievement of original syntheses of testosterone and its isomers and derivatives and degradation products, urinary steroids, terpenes and their important degradation products has been given. Mechanisms of Dieckmann cyclization, a novel dehydrogenation-addition reaction involving abietic acid and tetrachloro-o-benzoquinone, a rearrangement involving a substitution of cyclopentanone-2-carboxylic ester have been elucidated. An abnormaluv absorption exhibited by saturated 1,2-dicyano esters has been rationalized. Divergences in theord data of testosterone and 19-nortesto-sterone from their isomers have been explained by x-ray crystallographic studies of 8-isotestosterone, 8-iso-10-isotestosterone and 8-iso-10-iso-19-nortestosterone. A tentative explanation for the difference in their physiological activities has been suggested.

An Optimal Mechanism for Sponsored Search Auctions on the Web and Comparison With Other Mechanisms

In this paper, we first describe a framework to model the sponsored search auction on the web as a mechanism design problem. Using this framework, we describe two well-known mechanisms for sponsored search auction-Generalized Second Price (GSP) and Vickrey-Clarke-Groves (VCG). We then derive a new mechanism for sponsored search auction which we call optimal (OPT) mechanism. The OPT mechanism maximizes the search engine's expected revenue, while achieving Bayesian incentive compatibility and individual rationality of the advertisers. We then undertake a detailed comparative study of the mechanisms GSP, VCG, and OPT. We compute and compare the expected revenue earned by the search engine under the three mechanisms when the advertisers are symmetric and some special conditions are satisfied. We also compare the three mechanisms in terms of incentive compatibility, individual rationality, and computational complexity. Note to Practitioners-The advertiser-supported web site is one of the successful business models in the emerging web landscape. When an Internet user enters a keyword (i.e., a search phrase) into a search engine, the user gets back a page with results, containing the links most relevant to the query and also sponsored links, (also called paid advertisement links). When a sponsored link is clicked, the user is directed to the corresponding advertiser's web page. The advertiser pays the search engine in some appropriate manner for sending the user to its web page. Against every search performed by any user on any keyword, the search engine faces the problem of matching a set of advertisers to the sponsored slots. In addition, the search engine also needs to decide on a price to be charged to each advertiser. Due to increasing demands for Internet advertising space, most search engines currently use auction mechanisms for this purpose. These are called sponsored search auctions. A significant percentage of the revenue of Internet giants such as Google, Yahoo!, MSN, etc., comes from sponsored search auctions. In this paper, we study two auction mechanisms, GSP and VCG, which are quite popular in the sponsored auction context, and pursue the objective of designing a mechanism that is superior to these two mechanisms. In particular, we propose a new mechanism which we call the OPT mechanism. This mechanism maximizes the search engine's expected revenue subject to achieving Bayesian incentive compatibility and individual rationality. Bayesian incentive compatibility guarantees that it is optimal for each advertiser to bid his/her true value provided that all other agents also bid their respective true values. Individual rationality ensures that the agents participate voluntarily in the auction since they are assured of gaining a non-negative payoff by doing so.

A functional style of programming with CSP-like communication mechanisms

This paper introduces CSP-like communication mechanisms into Backus’ Functional Programming (FP) systems extended by nondeterministic constructs. Several new functionals are used to describe nondeterminism and communication in programs. The functionals union and restriction are introduced into FP systems to develop a simple algebra of programs with nondeterminism. The behaviour of other functionals proposed in this paper are characterized by the properties of union and restriction. The axiomatic semantics of communication constructs are presented. Examples show that it is possible to reason about a communicating program by first transforming it into a non-communicating program by using the axioms of communication, and then reasoning about the resulting non-communicating version of the program. It is also shown that communicating programs can be developed from non-communicating programs given as specifications by using a transformational approach.

Displacement Amplifying Compliant Mechanisms for Two-axis High-resolution Monolithic Inertial Sensors

Novel designs for two-axis, high-resolution, monolithic inertial sensors are presented in this paper. Monolithic, i.e., joint-less single-piece compliant designs are already common in micromachined inertial sensors such as accelerometers and gyroscopes. Here, compliant mechanisms are used not only to achieve de-coupling between motions along two orthogonal axes but also to amplify the displacements of the proof-mass. Sensitivity and resolution capabilities are enhanced because the amplified motion is used for sensing the measurand. A particular symmetric arrangement of displacement-amplifying compliant mechanisms (DaCMs) leads to de-coupled and amplified motion. An existing DaCM and a new topology-optimized DaCM are presented as a building block in the new arrangement. A spring-mass-lever model is presented as a lumped abstraction of the new arrangement. This model is useful for arriving at the optimal parameters of the DaCM and for performing system-level simulation. The new designs improved the performance by a factor of two or more.

A Comparative Study of the Formulations for Topology Optimization of Compliant Mechanisms

The topology optimization problem for the synthesis of compliant mechanisms has been formulated in many different ways in the last 15 years, but there is not yet a definitive formulation that is universally accepted. Furthermore, there are two unresolved issues in this problem. In this paper, we present a comparative study of five distinctly different formulations that are reported in the literature. Three benchmark examples are solved with these formulations using the same input and output specifications and the same numerical optimization algorithm. A total of 35 different synthesis examples are implemented. The examples are limited to desired instantaneous output direction for prescribed input force direction. Hence, this study is limited to linear elastic modeling with small deformations. Two design parameterizations, namely, the frame element based ground structure and the density approach using continuum elements, are used. The obtained designs are evaluated with all other objective functions and are compared with each other. The checkerboard patterns, point flexures, the ability to converge from an unbiased uniform initial guess, and the computation time are analyzed. Some observations are noted based on the extensive implementation done in this study. Complete details of the benchmark problems and the results are included. The computer codes related to this study are made available on the internet for ready access.

Structural basis for the functional and inhibitory mechanisms of beta-hydroxyacyl-acyl carrier protein dehydratase (FabZ) of Plasmodium falciparum

The beta-hydroxyacyl-acyl carrier protein dehydratase of Plasmodium falciparum (PfFabZ) catalyzes the third and important reaction of the fatty acid elongation cycle. The crystal structure of PfFabZ is available in hexameric (active) and dimeric (inactive) forms. However, PfFabZ has not been crystallized with any bound inhibitors until now. We have designed a new condition to crystallize PfFabZ with its inhibitors bound in the active site, and determined the crystal structures of four of these complexes. This is the first report on any FabZ enzyme with active site inhibitors that interact directly with the catalytic residues. Inhibitor binding not only stabilized the substrate binding loop but also revealed that the substrate binding tunnel has an overall shape of ``U''. In the crystal structures, residue Phe169 located in the middle of the tunnel was found to be in two different conformations, open and closed. Thus, Phe169, merely by changing its side chain conformation, appears to be controlling the length of the tunnel to make it suitable for accommodating longer substrates. The volume of the substrate binding tunnel is determined by the sequence as well as by the conformation of the substrate binding loop region and varies between organisms for accommodating fatty acids of different chain lengths. This report on the crystal structures of the complexes of PfFabZ provides the structural basis of the inhibitory mechanism of the enzyme that could be used to improve the potency of inhibitors against an important component of fatty acid synthesis common to many infectious organisms. (C) 2011 Elsevier Inc. All rights reserved.

A Kinematic Theory for Planar Hoberman and Other Novel Foldable Mechanisms

In this paper, we present a kinematic theory for Hoberman and other similar foldable linkages. By recognizing that the building blocks of such linkages can be modeled as planar linkages, different classes of possible solutions are systematically obtained including some novel arrangements. Criteria for foldability are arrived by analyzing the algebraic locus of the coupler curve of a PRRP linkage. They help explain generalized Hoberman and other mechanisms reported in the literature. New properties of such mechanisms including the extent of foldability, shape-preservation of the inner and outer profiles, multi-segmented assemblies and heterogeneous circumferential arrangements are derived. The design equations derived here make the conception of even complex planar radially foldable mechanisms systematic and easy. Representative examples are presented to illustrate the usage of the design equations and the kinematic theory.

Some mechanisms of tribofilm formation in metal/metal and ceramic/metal sliding interactions

Tribological interaction often generates new structures and materials which form the interface between the sliding pair. The new material designated tribofilm here may be protective or tribologically deleterious. The tribofilm plays a major role in determining the friction and wear of the interaction. Here, we give three examples: mechanically mixed, chemically generated and thermally activated, of tribofilms formed in three different tribological systems and speculate on the mechanism of their formation.

In vitro/In vivo assessment and mechanisms of toxicity of bioceramic materials and its wear particulates

With the progress in modern technological research, novel biomaterials are being largely developed for various biomedical applications. Over the past two decades, most of the research focuses on the development of a new generation of bioceramics as substitutes for hard tissue replacement. In reference to their application in different anatomical locations of a patient, newly developed bioceramic materials can potentially induce a toxic/harmful effect to the host tissues. Therefore, prior to clinical testing, relevant biochemical screening assays are to be performed at the cellular and molecular level, to address the issues of biocompatibility and long term performance of the implants. Along with testing strategies in the bulk material toxicity, a detailed evaluation should also be conducted to determine the toxicity of the wear products of the potential bioceramics. This is important as the bioceramics are intended to be implanted in patients with longer life expectancy and notwithstanding, the material will eventually release finer (mostly nanosized) sized debris particles due to continuous wear at articulating surfaces in the hostile corrosive environment of the human body. The wear particulates generated from a biocompatible bioceramic may act in a different way, inducing early/late aseptic loosening at the implant site, resulting in osteolysis and inflammation. Hence, a study on the chronic effects of the wear particulates, in terms of local and systemic toxicity becomes the major criteria in the toxicity evaluation of implantable bioceramics. In this broad perspective, this article summarizes some of the currently used techniques and knowledge in assessing the in vitro and in vivo cytotoxicity and genotoxicity of bioceramic implant materials. It also addresses the need to conduct a broad evaluation before claiming the biocompatibility and clinical feasibility of any new biomaterial. This review also emphasizes some of the case studies based on the experimental designs that are currently followed and its importance in the context of clinical applications.