Distinct functions of integrin alpha and beta subunit cytoplasmic domains in cell spreading and formation of focal adhesions.

Integrin-mediated cell adhesion often results in cell spreading and the formation of focal adhesions. We exploited the capacity of recombinant human alpha IIb beta 3 integrin to endow heterologous cells with the ability to adhere and spread on fibrinogen to study the role of integrin cytoplasmic domains in initiation of cell spreading and focal adhesions. The same constructs were also used to analyze the role of the cytoplasmic domains in maintenance of the fidelity of the integrin repertoire at focal adhesions. Truncation mutants of the cytoplasmic domain of alpha IIb did not interfere with the ability of alpha IIb beta 3 to initiate cell spreading and form focal adhesions. Nevertheless, deletion of the alpha IIb cytoplasmic domain allowed indiscriminate recruitment of alpha IIb beta 3 to focal adhesions formed by other integrins. Truncation of the beta 3 subunit cytoplasmic domain abolished cell spreading mediated by alpha IIb beta 3 and also abrogated recruitment of alpha IIb beta 3 to focal adhesions. This truncation also dramatically impaired the ability of alpha IIb beta 3 to mediate the contraction of fibrin gels. In contrast, the beta 3 subunit cytoplasmic truncation did not reduce the fibrinogen binding affinity of alpha IIb beta 3. Thus, the integrin beta 3 subunit cytoplasmic domain is necessary and sufficient for initiation of cell spreading and focal adhesion formation. Further, the beta 3 cytoplasmic domain is required for the transmission of intracellular contractile forces to fibrin gels. The alpha subunit cytoplasmic domain maintains the fidelity of recruitment of the integrins to focal adhesions and thus regulates their repertoire of integrins

Mol-CycleGAN - a generative model for molecular optimization

Designing a molecule with desired properties is one of the biggest challenges in drug development, as it requires optimization of chemical compound structures with respect to many complex properties. To augment the compound design process we introduce Mol-CycleGAN - a CycleGAN-based model that generates optimized compounds with high structural similarity to the original ones. Namely, given a molecule our model generates a structurally similar one with an optimized value of the considered property. We evaluate the performance of the model on selected optimization objectives related to structural properties (presence of halogen groups, number of aromatic rings) and to a physicochemical property (penalized logP). In the task of optimization of penalized logP of drug-like molecules our model significantly outperforms previous results

Distribution of carbon monoxide-producing neurons in human colon and in Hirschsprung's disease patients

Hirschsprung's disease (HSCR) is characterized by the absence of ganglion cells and impaired relaxation of the gut. Nitric oxide (NO) and, more recently, carbon monoxide (CO) have been identified as inhibitory neurotransmitters causing relaxation. A deficiency in NO has been reported in aganglionic gut; we hypothesized that CO could also be involved in impaired gut motility in HSCR. The aim of the study was to determine the distribution of CO-and NO-producing enzymes in the normal and aganglionic gut. We performed laser capture microdissection, reverse transcription-polymerase chain reaction, and immunohistochemistry on colon biopsies of normal controls (n = 9) and patients with HSCR (n = 10). The mRNA expression of heme oxygenase-2 (HO-2), immunoreactivities of HO-2 and NO synthase, was determined and compared. Results show a high level of expression of HO-2 mRNA localized in the myenteric plexus. Expression of HO-2 mRNA was also detected in the mucosa, submucosa, and muscular layer. Down-regulation of HO-2 mRNA expression was detected in the aganglionic colon. Immunoreactivities of HO-2 and NO synthase were localized mainly to the ganglion plexus and to nerve fibers within the muscle in the control colons and normoganglionic colons. HO-2-containing neurons were more abundant than NO synthase-containing neurons in the myenteric plexus. Nearly all of the NO synthase-containing neurons also contained HO-2. HO-2 and NO synthase were selectively absent in the myenteric and submucosal regions and in the muscle of the aganglionic colon. Our findings suggest involvement of both CO and NO in the pathophysiology of HSCR. Copyright 2002, Elsevier Science (USA). All rights reserved.postprin

A Gauge Invariant Theory for Time Dependent Heat Current

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A new adaptive interpolation algorithm for 3D ultrasound imaging with speckle reduction and edge preservation

Author name used in this publication: Qinghua HuangAuthor name used in this publication: Yongping ZhengAuthor name used in this publication: Minhua Lu2008-2009 > Academic research: refereed > Publication in refereed journalAccepted ManuscriptPublishe

Pricing in Social Networks with Negative Externalities

We study the problems of pricing an indivisible product to consumers who are embedded in a given social network. The goal is to maximize the revenue of the seller. We assume impatient consumers who buy the product as soon as the seller posts a price not greater than their values of the product. The product's value for a consumer is determined by two factors: a fixed consumer-specified intrinsic value and a variable externality that is exerted from the consumer's neighbors in a linear way. We study the scenario of negative externalities, which captures many interesting situations, but is much less understood in comparison with its positive externality counterpart. We assume complete information about the network, consumers' intrinsic values, and the negative externalities. The maximum revenue is in general achieved by iterative pricing, which offers impatient consumers a sequence of prices over time. We prove that it is NP-hard to find an optimal iterative pricing, even for unweighted tree networks with uniform intrinsic values. Complementary to the hardness result, we design a 2-approximation algorithm for finding iterative pricing in general weighted networks with (possibly) nonuniform intrinsic values. We show that, as an approximation to optimal iterative pricing, single pricing can work rather well for many interesting cases, but theoretically it can behave arbitrarily bad

Novel silica stabilization method for the analysis of fine nanocrystals using coherent X-ray diffraction imaging

High-energy X-ray Bragg coherent diffraction imaging (BCDI) is a well established synchrotron-based technique used to quantitatively reconstruct the three-dimensional morphology and strain distribution in nanocrystals. The BCDI technique has become a powerful analytical tool for quantitative investigations of nanocrystals, nanotubes, nanorods and more recently biological systems. BCDI has however typically failed for fine nanocrystals in sub-100 nm size regimes – a size routinely achievable by chemical synthesis – despite the spatial resolution of the BCDI technique being 20–30 nm. The limitations of this technique arise from the movement of nanocrystals under illumination by the highly coherent beam, which prevents full diffraction data sets from being acquired. A solution is provided here to overcome this problem and extend the size limit of the BCDI technique, through the design of a novel stabilization method by embedding the fine nanocrystals into a silica matrix. Chemically synthesized FePt nanocrystals of maximum dimension 20 nm and AuPd nanocrystals in the size range 60–65 nm were investigated with BCDI measurement at beamline 34-ID-C of the APS, Argonne National Laboratory. Novel experimental methodologies to elucidate the presence of strain in fine nanocrystals are a necessary pre-requisite in order to better understand strain profiles in engineered nanocrystals for novel device development

Cost-effective low-delay cloud video conferencing

The cloud computing paradigm has been advocated in recent video conferencing system design, which exploits the rich on-demand resources spanning multiple geographic regions of a distributed cloud, for better conferencing experience. A typical architectural design in cloud environment is to create video conferencing agents, i.e., virtual machines, in each cloud site, assign users to the agents, and enable inter-user communication through the agents. Given the diversity of devices and network connectivities of the users, the agents may also transcode the conferencing streams to the best formats and bitrates. In this architecture, two key issues exist on how to effectively assign users to agents and how to identify the best agent to perform a transcoding task, which are nontrivial due to the following: (1) the existing proximity-based assignment may not be optimal in terms of inter-user delay, which fails to consider the whereabouts of the other users in a conferencing session; (2) the agents may have heterogeneous bandwidth and processing availability, such that the best transcoding agents should be carefully identified, for cost minimization while best serving all the users requiring the transcoded streams. To address these challenges, we formulate the user-to-agent assignment and transcoding-agent selection problems, which targets at minimizing the operational cost of the conferencing provider while keeping the conferencing delay low. The optimization problem is combinatorial in nature and difficult to solve. Using Markov approximation framework, we design a decentralized algorithm that provably converges to a bounded neighborhood of the optimal solution. An agent ranking scheme is also proposed to properly initialize our algorithm so as to improve its convergence. The results from a prototype system implementation show that our design in a set of Internet-scale scenarios reduces the operational cost by 77% as compared to a commonly-adopted alternative, while simultaneously yielding lower conferencing delays.published_or_final_versio