Sphingosine 1-phosphate pKa and binding constants: intramolecular and intermolecular influences

The dissociation constant for an ionizable ligand binding to a receptor is dependent on its charge and therefore on its environmentally-influenced pKa value. The pKa values of sphingosine 1-phosphate (S1P) were studied computationally in the context of the wild type S1P1 receptor and the following mutants: E3.29Q, E3.29A, and K5.38A. Calculated pKa values indicate that S1P binds to S1P1 and its site mutants with a total charge of -1, including a +1 charge on the ammonium group and a -2 charge on the phosphate group. The dissociation constant of S1P binding to these receptors was studied as well. The models of wild type and mutant proteins originated from an active receptor model that was developed previously. We used ab initio RHF/6-31+G(d) to optimize our models in aqueous solution, where the solvation energy derivatives are represented by conductor-like polarizable continuum model (C-PCM) and integral equation formalism polarizable continuum model (IEF-PCM). Calculation of the dissociation constant for each mutant was determined by reference to the experimental dissociation constant of the wild type receptor. The computed dissociation constants of the E3.29Q and E3.29A mutants are three to five orders of magnitude higher than those for the wild type receptor and K5.38A mutant, indicating vital contacts between the S1P phosphate group and the carboxylate group of E3.29. Computational dissociation constants for K5.38A, E3.29A, and E3.29Q mutants were compared with experimentally determined binding and activation data. No measurable binding of S1P to the E3.29A and E3.29Q mutants was observed, supporting the critical contacts observed computationally. These results validate the quantitative accuracy of the model.     

Parametric optimization of sequence alignment

Theoptimal alignment or theweighted minimum edit distance between two DNA or amino acid sequences for a given set of weights is computed by classical dynamic programming techniques, and is widely used in molecular biology. However, in DNA and amino acid sequences there is considerable disagreement about how to weight matches, mismatches, insertions/deletions (indels or spaces), and gaps.Parametric sequence alignment is the problem of computing the optimal-valued alignment between two sequences as afunction of variable weights for matches, mismatches, spaces, and gaps. The goal is to partition the parameter space into regions (which are necessarily convex) such that in each region one alignment is optimal throughout and such that the regions are maximal for this property. In this paper we are primarily concerned with the structure of this convex decomposition, and secondarily with the complexity of computing the decomposition. The most striking results are the following: For the special case where only matches, mismatches, and spaces are counted, and where spaces are counted throughout the alignment, we show that the decomposition is surprisingly simple: all regions are infinite; there are at most n^2/3 regions; the lines that bound the regions are all of the form =c + (c + 0.5); and the entire decomposition can be found inO(knm) time, wherek is the actual number of regions, andn相似文献   

Efficient trace and revoke schemes

Our goal is to design encryption schemes for mass distribution of data , which enable to (1) deter users from leaking their personal keys, (2) trace the identities of users whose keys were used to construct illegal decryption devices, and (3) revoke these keys as to render the devices dysfunctional. We start by designing an efficient revocation scheme, based on secret sharing. It can remove up to t parties, is secure against coalitions of up to t users, and is more efficient than previous schemes with the same properties. We then show how to enhance the revocation scheme with traitor tracing and self-enforcement properties. More precisely, how to construct schemes such that (1) each user’s personal key contains some sensitive information of that user (e.g., the user’s credit card number), in order to make users reluctant to disclose their keys. (2) An illegal decryption device discloses the identity of users that contributed keys to construct the device. And, (3) it is possible to revoke the keys of corrupt users. For the last point, it is important to be able to do so without publicly disclosing the sensitive information.     

Flow in planar graphs with vertex capacities

Max-flow in planar graphs has always been studied with the assumption that there are capacities only on the edges. Here we consider a more general version of the problem when the vertices as well as edges have capacity constraints. In the context of general graphs considering only edge capacities is not restrictive, since the vertex-capacity problem can be reduced to the edge-capacity problem. However, in the case of planar graphs this reduction does not maintainplanarity and cannot be used. We study different versions of the planar flow problem (all of which have been extensively investigated in the context of edge capacities).A preliminary version of this paper appeared in theProceedings of the First Integer Programming and Combinatorial Optimization Conference, Waterloo, Canada, May 1990, pp. 367–383. Samir Khuller is currently supported by NSF Grant CCR-8906949. Part of this research was done while he was visiting the IBM Thomas J. Watson Research Center and was supported by an IBM Graduate Fellowship at Cornell University. Joseph Naor's work was supported by Contract ONR N00014-88-K-0166 while he was a post-doctoral fellow in the Department of Computer Science at Stanford University.     

Dynamic expression changes in vivo of adhesion and costimulatory molecules determine load and pattern of lymphoma liver metastasis

Although intradermal primary tumor growth and spontaneous liver metastasis of ESbL-lacZ lymphoma in syngeneic DBA/2 mice are progressive and malignant, they are characterized by a transient plateau period with a constant tumor diameter and a low number of metastasized cells in the liver. This period, which was shown to be immune dependent, was followed by a second expansion phase characterized by a preferential localization of tumor cells in the periportal areas of liver lobules (mosaic phenotype). To elucidate possible mechanisms leading to the plateau period as well as for the mosaic-like metastasis pattern, we investigated, using flow cytometry analysis, alterations in costimulatory and adhesion molecule expression in liver sinusoidal cells as well as in tumor cells isolated directly ex vivo throughout the kinetics of metastasis. In tumor and sinusoidal cells, we found up-regulation in the expression of MHC class II and B7 molecules during the plateau period. These molecules, which facilitate cell-mediated immune responses, were again down-regulated during the final exponential tumor growth and metastasis. In the final expansion phase, in which the mosaic phenotype of liver metastasis is seen, we detected a significant increase of leukocyte function-associated antigen-1/intercellular adhesion molecule-1 expression in both tumor and sinusoidal cells, suggesting tumor cell-sinusoidal cell interactions. vascular cell adhesion molecule-1/very late activated antigen-4 did not show any modification during the whole metastatic process. In vivo application of monoclonal antibodies directed to leukocyte function-associated antigen-1 and intercellular adhesion molecule-1 appeared to block the spread of metastasis, while no effect was seen with monoclonal antibodies directed to vascular cell adhesion molecule-1 and very late activated antigen-4. This study reveals in situ expression changes of cell surface molecules in tumor and host cells during metastasis. The changes seen during the plateau phase and during the second expansion phase differ, suggesting associations with mechanisms of immune control and tumor immune evasion, respectively.     

Hierarchical image representation for compression,filtering and normalization

Applications of pyramid data structure to image compression and image filtering are described. The compression scheme fits visual perception models, and filtering is computationally faster than filtering in the frequency domain. Image normalization is also possible.     

On the time and space complexity of computation using write-once memory or is pen really much worse than pencil?

We introduce a model of computation based on the use of write-once memory. Write-once memory has the property that bits may be set but not reset. Our model consists of a RAM with a small amount of regular memory (such as logarithmic orn ^α for α<1, wheren is the size of the problem) and a polynomial amount of write-once memory. Bounds are given on the time required to simulate on write-once memory algorithms which originally run on a RAM with a polynomial amount of regular memory. We attempt to characterize algorithms that can be simulated on our write-once memory model with very little slow-down. A persistent computation is one in which, at all times, the memory state of the computation at any previous point in time can be reconstructed. We show that any data structure or computation implemented on this write-once memory model can be made persistent without sacrificing much in the way of running time or space. The space requirements of algorithms running on the write-once model are studied. We show that general simulations of algorithms originally running on a RAM with regular memory by algorithms running on our write-once memory model require space proportional to the number of steps simulated. In order to study the space complexity further, we define an analogue of the pebbling game, called the pebble-sticker game. A sticker is different from a pebble in that it cannot be removed once placed on a node of the computation graph. As placing pebbles correspond to writes to regular memory, placing stickers correspond to writes to the write-once memory. Bounds are shown on pebble-sticker tradeoffs required to evaluate trees and planar graphs. Finally, we define the complexity class WO-PSPACE as the class of problems which can be solved with a polynomial amount of write-once memory, and show that it is equal toP. The research of S. Irani was supported by NSF Grant No. DCF-85-13926, and a Tandem Corporation Fellowship. R. Rubinfeld's research was supported by NSF Grant No. CCR 88-13632 and an IBM Graduate Fellowship.     

<Emphasis Type="BoldItalic">LAMA/CA</Emphasis>: A Load-Adaptive MAC Protocol for Short Packets

An efficient Media Access Control (MAC) protocol for wireless Internet access is developed in this study. The proposed access protocol exploits the fact that very often the Internet access messages, such as HTTP download requests, are based on short packets. In addition, whenever the user is able to access to multiple overlapping base stations (e.g., in WiMAX access networks, or in 3GPP cellular networks), the proposed protocol enables the user to select the least loaded base station. Consequently, the user gets a better quality of service, while load balancing is achieved by preferring links that are less loaded over congested links. The key idea is to adjust the access probability to the load on the local link, and to use a different access protocol for short messages. Delay insensitive and long messages are transmitted using a Request To Send (RTS) and Clear To Send (CTS) mechanism, in a similar way to IEEE 802.11, over hops that are able to support this protocol type, while short and delay-sensitive messages are transmitted using another method, that offers a reduced call delivery delay, as well as better channel utilization. Whenever the message length drops below a certain threshold (evaluated in this study), the overhead of transmitting an RTS and CTS messages becomes too large. The analysis in this study shows that this threshold is load-dependent. Whenever the message length drops below this load-dependent threshold, this study proposes to use a protocol which is more efficient for short messages transmissions, such as HTTP download requests, Short Message Service (SMS) messages, and signaling messages. The proposed MAC protocol is especially suitable for 3G and beyond cellular networks. Whenever there are number of channels that can be possibly used to deliver a message, it enables to select the least loaded channel among several channels.