Showing papers by "Weizmann Institute of Science published in 2000"

Dynamic Logic

Abstract: From the Publisher: Among the many approaches to formal reasoning about programs, Dynamic Logic enjoys the singular advantage of being strongly related to classical logic. Its variants constitute natural generalizations and extensions of classical formalisms. For example, Propositional Dynamic Logic (PDL) can be described as a blend of three complementary classical ingredients: propositional calculus, modal logic, and the algebra of regular events. In First-Order Dynamic Logic (DL), the propositional calculus is replaced by classical first-order predicate calculus. Dynamic Logic is a system of remarkable unity that is theoretically rich as well as of practical value. It can be used for formalizing correctness specifications and proving rigorously that those specifications are met by a particular program. Other uses include determining the equivalence of programs, comparing the expressive power of various programming constructs, and synthesizing programs from specifications. This book provides the first comprehensive introduction to Dynamic Logic. It is divided into three parts. The first part reviews the appropriate fundamental concepts of logic and computability theory and can stand alone as an introduction to these topics. The second part discusses PDL and its variants, and the third part discusses DL and its variants. Examples are provided throughout, and exercises and a short historical section are included at the end of each chapter.

Scaling Limits of Loop-Erased Random Walks and Uniform Spanning Trees

Abstract: The uniform spanning tree (UST) and the loop-erased random walk (LERW) are strongly related probabilistic processes. We consider the limits of these models on a fine grid in the plane, as the mesh goes to zero. Although the existence of scaling limits is still unproven, subsequential scaling limits can be defined in various ways, and do exist. We establish some basic a.s. properties of these subsequential scaling limits in the plane. It is proved that any LERW subsequential scaling limit is a simple path, and that the trunk of any UST subsequential scaling limit is a topological tree, which is dense in the plane.

Organizing Principles for a Diversity of GABAergic Interneurons and Synapses in the Neocortex

Abstract: A puzzling feature of the neocortex is the rich array of inhibitory interneurons. Multiple neuron recordings revealed numerous electrophysiological-anatomical subclasses of neocortical gamma-aminobutyric acid-ergic (GABAergic) interneurons and three types of GABAergic synapses. The type of synapse used by each interneuron to influence its neighbors follows three functional organizing principles. These principles suggest that inhibitory synapses could shape the impact of different interneurons according to their specific spatiotemporal patterns of activity and that GABAergic interneuron and synapse diversity may enable combinatorial inhibitory effects in the neocortex.

The Random Oracle Methodology, Revisited

Abstract: We take a critical look at the relationship between the security of cryptographic schemes in the Random Oracle Model, and the security of the schemes that result from implementing the random oracle by so called "cryptographic hash functions". The main result of this paper is a negative one: There exist signature and encryption schemes that are secure in the Random Oracle Model, but for which any implementation of the random oracle results in insecure schemes. In the process of devising the above schemes, we consider possible definitions for the notion of a "good implementation" of a random oracle, pointing out limitations and challenges.

Privacy Preserving Data Mining

Abstract: In this paper we introduce the concept of privacy preserving data mining. In our model, two parties owning confidential databases wish to run a data mining algorithm on the union of their databases, without revealing any unnecessary information. This problem has many practical and important applications, such as in medical research with confidential patient records. Data mining algorithms are usually complex, especially as the size of the input is measured in megabytes, if not gigabytes. A generic secure multi-party computation solution, based on evaluation of a circuit computing the algorithm on the entire input, is therefore of no practical use. We focus on the problem of decision tree learning and use ID3, a popular and widely used algorithm for this problem. We present a solution that is considerably more efficient than generic solutions. It demands very few rounds of communication and reasonable bandwidth. In our solution, each party performs by itself a computation of the same order as computing the ID3 algorithm for its own database. The results are then combined using efficient cryptographic protocols, whose overhead is only logarithmic in the number of transactions in the databases. We feel that our result is a substantial contribution, demonstrating that secure multi-party computation can be made practical, even for complex problems and large inputs.

arrow encodes an LDL-receptor-related protein essential for Wingless signalling

Abstract: The Wnt family of secreted molecules functions in cell-fate determination and morphogenesis during development in both vertebrates and invertebrates (reviewed in ref. 1). Drosophila Wingless is a founding member of this family, and many components of its signal transduction cascade have been identified, including the Frizzled class of receptor. But the mechanism by which the Wingless signal is received and transduced across the membrane is not completely understood. Here we describe a gene that is necessary for all Wingless signalling events in Drosophila. We show that arrow gene function is essential in cells receiving Wingless input and that it acts upstream of Dishevelled. arrow encodes a single-pass transmembrane protein, indicating that it may be part of a receptor complex with Frizzled class proteins. Arrow is a low-density lipoprotein (LDL)-receptor-related protein (LRP), strikingly homologous to murine and human LRP5 and LRP6. Thus, our data suggests a new and conserved function for this LRP subfamily in Wingless/Wnt signal reception.

Efficient algorithms for solving overdefined systems of multivariate polynomial equations

Abstract: The security of many recently proposed cryptosystems is based on the difficulty of solving large systems of quadratic multivariate polynomial equations. This problem is NP-hard over any field. When the number of equations m is the same as the number of unknowns n the best known algorithms are exhaustive search for small fields, and a Grobner base algorithm for large fields. Grobner base algorithms have large exponential complexity and cannot solve in practice systems with n ≥ 15. Kipnis and Shamir [9] have recently introduced a new algorithm called "relinearization". The exact complexity of this algorithm is not known, but for sufficiently overdefined systems it was expected to run in polynomial time. In this paper we analyze the theoretical and practical aspects of relinearization. We ran a large number of experiments for various values of n and m, and analysed which systems of equations were actually solvable. We show that many of the equations generated by relinearization are linearly dependent, and thus relinearization is less efficient that one could expect. We then develop an improved algorithm called XL which is both simpler and more powerful than relinearization. For all 0 < ∈ ≤ 1/2, and m ≥ ∈n2, XL and relinearization are expected to run in polynomial time of approximately nO(1/√Ɛ). Moreover, we provide strong evidence that relinearization and XL can solve randomly generated systems of polynomial equations in subexponential time when m exceeds n by a number that increases slowly with n.

Coupled two-way clustering analysis of gene microarray data

Abstract: We present a coupled two-way clustering approach to gene microarray data analysis. The main idea is to identify subsets of the genes and samples, such that when one of these is used to cluster the other, stable and significant partitions emerge. The search for such subsets is a computationally complex task. We present an algorithm, based on iterative clustering, that performs such a search. This analysis is especially suitable for gene microarray data, where the contributions of a variety of biological mechanisms to the gene expression levels are entangled in a large body of experimental data. The method was applied to two gene microarray data sets, on colon cancer and leukemia. By identifying relevant subsets of the data and focusing on them we were able to discover partitions and correlations that were masked and hidden when the full dataset was used in the analysis. Some of these partitions have clear biological interpretation; others can serve to identify possible directions for future research.

Knowledge and common knowledge in a distributed environment

Abstract: Reasoning about knowledge seems to play a fundamental role in distributed systems. Indeed, such reasoning is a central part of the informal intuitive arguments used in the design of distributed protocols. Communication in a distributed system can be viewed as the act of transforming the system's state of knowledge. This paper presents a general framework for formalizing and reasoning about knowledge in distributed systems. We argue that states of knowledge of groups of processors are useful concepts for the design and analysis of distributed protocols. In particular, distributed knowledge corresponds to knowledge that is ``distributed'' among the members of the group, while common knowledge corresponds to a fact being ``publicly known''. The relationship between common knowledge and a variety of desirable actions in a distributed system is illustrated. Furthermore, it is shown that, formally speaking, in practical systems common knowledge cannot be attained. A number of weaker variants of common knowledge that are attainable in many cases of interest are introduced and investigated.

Elastic turbulence in a polymer solution flow

Abstract: Turbulence is a ubiquitous phenomenon that is not fully understood. It is known that the flow of a simple, newtonian fluid is likely to be turbulent when the Reynolds number is large (typically when the velocity is high, the viscosity is low and the size of the tank is large). In contrast, viscoelastic fluids such as solutions of flexible long-chain polymers have nonlinear mechanical properties and therefore may be expected to behave differently. Here we observe experimentally that the flow of a sufficiently elastic polymer solution can become irregular even at low velocity, high viscosity and in a small tank. The fluid motion is excited in a broad range of spatial and temporal scales, and we observe an increase in the flow resistance by a factor of about twenty. Although the Reynolds number may be arbitrarily low, the observed flow has all the main features of developed turbulence. A comparable state of turbulent flow for a newtonian fluid in a pipe would have a Reynolds number as high as 10(5) (refs 1, 2). The low Reynolds number or 'elastic' turbulence that we observe is accompanied by significant stretching of the polymer molecules, resulting in an increase in the elastic stresses of up to two orders of magnitude.

Oncogenic mutations of the p53 tumor suppressor: the demons of the guardian of the genome.

Abstract: The p53 guardian of the genome is inactivated in the majority of cancers, mostly through missense mutations that cause single residue changes in the DNA binding core domain of the protein. Not only do such mutations result in the abrogation of wild-type p53 activity, but the expressed p53 mutant proteins also tend to gain oncogenic functions, such as interference with wild-type p53-independent apoptosis. Because p53 mutants are highly expressed in cancer cells and not in normal cells, their reactivation to wild-type p53 function may eliminate the cancer by apoptosis or another p53-dependent mechanism. Several studies that embarked on this quest for reactivation have succeeded in restoring wildtype p53 activity to several p53 mutants. However, mutants with more extensive structural changes in the DNA binding core domain may be refractory to reactivation to the wild-type p53 phenotype. Therefore, understanding the structure and functions of oncogenic p53 mutants may lead to more potent reactivation modalities or to the ability to eliminate mutant p53 gain of function.

Nature of Photovoltaic Action in Dye-Sensitized Solar Cells

Abstract: We explain the cause for the photocurrent and photovoltage in nanocrystalline, mesoporous dye-sensitized solar cells, in terms of the separation, recombination, and transport of electronic charge as well as in terms of electron energetics. On the basis of available experimental data, we confirm that the basic cause for the photovoltage is the change in the electron concentration in the nanocrystalline electron conductor that results from photoinduced charge injection from the dye. The maximum photovoltage is given by the difference in electron energies between the redox level and the bottom of the electron conductor's conduction band, rather than by any difference in electrical potential in the cell, in the dark. Charge separation occurs because of the energetic and entropic driving forces that exist at the dye/electron conductor interface, with charge transport aided by such driving forces at the electron conductor/contact interface. The mesoporosity and nanocrystallinity of the semiconductor are importa...

Induction of the chemokine stromal-derived factor-1 following DNA damage improves human stem cell function

Abstract: The chemokine stromal-derived factor-1 (SDF-1) controls many aspects of stem cell function. Details of its regulation and sites of production are currently unknown. We report that in the bone marrow, SDF-1 is produced mainly by immature osteoblasts and endothelial cells. Conditioning with DNA-damaging agents (ionizing irradiation, cyclophosphamide, and 5-fluorouracil) caused an increase in SDF-1 expression and in CXCR4-dependent homing and repopulation by human stem cells transplanted into NOD/SCID mice. Our findings suggest that immature osteoblasts and endothelial cells control stem cell homing, retention, and repopulation by secreting SDF-1, which also participates in host defense responses to DNA damage.

Generation of oscillations by the p53-Mdm2 feedback loop: A theoretical and experimental study

Abstract: The intracellular activity of the p53 tumor suppressor protein is regulated through a feedback loop involving its transcriptional target, mdm2. We present a simple mathematical model suggesting that, under certain circumstances, oscillations in p53 and Mdm2 protein levels can emerge in response to a stress signal. A delay in p53-dependent induction of Mdm2 is predicted to be required, albeit not sufficient, for this oscillatory behavior. In line with the predictions of the model, oscillations of both p53 and Mdm2 indeed occur on exposure of various cell types to ionizing radiation. Such oscillations may allow cells to repair their DNA without risking the irreversible consequences of continuous excessive p53 activation.

Molecular mechanisms underlying ErbB2/HER2 action in breast cancer.

Abstract: Overexpression of ErbB2, a receptor-like tyrosine kinase, is shared by several types of human carcinomas. In breast tumors the extent of overexpression has a prognostic value, thus identifying the oncoprotein as a target for therapeutic strategies. Already, antibodies to ErbB2 are used in combination with chemotherapy in the treatment of metastasizing breast cancer. The mechanisms underlying the oncogenic action of ErbB2 involve a complex network in which ErbB2 acts as a ligand-less signaling subunit of three other receptors that directly bind a large repertoire of stroma-derived growth factors. The major partners of ErbB2 in carcinomas are ErbB1 (also called EGFR) and ErbB3, a kinase-defective receptor whose potent mitogenic action is activated in the context of heterodimeric complexes. Why ErbB2-containing heterodimers are relatively oncopotent is a function of a number of processes. Apparently, these heterodimers evade normal inactivation processes, by decreasing the rate of ligand dissociation, internalizing relatively slowly and avoiding the degradative pathway by returning to the cell surface. On the other hand, the heterodimers strongly recruit survival and mitogenic pathways such as the mitogen-activated protein kinases and the phosphatidylinositol 3-kinase. Hyper-activated signaling through the ErbB-signaling network results in dysregulation of the cell cycle homeostatic machinery, with upregulation of active cyclin-D/CDK complexes. Recent data indicate that cell cycle regulators are also linked to chemoresistance in ErbB2-dependent breast carcinoma. Together with D-type cyclins, it seems that the CDK inhibitor p21waf1 plays an important role in evasion from apoptosis. These recent findings herald a preliminary understanding of the output layer which connects elevated ErbB-signaling to oncogenesis and chemoresistance.

The dynamics of object-selective activation correlate with recognition performance in humans.

Abstract: To investigate the relationship between perceptual awareness and brain activity, we measured both recognition performance and fMRI signal from object-related areas in human cortex while images were presented briefly using a masking protocol. Our results suggest that recognition performance is correlated with selective activation in object areas. Selective activation was correlated to object naming when exposure duration was varied from 20 to 500 milliseconds. Subjects' recognition during identical visual stimulation could be enhanced by training, which also increased the fMRI signal. Overall, the correlation between recognition performance and fMRI signal was highest in occipitotemporal object areas (the lateral occipital complex).

Biochemical and clinical implications of the ErbB/HER signaling network of growth factor receptors.

Abstract: Carcinoma, cancer of epithelial cells, is a major cause of morbidity and mortality in Western societies. Clonal fixation and propagation of oncogenic genetic changes, sporadically accumulating in epithelial cells, depend on growth factors and their surface receptors. One of the large families of receptors is that of the ErbB tyrosine kinases, which bind multiple neuregulins and other epidermal growth factor-like molecules. Certain ErbB members and their ligands are involved in human cancers of various origins. However, most of the clinical data relate to ErbB-2, a protein whose overexpression in subsets of carcinomas can predict poor prognosis. Although no ligand has so far been assigned to ErbB-2, recent biochemical evidence implies that this oncoprotein operates as a shared receptor subunit of other ErbBs. Several biochemical attributes enable ErbB-2 to act as an epithelial cell amplifier of stroma-derived growth factor signals: It delays ligand dissociation, enhances coupling to the mitogen-activated protein kinase pathway, and impedes the rate of receptor downregulation. The realization that ErbB-2 is a master regulator of a signaling network that drives epithelial cell proliferation identifies this protein as a target for cancer therapy. Indeed, various ErbB-2-directed therapeutic approaches, including immunological and genetic therapies, demonstrate promising clinical potential.

Dynamics and segregation of cell-matrix adhesions in cultured fibroblasts

Abstract: Here we use time-lapse microscopy to analyse cell-matrix adhesions in cells expressing one of two different cytoskeletal proteins, paxillin or tensin, tagged with green fluorescent protein (GFP). Use of GFP-paxillin to analyse focal contacts and GFP-tensin to study fibrillar adhesions reveals that both types of major adhesion are highly dynamic. Small focal contacts often translocate, by extending centripetally and contracting peripherally, at a mean rate of 19 micrometers per hour. Fibrillar adhesions arise from the medial ends of stationary focal contacts, contain alpha5beta1 integrin and tensin but not other focal-contact components, and associate with fibronectin fibrils. Fibrillar adhesions translocate centripetally at a mean rate of 18 micrometers per hour in an actomyosin-dependent manner. We propose a dynamic model for the regulation of cell-matrix adhesions and for transitions between focal contacts and fibrillar adhesions, with the ability of the matrix to deform functioning as a mechanical switch.

Certificate revocation and certificate update

Abstract: We present a solution for the problem of certificate revocation. This solution represents certificate revocation lists by authenticated dictionaries that support: (1) efficient verification whether a certificate is in the list or not and (2) efficient updates (adding/removing certificates from the list). The suggested solution gains in scalability, communication costs, robustness to parameter changes, and update rate. Comparisons to the following solutions (and variants) are included: "traditional" certificate revocation lists (CRLs), Micali's (see Tech. Memo MIT/LCS/TM-542b, 1996) certificate revocation system (CRS), and Kocher's (see Financial Cryptography-FC'98 Lecture Notes in Computer Science. Berlin: Springer-Verlag, 1998, vol.1465, p.172-7) certificate revocation trees (CRT). We also consider a scenario in which certificates are not revoked, but frequently issued for short-term periods. Based on the authenticated dictionary scheme, a certificate update scheme is presented in which all certificates are updated by a common message. The suggested solutions for certificate revocation and certificate update problems are better than current solutions with respect to communication costs, update rate, and robustness to changes in parameters, and are compatible, e.g., with X.500 certificates.

Real Time Cryptanalysis of A5/1 on a PC

Abstract: A5/1 is the strong version of the encryption algorithm used by about 130 million GSM customers in Europe to protect the over-the-air privacy of their cellular voice and data communication. The best published attacks against it require between 240 and 245 steps. This level of security makes it vulnerable to hardware-based attacks by large organizations, but not to software-based attacks on multiple targets by hackers. In this paper we describe new attacks on A5/1, which are based on subtle flaws in the tap structure of the registers, their noninvertible clocking mechanism, and their frequent resets. After a 248 parallelizable data preparation stage (which has to be carried out only once), the actual attacks can be carried out in real time on a single PC. The first attack requires the output of the A5/1 algorithm during the first two minutes of the conversation, and computes the key in about one second. The second attack requires the output of the A5/1 algorithm during about two seconds of the conversation, and computes the key in several minutes. The two attacks are related, but use different types of time-memory tradeoffs. The attacks were verified with actual implementations, except for the preprocessing stage which was extensively sampled rather than completely executed. REMARK: We based our attack on the version of the algorithm which was derived by reverse engineering an actual GSM telephone and published at http://www.scard.org. We would like to thank the GSM organization for graciously confirming to us the correctness of this unofficial description. In addition, we would like to stress that this paper considers the narrow issue of the cryptographic strength of A5/1, and not the broader issue of the practical security of fielded GSM systems, about which we make no claims.

Phospholipase D: molecular and cell biology of a novel gene family.

Abstract: Interaction of extracellular-signal molecules with cell-surface receptors often activates a phospholipase D (PLD)-mediated hydrolysis of phosphatidylcholine and other phospholipids, generating phosphatidic acid. The activation of PLD is believed to play an important role in the regulation of cell function and cell fate. Multiple PLD activities were characterized in eukaryotic cells, and, more recently, several PLD genes have been cloned. A PLD gene superfamily, defined by a number of structural domains and sequence motifs, also includes phosphatidyltransferases and certain phosphodiesterases. Among the eukaryotic PLD genes are those from mammals, nematodes, fungi and plants. The present review focuses on the structure, localization, regulation and possible functions of cloned mammalian and yeast PLDs. In addition, an overview of plant PLD genes, and of several distinct PLD activities that have not yet been cloned, is provided. Emerging evidence from recent work employing new molecular tools indicates that different PLD isoforms are localized in distinct cellular organelles, where they are likely to serve diverse functions in signal transduction, membrane vesicle trafficking and cytoskeletal dynamics.

DC-SIGN-ICAM-2 interaction mediates dendritic cell trafficking

Abstract: Dendritic cells (DCs) are recruited from blood into tissues to patrol for foreign antigens. After antigen uptake and processing, DCs migrate to the secondary lymphoid organs to initiate immune responses. We now show that DC-SIGN, a DC-specific C-type lectin, supports tethering and rolling of DC-SIGN-positive cells on the vascular ligand ICAM-2 under shear flow, a prerequisite for emigration from blood. The DC-SIGN-ICAM-2 interaction regulates chemokine-induced transmigration of DCs across both resting and activated endothelium. Thus, DC-SIGN is central to the unusual trafficking capacity of DCs, further supported by the expression of DC-SIGN on precursors in blood and on immature and mature DCs in both peripheral and lymphoid tissues.

The use of stable isotopes to study ecosystem gas exchange.

Abstract: Stable isotopes are a powerful research tool in environmental sciences and their use in ecosystem re- search is increasing. In this review we introduce and dis- cuss the relevant details underlying the use of carbon and oxygen isotopic compositions in ecosystem gas ex- change research. The current use and potential develop- ments of stable isotope measurements together with con- centration and flux measurements of CO2 and water va- por are emphasized. For these applications it is critical to know the isotopic identity of specific ecosystem compo- nents such as the isotopic composition of CO 2 , organic matter, liquid water, and water vapor, as well as the associated isotopic fractionations, in the soil-plant- atmosphere system. Combining stable isotopes and con- centration measurements is very effective through the use of "Keeling plots." This approach allows the identifi- cation of the isotopic composition and the contribution of ecosystem, or ecosystem components, to the exchange fluxes with the atmosphere. It also allows the estimation of net ecosystem discrimination and soil disequilibrium effects. Recent modifications of the Keeling plot ap- proach permit examination of CO2 recycling in ecosys- tems. Combining stable isotopes with dynamic flux mea- surements requires precision in isotopic sampling and analysis, which is currently at the limit of detection. Combined with the micrometeorological gradient ap- proach (applicable mostly in grasslands and crop fields), stable isotope measurements allow separation of net CO 2 exchange into photosynthetic and soil respiration compo- nents, and the evapotranspiration flux into soil evapora- tion and leaf transpiration. Similar applications in con- junction with eddy correlation techniques (applicable to forests, in addition to grasslands and crop fields) are more demanding, but can potentially be applied in com- bination with the Keeling plot relationship. The advance and potential in using stable isotope measurements should make their use a standard component in the limit- ed arsenal of ecosystem-scale research tools.

Acceleration of quantum decay processes by frequent observations

Abstract: In theory, the decay of any unstable quantum state can be inhibited by sufficiently frequent measurements--the quantum Zeno effect. Although this prediction has been tested only for transitions between two coupled, essentially stable states, the quantum Zeno effect is thought to be a general feature of quantum mechanics, applicable to radioactive or radiative decay processes. This generality arises from the assumption that, in principle, successive observations can be made at time intervals too short for the system to change appreciably. Here we show not only that the quantum Zeno effect is fundamentally unattainable in radiative or radioactive decay (because the required measurement rates would cause the system to disintegrate), but also that these processes may be accelerated by frequent measurements. We find that the modification of the decay process is determined by the energy spread incurred by the measurements (as a result of the time-energy uncertainty relation), and the distribution of states to which the decaying state is coupled. Whereas the inhibitory quantum Zeno effect may be feasible in a limited class of systems, the opposite effect--accelerated decay--appears to be much more ubiquitous.