Blockchain Papers

Iftach Haitner, Alon Rosen, Ronen Shaltiel

No abstract is available for this record.

Ilan Adler, Constantinos Daskalakis, Christos H. Papadimitriou

No abstract is available for this record.

Zecheng Wang, Haifeng Qian, Zhibin Li

We propose a distributed key generation protocol for pairing-based cryptosystems which is adaptively secure in the erasure-free and secure channel model, and at the same time completely avoids the use of interactive zero-knowledge proofs. Utilizing it as the threshold key generation protocol, we present a secure (t,n) threshold signature scheme based on the Waters' signature scheme. We prove that our scheme is unforgeable and robust against any adaptive adversary who can choose players for corruption at any time during the run of the protocols and make adaptive chosen-message attacks. And the security proof of ours is in the standard model (without random oracles). In addition our scheme achieves optimal resilience, that is, the adversary can corrupt any t<n/2 players.

Tsz Hon Yuen, Qiong Huang, Yi Mu, Willy Susilo · 6 authors

No abstract is available for this record.

Hendrik Tews, Bart Jacobs

No abstract is available for this record.

Mira Belenkiy, Melissa Chase, Markulf Kohlweiss, Anna Lysyanskaya

Abstract. Efficient non-interactive zero-knowledge proofs are a powerful tool for solving many cryptographic problems. We apply the recent Groth-Sahai (GS) proof system for pairing product equations (Eurocrypt 2008) to two related cryptographic problems: compact e-cash (Eurocrypt 2005) and simulatable verifiable random functions (CRYPTO 2007). We present the first efficient compact e-cash scheme that does not rely on a random oracle. To this end we construct efficient GS proofs for signature possession, pseudo randomness and set membership. The GS proofs for pseudorandom functions give rise to a much cleaner and substantially faster construction of simulatable verifiable random functions (sVRF) under a weaker number theoretic assumption. We obtain the first efficient fully simulatable sVRF with a polynomial sized output domain (in the security parameter). 1

Michel Abdalla⋆, Céline Chevalier, David Pointcheval

No abstract is available for this record.

Rafael Pass, Wei-Lung Dustin Tseng, Douglas Wikström

We show that only languages in BPP have public-coin black-box zero-knowledge protocols that are secure under an unbounded (polynomial) number of parallel repetitions. This result holds both in the plain model (without any setup) and in the bare public key model (where the prover and the verifier have registered public keys). We complement this result by constructing a public-coin black-box zero-knowledge proof based on one-way functions that remains secure under any a priori bounded number of concurrent executions. A key step (of independent interest) in the analysis of our lower bound shows that any public-coin protocol, when repeated sufficiently in parallel, satisfies a notion of “resettable soundness” if the verifier picks its random coins using a pseudorandom function.

Ronald Cramer, Ivan Damgård, Marcel Keller

No abstract is available for this record.

Jan Camenisch, Aggelos Kiayias, Moti Yung

No abstract is available for this record.

Mira Belenkiy, Jan Camenisch, Melissa Chase, Markulf Kohlweiss · 6 authors

No abstract is available for this record.

Aggelos Kiayias, Hong-Sheng Zhou

No abstract is available for this record.

Wang Yu-wu, You-Bang Zhan, (1)淮阴师范学院计算机科学系,淮安 223300; (2)淮阴师范学院物理系,淮安 223300

A theoretical scheme for zero-knowledge proof quantum identity authentication is proposed by the absolutely impartial third party CA， which has been realized based on remote state preparation and assisted cloning controlled means. In the process of identification， only CA knows the information of quantum identity card and the first party Alice and the second party Bob can accomplish the quantum identity authentication without knowing it. We discuss the probability of accomplishing this job. The security of this scheme is unconditional and it is guaranteed by quantum mechanism.

Essam Ghadafi, Nigel P. Smart, Bogdan Warinschi

No abstract is available for this record.

B. Wunderlich

Early structure models of crystals go back to the 17th century.1, 2 By studying the external regularity of the crystals and their optical properties, an arrangement of the fundamental particles as shown in Figure 1(a) was suggested without actual knowledge of their size and nature. It took about 200 years until the molecular details could be ascertained, as shown for NaCl in Figure 1(b).3 Note that this was before X-ray diffraction was available for precise crystal structure determination.8 At about the same time, thermodynamics reached the present-day precision.4, 9 It represents the macroscopic tool to describe phases. Thereafter, microscopic experimental crystal structures were amassed by X-ray diffraction. Parallel, large numbers of heat capacities (at constant pressure), Cp, were determined by adiabatic calorimetry, often covering the temperature region from close to absolute zero to beyond the equilibrium melting temperature, T. Tables of the integral thermodynamic functions enthalpy, H, free enthalpy, G, and entropy, S, were collected for many substances as a function of temperature.10, 11 On the basis of the macroscopic thermodynamics and the microscopic structure, the molecular motion within the crystals was assesses by approximation and in detail.12-14 (a–d) Development of the knowledge about crystal structure (a2 and b3), phase property and size (c4, 5, 6), and the 10 basic states of matter (d7). The next step involved the evaluation of the properties of smaller and disordered crystals. As the main change in property, experiments on small crystals showed a lower melting temperature, Tm. This change in Tm could be described by the Gibbs-Thomson equation based on their surface area and the specific surface free energies.5 The same treatment was useful later, when analyzing lamellar polymer crystals.6 Figure 1(c) summarizes the historical definitions of the thermodynamic properties of macrophases and microphases, with the former being, in at least one dimension, larger than 1000 nm (1 μm). The Gibbs-Thomson equation listed in Figure 1(c) applies to the melting point lowering, ΔT, of lamellar, microphase crystals (𝓁 < 1.0 μm). The earlier suggestion that microphases in the form of colloids where a “fourth state of matter” could be discarded after understanding the effects of surface free energy and surface charges. More recently, nanophases are of general interest for objects marginally larger than the limit of a few ångstroms, set by the homogeneity of the phase due to the atomic structure and the fluctuations of the thermodynamic properties because of a too small sampling volume.15 Experiments following the glass transition of unsupported polymer spheres of decreasing size16 suggested that as long as a small phase has unchanged bulk material within its center, there is no reason to apply a different name to a small microphase.17 As one, however, approaches a size so small that the opposing surfaces leave no unchanged bulk material, it was found that there is a size-range for an entirely new phase, a true “nanophase.”15, 17 An updated thermodynamic description of phases is given in Figure 1(d). It contains a list of the possible phase types when considering not only degrees of condensation and ordering, but also the differences in modes of molecular motion. Figure 1(d) expands the basic, classical states of matter to ten.7, 18 The phases known since antiquity, have been linked in the early 19th century to their newly proven atomic nature.19, 20 The expansion with intermediate phases (mesophases) was discovered over the last 150 years.21 On the left side of the figure, it is indicated that the mesophases become increasingly more “solid” when changing in order toward the crystal. Unfortunately, crystals may have a broad range of solidity, so that the term “solid” is not a scientific, operational definition22 for their state. Glasses, in turn, have an easily measured glass transition temperature, Tg, which can be identified as a solid/liquid transition.23 The mesophases often possess a Cp close to that of the melt. On quenching, they undergo a glass transition similar to liquids. This leads to the three mesophase glasses indicated (from top to bottom: liquid crystal glass, plastic crystal glass, and condis crystal glass). Recently, it was observed, that some polymeric crystals, like aliphatic nylons and polyoxides, may even approach liquid-like mobility on heating before melting or undergoing a disordering transition. This change in mobility causes a change in heat capacity as in a glass transition, that is, the crystal displays a glass transition.24 Crystals that remain “truly” solid up to Tm become a mobile liquid on fusion. Turning to the right side of Figure 1(d), one notes that only the gas connects to all condensed phases. The entropy change of a liquid to a gas without change in the molecular structure is expressed empirically by Trouton's rule.25 The disordering of a crystal to a liquid follows the empirical rule of Richards as long as the ordering species are spherical.26 Nonspherical species follow Walden's rule,27 and for conformational disordering, a similar empirical entropy increase was observed as for spheres.28 The possible transitions between the condensed phases are marked in Figure 1(d) and their overall entropy of fusion is expressed in terms of the three types of disorder by the boxed equation.29, 30 Today, this development of the knowledge about crystal structures, phase properties and sizes, and the states of matter are supported by a wide range of experiments. The macroscopic picture is supplied by the equilibrium and nonequilibrium thermodynamics, based on calorimetry, and is supported by direct experimental evidence about the microscopic structure as well as the molecular motion. Furthermore, the enormous increase in computational capability allows to simulate molecular structure and motion. The time scale of importance, the picosecond, however, is far removed from human experience. The present summary is to establish the needed developments to attain a base for the detection of flaws in the still incomplete description of the thermodynamics and kinetics of crystallization of flexible molecules and their phase structures. In the next three sections, the often neglected problems of nucleation of a new phase of increased order will be analyzed and the nanophase structure of macromolecules will be probed as to its influence across the interfaces. In the conclusions, a view towards the enormous job of supplying details about the resolution of the indicated problems is summarized. The development of the idea of primary and secondary nucleation as they were ultimately applied to the crystallization of semicrystalline macromolecules are described in this section.31 The classical concept of crystal nucleation was already suggested by Gibbs about 130 years ago.32 The description of small phases as a function of size was discussed in Figure 1(c) and led to the free enthalpy plots describing primary nucleation given in Figure 2(a). The curves are scaled to the free enthalpies of polyethylene crystals. The boxed numbers in the graph on the right of Figure 2(a) represent the free enthalpy in convenient units at an approximately 40 K supercooling. They indicate a saddle point (*), calculated by the given equations. The system must travel across it to become stable. Obviously, at T the size of the nucleus is infinity, that is, no nucleation is possible. The larger the supercooling, the lower is the barrier for a move into the region of negative ΔG. About 60 years ago, a mathematical expression for the nucleation rate was derived by Turnbull and Fisher33 written in Figure 2(b). This was fitted to experiments on homogeneous nucleation with sufficiently small polyethylene droplets in silicone oil, eliminating the effect of accidental, heterogeneous nuclei. The result is the graph in Figure 2(b), based on the two-dimensional plot of Figure 2(a).36 There is a region of about 30 K in polyethylene where primary, homogeneous nucleation is not observed, followed by increasingly fast nucleation which slows as the melt viscosity, η, increases and reaches zero when the glass transition at 250 K is approached.31 (a–d) Free enthalpy of primary nucleation of a tetragonal crystal of dimension i = a × a × 𝓁 and expressed by the equations (a31); rate of primary nucleation, calculated analogous to part a (b31, 33); and the basic surface effects leading to secondary nucleation (c,34 d35). To assess the further crystallization after homogeneous or heterogeneous nucleation, the Kossel model of a crystal was used.34 Figure 2(c) illustrates that on a cubic crystal there are five distinguishable locations of different surface free energy for crystallization or melting. Only position 3 has no change in surface free energy, that is, at position 3 crystallization (or melting) should occur at equal rates. Position 1 would require a secondary nucleation on the smooth crystal surface, and position 2, a tertiary nucleation of a new row on a step in the surface. Positions 4 and 5 would be stable and require a positive free enthalpy for removal from the crystal. This model was transferred 30 years later to the crystallization of polymers by Lauritzen and Hoffman35 by simplifying a polymer crystal as shown in Figure 2(d). It was the basis for the description of polymer crystallization for many years with numerous improvements and fine tunings,37 and is often still applied today. Figure 3(a) the for the secondary nucleation of analogous to homogeneous needed to be given for the observed crystallization in form of a but 𝓁 with a positive ΔG. Furthermore, it was that an of similar as for crystallization with a atomic step should the experiments on Early of the polymer as shown in Figure in a to the of the and from the of a molecular of one can that a with 𝓁 = nm which a crystal is only one of about In the in energy so that there is not only an but also an which of Figure temperature In present-day of secondary nucleation, the thermodynamic functions are as of temperature, the that of heat capacities are available for many for the heat capacity been measured by and was linked to its and by crystals of close to could be by crystallization in the condis phase of the condis phase to the phase by removal of the the equilibrium melting temperature was by to the from by and could be shown to the experimental equilibrium melting temperature = but the was leads to a 3 K a when small degrees of supercooling. Today, the contains and thermodynamic functions for 200 polymers and with the of the rate equation of Figure to secondary nucleation is the of the secondary polymer on a smooth crystal surface, as shown in Figure 2(d). as the on its molecular model of a surface a with new surface. This the or surface as the only to secondary It will be shown in the last of this that surfaces to to crystal Furthermore, and thermodynamic evidence of the of secondary nucleation will be in the next (a–d) and and experiments of possible secondary nucleation of all it was that for years the model for polymer crystallization was the to secondary at found The evidence for secondary nucleation was a large of on crystal as shown in Figure have an and could be fitted to nucleation rate as in Figure It was from the experimental of Figure that in the model would ultimately have to to a mathematical description of similar The direct experimental of the of secondary nucleation in polymers is about 40 years An of a of crystals of polyethylene is shown in Figure that should be for secondary nucleation can be on the surface. the was the was to melt some and to the surface with crystals. The area as in Figure is in Figure The on the surface should have secondary nucleation, but by following the crystal it is that not as crystal nucleation The crystals, however, are in indicated by their the of secondary surface of crystals of after heating to K for 3 to a small of crystals. indicate 1.0 from with from the crystallization of of was by experiments with the equilibrium phase by crystals were by up to a of about was The polymer was melting more than from the phase the of a solid This was to crystals from and from the at The after crystallization from can be and by were analyzed and the of is shown as 2 in Figure on crystallization from the melt are as 1 after the by K due to the increase of the melting temperature on of The melt was and so that the could only and were by calorimetry, was to the temperature and to on of the At the crystallization temperature, the curves up to far the by the phase as is this all curves approach the same limit at temperature, at there must be a for to the different the equilibrium melting or temperature of the given The that this is the equilibrium at the saddle point of secondary nucleation in Figure 3(a) is not Only one of many molecules could in this be by secondary On the basis of was molecular nucleation, similar to secondary nucleation was needed for of the molecular nucleation is as Figure It the step of nucleation by and the which sufficiently of the could at a different This nucleation of a could be followed by similar The in more than one form as were discovered earlier by On the molecules in different locations form a to the melting crystal. The are by after by This picture of the thermodynamics and kinetics of crystallization of flexible molecules is by years on the molecular of the of species their equilibrium melting temperature of molecular the of the of the nucleation and of and polyethylene crystals from the the description of the further developments must be In the in the of crystallization of flexible macromolecules a The possible of or at the lamellar surfaces of polymer crystals a It that were a could be found for by of the however, is based on with only by by all on it was from on to for polymer and interest It up only with a new of and new The is in the of more on the The new development with the of surface into the description of polymer crystals, or the secondary nucleation The of a was an early in the crystallization of small from the gas flexible were for the a model of was it no to the nonequilibrium of Figure suggestion of the a mesophase it is that the in Figure must intermediate order before the and a of polymers possess stable or for polyethylene (at and many mesophases are to be stable at the of following the molecular motion of of on a to a view of the crystallization in the to and follow possible in polymer crystals and to the motion involved in the of crystal but the time of to follow crystallization was still too could be To the to more was the many and the cubic an nucleation of nucleation and could be supported by the ultimately also the of molecular was in the as a new tool to and It is applied as calorimetry, Figure the limit of the of crystallization and melting of and experiments and were is a where the is about a temperature with a The were three of an of the and and broad The is to a of This limit of also with Figure where true is up to about It was that in the of glass or surfaces no in the crystallization of by homogeneous This found an by the of of long on by atomic The only K the bulk T. Figure also that the is not by the in the crystal with larger is by heating and as with Figure for As long as T is within the melting and crystallization are The and incomplete phase transitions due to time and a of the and 5 are indicated by the measured by the and the which to the and liquid heat The in Figure the of the of melting and crystallization with a of than the experimental limit of the heating rate to 30 K not change the of melting (at beyond the which was for in Figure 1 K 10 K The of in at larger than 10 K and reached a of 10 K at 30 K experiments a of the of crystallization by the enormous of possible of the in the to the no of crystal with the rate of after primary More on the kinetics of molecular nucleation and its influence on in the Turnbull and equation of Figure has not been as Today, with calorimetry, can be to as as K range of may a direct of molecular nucleation kinetics with changing molecular (a–d) of melting and crystallization of for a of melting in nucleation as step of crystallization after homogeneous or heterogeneous nucleation, in to an between crystal and the melt which must influence the This effect would in the Turnbull and equation of Figure and will be in the last On of the of semicrystalline it was found when the that the glass transition was to temperature and the increase in Cp at was often smaller than from the This in was the and is as the development of it possible to heat effects from the heat capacity in the temperature range between and Tm. from the of this it was found that many crystals a of of by the melting from Cp, a glass transition could be identified for a of polymers the of the phase, for the By a transition temperature, the of a that the not only of a but represents a phase between the crystal and the bulk phases. the influence on the heat capacity by melting and the it possible to the molecular motion within the crystals in this temperature It was found that polymer crystals an of conformational motion as the melting temperature is In many this molecular motion could also be and by solid state X-ray and molecular In of which is available as material, this increase in conformational mobility was discovered to at about In some this motion even reaches a glass transition of the crystal as in the of Figure 1(d). In a of polymer crystals, a transition to a mesophase as is long for for polyethylene at and To a semicrystalline material and to its it is to and three possible phase and more than one, The influence of phases on the overall thermodynamics and the kinetics of crystallization are analyzed in this The observed on is in Figure for It at the phase and is in the temperature range were melting is also observed, a close between the small of different surface melting was earlier by X-ray In this the at the surface over a wide temperature not the crystal and at a lower temperature than the By a larger of experiments on it was that only semicrystalline with and The melting is by the of to At lower temperature the is larger and it approaches zero at the of melting. The the the is the melting. It increases with and with The effect is in Figure on the of a and melting occur to the glass transition region and are at The crystallization in Figure on at 10 K a On with only of this because of to the by the of the is The broad melting is at a temperature than the main crystallization To be linked to the the melting must be a It can be by considering the molecular nucleation of Figure The of the are from the more of the so that melting can only occur at a The however, can as a molecular nucleus for the which within the of Crystals of macromolecules with or no of melting have also been Figure the for a without At this it is to crystals of and or of no (a–d) of the melting and crystallization of a of different polymers for melting of crystals of of different of polymers are or melting was observed for of Figure a of similar as in Figure similar melting was also observed for the crystal was determined by on from It of a lamellar structure as for of a to of within the The of the polymer was in this not to the homogeneous to like an their of than the limit of The polymeric was the that the crystallization and melting are close to that of a of similar The of of the different to influence the molecular nucleation and to be The has a influence on the crystallization of flexible in there is no of the as in there is a of the glass transition to temperature in all semicrystalline the intermediate phase was proven by on This intermediate phase was and on the top and of the This intermediate phase for of the and in solid state experiments it an intermediate mobility between that of the and This has also been by a between X-ray and The size of this intermediate phase was to be about nm for melt More is a of the but from the of the Figure for The Cp for the solid and the mobile could be calculated from of the The glass transitions can easily be from the K all polymer is and the indicated equation for the can be to represent of the and the of the all three phases must be when the by K no can be determined because glass and crystal have close to the same this for the and with it the of the crystallization not apply to by X-ray diffraction. is the of a phase the melting temperature, as for and in Figure experiments of this polymer by already that there was no glass transition the melting that is, the a the the melting the crystals as but it also the The of a is not far the melting temperature, but increases sufficiently when in the phase, as indicated by the experiments in Figure The melting rate is by the glass transition and the T is the of the but melting is at and the glass transition The melting kinetics could be followed and after some of the one of could melt for three units of Note that there is also no of melting in This an not by from the melt. The glass transition is sufficiently that nucleation leads to the of the its glass transition and further To the glass transition to be by the of a On one not only of the crystals, but also the On this is transferred to the the of it was possible to this by X-ray The of the that of a similar result was with The phase structure of semicrystalline polymers is a more system than for small On the basis of the updated phase description in Figure 1 of macroscopic and as well as molecular order and a arrangement of and nanophases was the classical model of Figure 2, one can the homogeneous nucleation of crystals of small as well as large the of the term may be to to this approach to the kinetics of polymer crystals the secondary nucleation of 2 and 3 4 and 5 supported the to a molecular (or nucleation to for direct of crystal without secondary nucleation, of of molecules the equilibrium temperature of their phase and the on of the limit of molecular nucleation a given set of experimental and the on melting and their They indicate that of sufficiently long molecules with a of the macromolecules are for and one can with the to heat capacities and to the thermodynamic functions in the temperature range between and Tm. to the picture that crystal in semicrystalline polymers is by an phase that has at least a glass transition from the phase, and in many leads to a with a glass transition a nanophase semicrystalline as and the may remain and on a structure which at their with a possible heat the of and that no one picture applies to all The details of must be before a description of the thermodynamics and kinetics of crystallization is an enormous which has by only The are available for this for evaluation of the thermodynamics, its and by even the of X-ray diffraction can the structure of all may assess the molecular and the The expression shown in Figure could still describe the experimental crystal as a function of temperature in Figure however, must a set of and the step of the crystallization can be by the of Figure The of may be from at fast the entropy and energy of the The of should into the by the because the of the in Figure are not to have the should be to represent all thermodynamic functions with their temperature In the this was supported by the of and the of and of of at and by for the of The a to or the form of this or to for

Andrew Chi-Chih Yao, Frances Yao, Yunlei Zhao

No abstract is available for this record.

C. G. Schmidt

This is part of an occasional series that recalls some of the stories reported 10 years ago in the News section of the Journal. In 1998, JNCI published a two-part feature about efforts to overcome multidrug resistance in cancer, which at the time was thought to be governed chiefly by a superfamily of molecular transporters, known as ATP-binding cassette (ABC) proteins. ABC transporters act as efflux pumps, which expel toxins and drugs from a cell. By reversing those transporters in cancer cells—particularly P-glycoprotein (Pgp), which was, and still is, the best-characterized among them—researchers hoped to overcome drug resistance, a primary cause of treatment failure. A decade later, efforts to reverse Pgp have proven futile, in part because the transport protein is also expressed by healthy tissues—leading to unacceptable side effects when its activity is knocked out. Furthermore, dozens of other ABC transport proteins identified within the last 10 years can take over for Pgp when its activity is reversed in cancer cells. Scientists are still studying clinical opportunities with ABC transporters, but drug resistance in cancer remains as much a problem now as it ever was. Even so, scientists have new leads to follow. Advances in molecular biology, driven by genomics and related fields, have revealed new resistance mechanisms and broadened opportunities to overcome it, said Michael M. Gottesman , M.D., head of the National Cancer Institute's molecular cell genetics section. “We just have to apply the mechanistic knowledge we’re gaining in the laboratory towards progress in the clinic.” Michael M. Gottesman, M.D. Today, those efforts are proceeding on dual fronts. Whereas scientists 10 years ago were concerned only with multidrug resistance against chemotherapy, those working today must also contend with single-drug resistance to newer, targeted therapies such as imatinib (Gleevec), a drug for chronic myelogenous leukemia (CML) and other cancers that inactivates a cancer-inducing protein called Bcr-Abl. Unlike chemotherapy—which kills rapidly dividing cells regardless of whether they’re cancerous—targeted therapies interfere with specific molecules involved in cancer and tumor growth. The new era of targeted therapy was supposed to leave chemotherapy behind and multidrug resistance behind with it. That's because researchers associated such resistance almost exclusively with efflux pumps, which act against a broad array of natural and synthetic toxins. By using nontoxic compounds targeted against specific molecules in carcinogenesis, scientists hoped that they could avoid resistance. But those expectations were dashed when clinicians found that although patients typically respond well to imatinib—among the first targeted drugs to reach the market—many also relapse within 3–5 years. Confronted with that distressing problem, scientists were reluctant to blame mechanisms like efflux, which were generally attributed to multidrug resistance and chemotherapy, for imatinib resistance. Instead, their explanations veered toward gene mutations that, by chance, might allow CML cells to survive imatinib exposure. In that scenario, most CML cells are killed by the drug, but those with mutations that favor survival multiply over time, leading to relapse. Scientists call this type of drug resistance “acquired.” To an extent, subsequent research has borne out this hypothesis, which was proposed when imatinib resistance was first observed, within a few years of the drug's approval by the U.S. Food and Drug Administration in 2001. More than a dozen gene mutations have since been implicated, of which the most effective is T315I, according to Susan Bates, M.D., director of the NCI's molecular therapeutics section. This simple variation alters Bcr-Abl's three-dimensional binding site, thus blocking imatinib's access to the target protein. But Bates argues that mutations alone can’t account entirely for imatinib resistance. Patients whose leukemic cells have identical mutations can vary with respect to the degree of resistance, she said, which suggests that other factors—including mechanisms linked to multidrug resistance—are also at play. “For example, interindividual variation has been found in the amount of Gleevec that winds up in the bloodstream, which could reflect differences in cellular absorption of the drug,” Bates explained. “We can’t rule out that ABC transporters might be involved, given that Gleevec is a substrate for at least two: Pgp and breast cancer resistance protein. In CML cells, those transporters reduce the amount of Gleevec that reaches the protein target, and that fosters resistance.” (However, variation in resistance among patients could also be due in part to behavioral factors, such as adherence to the drug regimen [ see JNCI 2008; 100: 912–3 ].) While researchers work to tease out resistance mechanisms against targeted therapies, efforts to overcome multidrug resistance to chemotherapy are making headway. Researchers in Gottesman's lab at NCI, who are among the leaders in this area, approach the problem by using three general strategies. Gottesman's research team collaborates with pharmaceutical companies to develop drugs that circumvent known resistance mechanisms. Compounds that evade ABC transporters—of which there are 48, according to current estimates—fall into that general category. Epothilones, for example, a new class of cytotoxic molecules identified as potential chemotherapy agents, aren’t recognized by Pgp. “This provides proof of concept that new classes of anticancer agents that don’t interact with multidrug transporters can be developed,” he said. This approach is currently in early developmental stages, with no compounds in clinical trials. Applying an alternate approach, the team strives to block resistance by inhibiting or reversing it. Clinical applications based on this approach would involve drug combinations: one drug to inhibit the resistance mechanism and another to kill the cancer cell. This strategy already has a long and unsuccessful history, exemplified by compounds such as PSC-833, a Pgp-reversing agent tested often in clinical trials. PSC-833 failed in part because of unpredictable pharmacokinetic interactions, leading to underdosing in some patients and overdosing in others. Scientists now hope to overcome that problem with third- and fourth-generation inhibitors designed for low pharmacokinetic interactions, as well as tight binding with target proteins. According to researchers in Gottesman's laboratory, promising candidates include tariquidar, a compound that offers extended Pgp inhibition, now in phase III clinical trials, and CBT-1, a plant alkaloid that inhibits Pgp in addition to an ABC transporter known as MRP1. The third strategy exploits certain unique features of multidrug-resistant cells, such as high surface expression of Pgp or a paradoxical hypersensitivity to a range of compounds. These features make it possible to target these cells directly, Gottesman said. For instance, thiosemicarbazones—a class of compounds with known antiviral, antimicrobial, and anticancer activity—kill resistant cells through Pgp-related mechanisms. This approach has not yet produced compounds for clinical trials. Scientists have also focused on the influx mechanisms that cells use to absorb certain compounds, including cancer drugs, instead of the efflux pumps that they use to expel them. Solute-carrier (SLC) protein transporters, recognized as the largest superfamily of membrane proteins, participate in these influx processes. Jeffrey Moscow, M.D., chief of pediatric hematology/oncology at the University of Kentucky Medical Center in Lexington, is now working to identify SLCs expressed uniquely by cancer cells. By harnessing these proteins, he hopes to pump drugs into a cancer cell faster than efflux transporters can pump them out. He's already identified an SLC expressed uniquely by lung and gastrointestinal malignancies, known as OATBIB3, and another expressed by leukemia, known as SLC22A16. “In these cases, the specificity of therapy would be determined by the expression of the solute carriers,” he said. Efforts to overcome single-drug resistance to targeted therapies differ from those applied to multidrug resistance. Instead of circumventing, inhibiting, or targeting mechanisms that cancer cells use to avoid poisons, scientists try to augment their treatment options with additional molecular targets, said Jeffrey Settleman, Ph.D., a professor at Harvard Medical School and scientific director of the Massachusetts General Hospital Cancer Center. Settleman's laboratory has accumulated the largest collection of human cancer cell lines in existence—more than 1,000 in all, representing all the major tissue types. With automated screening technology, he and his colleagues test putative targeted therapies until they find a positive hit in a sensitive cell line. Those lines are treated with the drug until only the resistant cells remain. By culturing those cells, Settleman's team can look for mutations that confer resistance, as well as for new targets to which the cells might be sensitive. The clinical strategy for managing resistance in targeted therapy, Settleman said, entails drug combinations to inhibit several targets sequentially. “The scenario could be that we convert cancer to a chronic disease by giving drugs in succession; as resistance develops to one drug, we shift to another,” he said. This approach is already being used now. For instance, CML patients who become resistant to imatinib can be treated with dasatinib (Sprycel). In a melanoma cell line, Settleman's laboratory recently modeled the acquisition of resistance to a candidate Raf kinase inhibitor. They found that resistant cells merely switched their metabolic dependency from Raf to another related kinase. “Raf kinase inhibitors are being tested clinically now,” Settleman said. “It's early days for these compounds, and we’re not sure they’re going to work. But if they do, we may have zeroed in on the resistance mechanism in advance.” The ability to switch from one kinase to another shows how adaptable cancer cells are in the face of drug pressure. But fortunately, it appears that cancer cells have at most three to four resistance mechanisms that they can direct against any particular compound, Settleman said. “And that shows we’re ultimately dealing with a manageable problem,” he said. “It indicates how important it is to tackle resistance from more than one angle. We’re faced with the same resistance mechanisms that infectious microbes use to evolve and mutate their way around a drug. We treat [human immunodeficiency virus] with multidrug cocktails, and we’ll be doing more of the same with cancer; our aim is to cut off the cells’ options to adapt.” So, although the previous 10 years revealed new mechanisms in cancer cell biology, including roles played by cancer stem cells that could offer the best therapeutic targets of all, accelerated research during the coming decade might bring the problem of resistance under better control. But doing that won’t be easy, Settleman admitted. “Cancer cells are crafty organisms in their own right,” he said. “And resistance is still the final frontier in treatment.”

Justin Bledin

No abstract is available for this record.

Robert G. Webster

Graeme Laver, one of Australia’s greatest influenza research scientists, died after collapsing en route to an influenza meeting in Portugal in September 2008. Graeme was born in Victoria, educated at Ivanhoe Grammar School and graduated from the University of Melbourne in biochemistry. He received his PhD in biochemistry at the University of London before returning to the John Curtin School of Medical Research at the Australian National University (ANU) in 1958. After the Burnet School at the Walter and Eliza Hall Institute in Melbourne changed its focus from influenza to immunology, the influenza research program moved with Frank Fenner’s group to ANU, where it was anchored by Stephan Fazekas de St. Groth. There the pioneering influenza work of Sir MacFarlane Burnet continued, with Graeme Laver as biochemist and Stephan Fazekas as the mathematical modeler of virus neutralization. I (Rob Webster) joined the group in 1959 to carry on the virus neutralization studies. To elucidate the subunit structure of influenza viruses, Graeme gently dissociated the lipid bilayer of the virus with the mild detergent sodium deoxycholate and established the basis for the first Australian subunit influenza vaccine. Before that accomplishment, only intact inactivated influenza vaccines had been used in Australia and they were considered undesirably reactogenic. Studies first in rabbits and then in children established the proof of principle for the vaccine. The ANU paid Laver and myself 10 shillings each for the patent rights. Australian subunit influenza vaccines have been further improved, but the fundamental principle established by Laver remains the same: that the proteins must be kept in their native conformation for the vaccine to be effective. Further studies with Robin Valentine of the National Institute of Medical Research at Mill Hill, London, established the morphology of the hemagglutinin (HA) and neuraminidase (NA) subunits by electron microscopy, and later work with Nick Wrigley produced the first electron microscopy images of antigen-antibody complexes. After the emergence of the Asian influenza pandemic in 1957 the influenza community, led by Martin Kaplan of the World Health Organization (WHO), began searching for the origins of influenza pandemics. During a fishing trip to the Southeast coast of Australia, near Bateman’s Bay, New South Wales, Laver and I found the beaches littered with dead mutton birds (Puffinus pacificus). Knowing that A/Tern/South Africa/61 (H5N3) influenza virus had been isolated from seabirds, we speculated that the mutton birds might have been killed by an influenza virus. In 1970, serological studies of mutton birds on the Great Barrier Reef of Australia found the first evidence of human N2 neuraminidase–inhibiting antibodies, and in 1973 influenza viruses were isolated for the first time from wild migratory seabirds. These findings provided the first links in the chain of evidence that subsequently showed that the migratory aquatic birds of the world are the natural reservoirs of all influenza A viruses. Studies on the structure of influenza virus neuraminidase began with Graeme’s keynote paper in 1978 on crystallization of the heads of the human N2 neuraminidase molecule (Virology 1978; 96: 78–87). These and subsequent studies culminated in the resolution of the three-dimensional structure of the neuraminidase, with Peter Colman and Jose Varghese. With this information, Mark von Itzstein was able to design the first structure-based anti-influenza drug, zanamivir (Relenza). Further development using NA crystals provided by Graeme led to the development of the orally available anti-influenza drug oseltamivir (Tamiflu). The WHO Global Influenza Surveillance Network was established in 1952 to keep up with antigenic drift in influenza viruses and to recommend changes in vaccine strains to stay abreast of antigenic variation. However, there was no fundamental understanding of the mechanisms involved until Graeme Laver began peptide mapping of the hemagglutinin (HA) molecule and provided evidence of multiple antigenic determinants on HA spikes (Virology 1974; 59: 230–244). The advent of monoclonal antibodies by Georges Kohler and Caesar Milstein and their use to select influenza virus escape mutants, together with sequence analysis of the HA molecules (Virology 1979; 98: 226–237), established that a single amino acid change in the HA would allow the influenza virus to escape neutralization. Antigenic mapping of the HA and NA molecules soon followed and, ultimately, establishment of the antibody binding domains and visualization of the epitopes on the NA subunits (Nature 1987; 326: 358–363). Thus, the mechanism of antigenic drift in influenza and the epitopes involved were elucidated thanks to the seminal work of the Laver laboratory. Graeme Laver had a sense of adventure in all aspects of his life, from family to friends to research, and was always a free spirit who was willing to challenge bureaucracy when they “got it wrong”. He was an avid skier, mountaineer, gardener and axeman. In later life, his scientific passion was the production of perfect crystals of NA through studies in zero gravity on the Russian MIR space station and crystallization chambers set up in every laboratory he visited. Some of the most beautiful crystals were the N9 neuraminidase of an influenza virus isolated from a noddy tern on the Great Barrier Reef. Photographs of these crystals appeared on the covers of many scientific journals, and Graeme and photographer Julie Macklin were awarded the Nikon “Small World” prize in 1987. In addition to influenza, Graeme made contributions to our knowledge about adenoviruses, sialidases and paramyxoviruses. His multiple scientific achievements were recognized by his election to the Royal Society of London in 1987 and by co-receipt of the Australia Prize with Peter Coleman, Mark von Itzstein and Paul Janssen in 1996. In its efforts to prepare for an influenza pandemic and to identify the best options for controlling seasonal influenza, the global community owes a very special debt to Graeme Laver. The current strategies for control of both pandemic and seasonal influenza, the stockpiles of anti-influenza drugs and prepandemic vaccines are products of his life’s work. His final mission was to have anti-influenza drugs made available over the counter so that every household could have an immediate supply in the face of a pandemic. He argued that this option would have no effect on the emergence of resistance and could save millions of lives in the event of infrastructure failure. New Zealand has taken the lead in following his visionary advice.

Payman Mohassel, Enav Weinreb

No abstract is available for this record.

Joël Alwen, Abhi Shelat, Ivan Visconti

No abstract is available for this record.

Lu Li, Jinsong Han, Yunhao Liu, Lei Hu · 7 authors

Most of the current trust models in peer-to-peer (P2P) systems are identity based, which means that in order for one peer to trust another, it needs to know the other peer's identity. Hence, there exists an inherent tradeoff between trust and anonymity. To the best of our knowledge, there is currently no P2P protocol that provides complete mutual anonymity as well as authentication and trust management. We propose a zero-knowledge authentication scheme called pseudo trust (PT), where each peer, instead of using its real identity, generates an unforgeable and verifiable pseudonym using a one-way hash function. A novel authentication scheme based on zero-knowledge proof is designed so that peers can be authenticated without leaking any sensitive information. With the help of PT, most existing identity-based trust management schemes become applicable in mutual anonymous P2P systems. We analyze the security and the anonymity in PT, and evaluate its performance using trace-driven simulations and a prototype PT-enabled P2P network. The strengths of our design include (1) no need for a centralized trusted party or CA, (2) high scalability and security, (3) low traffic and cryptography processing overheads, and (4) man-in-middle attack resistance.

Guomin Yang, Jing Chen, Duncan S. Wong, Xiaotie Deng · 5 authors

No abstract is available for this record.

Yi Deng

提出了一种从3轮公开掷币的对任何NP语言的诚实验证者零知识证明系统到纯公钥模型下4轮(轮最优)对同一语言的具有并发合理性的并发零知识证明系统.该转化方法有如下优点:1) 它只引起O(1)(常数个)额外的模指数运算,相比Di Crescenzo等人在ICALP 05上提出的需要((n)个额外的模指数运算的转化方法,该系统在效率上有着本质上的提高,而所需的困难性假设不变;2) 在离散对数假设下,该转化方法产生一个完美零知识证明系统.注意到Di Crescenzo等人提出的系统只具有计算零知识性质.该转化方法依赖于一个特殊的对承诺中的离散对数的3轮诚实验证者零知识的证明系统.构造了两个基于不同承诺方案的只需要常数个模指数运算的系统,这种系统可能有着独立价值.;This paper shows how to efficiently transform any 3-round public-coin honest verifier zero knowledge argument system for any language in NP into a 4 round (round-optimal) concurrent zero knowledge argument for the same language in the bare public-key model. The transformation has the following properties: 1) incurs only O(1) (small constant, about 20) additional modular exponentiations. Compared to the concurrent zero knowledge protocol proposed by Di Crescenzo and Visconti in ICALP 2005, in which their transformation requires an overhead of ((n), the protocol is significantly more efficient under the same intractability assumptions; 2) yields a perfect zero knowledge argument under DL assumption. Note that the Di Crescenzo, et al.'s argument system enjoys only computational zero knowledge property. The transformation relies on a specific 3-round honest verifier zero knowledge proof of knowledge for committed discrete log. Such protocols that require only O(1) modular exponentiations based on different kinds of commitment scheme are developed and they may be of independent interest.