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We introduce algorithms for lattice basis reduction that are improvements of the famous L3-algorithm. If a random L3-reduced lattice basis b1,b2,...,bn is given such that the vector of reduced Gram-Schmidt coefficients ({µi,j} 1<= j< i<= n) is uniformly distributed in [0,1)n(n-1)/2, then the pruned enumeration finds with positive probability a shortest lattice vector. We demonstrate the power of these algorithms by solving random subset sum problems of arbitrary density with 74 and 82 many weights, by breaking the Chor-Rivest cryptoscheme in dimensions 103 and 151 and by breaking Damgard's hash function.
We call a vector x/spl isin/R/sup n/ highly regular if it satisfies =0 for some short, non-zero integer vector m where <...> is the inner product. We present an algorithm which given x/spl isin/R/sup n/ and /spl alpha//spl isin/N finds a highly regular nearby point x' and a short integer relation m for x'. The nearby point x' is 'good' in the sense that no short relation m~ of length less than /spl alpha//2 exists for points x~ within half the x'-distance from x. The integer relation m for x' is for random x up to an average factor 2/sup /spl alpha//2/ a shortest integer relation for x'. Our algorithm uses, for arbitrary real input x, at most O(n/sup 4/(n+log A)) many arithmetical operations on real numbers. If a is rational the algorithm operates on integers having at most O(n/sup 5/+n/sup 3/(log /spl alpha/)/sup 2/+log(/spl par/qx/spl par//sup 2/)) many bits where q is the common denominator for x.
We study the following problem: given x element Rn either find a short integer relation m element Zn, so that =0 holds for the inner product <.,.>, or prove that no short integer relation exists for x. Hastad, Just Lagarias and Schnorr (1989) give a polynomial time algorithm for the problem. We present a stable variation of the HJLS--algorithm that preserves lower bounds on lambda(x) for infinitesimal changes of x. Given x \in {\RR}^n and \alpha \in \NN this algorithm finds a nearby point x' and a short integer relation m for x'. The nearby point x' is 'good' in the sense that no very short relation exists for points \bar{x} within half the x'--distance from x. On the other hand if x'=x then m is, up to a factor 2^{n/2}, a shortest integer relation for \mbox{x.} Our algorithm uses, for arbitrary real input x, at most \mbox{O(n^4(n+\log \alpha))} many arithmetical operations on real numbers. If x is rational the algorithm operates on integers having at most \mbox{O(n^5+n^3 (\log \alpha)^2 + \log (\|q x\|^2))} many bits where q is the common denominator for x.
Black box cryptanalysis applies to hash algorithms consisting of many small boxes, connected by a known graph structure, so that the boxes can be evaluated forward and backwards by given oracles. We study attacks that work for any choice of the black boxes, i.e. we scrutinize the given graph structure. For example we analyze the graph of the fast Fourier transform (FFT). We present optimal black box inversions of FFT-compression functions and black box constructions of collisions. This determines the minimal depth of FFT-compression networks for collision-resistant hashing. We propose the concept of multipermutation, which is a pair of orthogonal latin squares, as a new cryptographic primitive that generalizes the boxes of the FFT. Our examples of multipermutations are based on the operations circular rotation, bitwise xor, addition and multiplication.
Parallel FFT-hashing
(1994)
We propose two families of scalable hash functions for collision resistant hashing that are highly parallel and based on the generalized fast Fourier transform (FFT). FFT hashing is based on multipermutations. This is a basic cryptographic primitive for perfect generation of diffusion and confusion which generalizes the boxes of the classic FFT. The slower FFT hash functions iterate a compression function. For the faster FFT hash functions all rounds are alike with the same number of message words entering each round.
We report on improved practical algorithms for lattice basis reduction. We propose a practical floating point version of theL3-algorithm of Lenstra, Lenstra, Lovász (1982). We present a variant of theL3-algorithm with "deep insertions" and a practical algorithm for block Korkin—Zolotarev reduction, a concept introduced by Schnorr (1987). Empirical tests show that the strongest of these algorithms solves almost all subset sum problems with up to 66 random weights of arbitrary bit length within at most a few hours on a UNISYS 6000/70 or within a couple of minutes on a SPARC1 + computer.
We call a distribution on n bit strings (", e) locally random, if for every choice of e · n positions the induced distribution on e bit strings is in the L1 norm at most " away from the uniform distribution on e bit strings. We establish local randomness in polynomial random number generators (RNG) that are candidate one way functions. Let N be a squarefree integer and let f1, . . . , f be polynomials with coe±- cients in ZZN = ZZ/NZZ. We study the RNG that stretches a random x 2 ZZN into the sequence of least significant bits of f1(x), . . . , f(x). We show that this RNG provides local randomness if for every prime divisor p of N the polynomials f1, . . . , f are linearly independent modulo the subspace of polynomials of degree · 1 in ZZp[x]. We also establish local randomness in polynomial random function generators. This yields candidates for cryptographic hash functions. The concept of local randomness in families of functions extends the concept of universal families of hash functions by Carter and Wegman (1979). The proofs of our results rely on upper bounds for exponential sums.
We propose two improvements to the Fiat Shamir authentication and signature scheme. We reduce the communication of the Fiat Shamir authentication scheme to a single round while preserving the e±ciency of the scheme. This also reduces the length of Fiat Shamir signatures. Using secret keys consisting of small integers we reduce the time for signature generation by a factor 3 to 4. We propose a variation of our scheme using class groups that may be secure even if factoring large integers becomes easy.
We introduce novel security proofs that use combinatorial counting arguments rather than reductions to the discrete logarithm or to the Diffie-Hellman problem. Our security results are sharp and clean with no polynomial reduction times involved. We consider a combination of the random oracle model and the generic model. This corresponds to assuming an ideal hash function H given by an oracle and an ideal group of prime order q, where the binary encoding of the group elements is useless for cryptographic attacks In this model, we first show that Schnorr signatures are secure against the one-more signature forgery : A generic adversary performing t generic steps including l sequential interactions with the signer cannot produce l+1 signatures with a better probability than (t 2)/q. We also characterize the different power of sequential and of parallel attacks. Secondly, we prove signed ElGamal encryption is secure against the adaptive chosen ciphertext attack, in which an attacker can arbitrarily use a decryption oracle except for the challenge ciphertext. Moreover, signed ElGamal encryption is secure against the one-more decryption attack: A generic adversary performing t generic steps including l interactions with the decryption oracle cannot distinguish the plaintexts of l + 1 ciphertexts from random strings with a probability exceeding (t 2)/q.
Assuming a cryptographically strong cyclic group G of prime order q and a random hash function H, we show that ElGamal encryption with an added Schnorr signature is secure against the adaptive chosen ciphertext attack, in which an attacker can freely use a decryption oracle except for the target ciphertext. We also prove security against the novel one-more-decyption attack. Our security proofs are in a new model, corresponding to a combination of two previously introduced models, the Random Oracle model and the Generic model. The security extends to the distributed threshold version of the scheme. Moreover, we propose a very practical scheme for private information retrieval that is based on blind decryption of ElGamal ciphertexts.
Let b1, . . . , bm 2 IRn be an arbitrary basis of lattice L that is a block Korkin Zolotarev basis with block size ¯ and let ¸i(L) denote the successive minima of lattice L. We prove that for i = 1, . . . ,m 4 i + 3 ° 2 i 1 ¯ 1 ¯ · kbik2/¸i(L)2 · ° 2m i ¯ 1 ¯ i + 3 4 where °¯ is the Hermite constant. For ¯ = 3 we establish the optimal upper bound kb1k2/¸1(L)2 · µ3 2¶m 1 2 1 and we present block Korkin Zolotarev lattice bases for which this bound is tight. We improve the Nearest Plane Algorithm of Babai (1986) using block Korkin Zolotarev bases. Given a block Korkin Zolotarev basis b1, . . . , bm with block size ¯ and x 2 L(b1, . . . , bm) a lattice point v can be found in time ¯O(¯) satisfying kx vk2 · m° 2m ¯ 1 ¯ minu2L kx uk2.
With ubiquitous use of digital camera devices, especially in mobile phones, privacy is no longer threatened by governments and companies only. The new technology creates a new threat by ordinary people, who now have the means to take and distribute pictures of one’s face at no risk and little cost in any situation in public and private spaces. Fast distribution via web based photo albums, online communities and web pages expose an individual’s private life to the public in unpreceeded ways. Social and legal measures are increasingly taken to deal with this problem. In practice however, they lack efficiency, as they are hard to enforce in practice. In this paper, we discuss a supportive infrastructure aiming for the distribution channel; as soon as the picture is publicly available, the exposed individual has a chance to find it and take proper action.
Korrektur zu: C.P. Schnorr: Security of 2t-Root Identification and Signatures, Proceedings CRYPTO'96, Springer LNCS 1109, (1996), pp. 143-156 page 148, section 3, line 5 of the proof of Theorem 3. Die Korrektur wurde präsentiert als: "Factoring N via proper 2 t-Roots of 1 mod N" at Eurocrypt '97 rump session.
Let G be a finite cyclic group with generator \alpha and with an encoding so that multiplication is computable in polynomial time. We study the security of bits of the discrete log x when given \exp_{\alpha}(x), assuming that the exponentiation function \exp_{\alpha}(x) = \alpha^x is one-way. We reduce he general problem to the case that G has odd order q. If G has odd order q the security of the least-significant bits of x and of the most significant bits of the rational number \frac{x}{q} \in [0,1) follows from the work of Peralta [P85] and Long and Wigderson [LW88]. We generalize these bits and study the security of consecutive shift bits lsb(2^{-i}x mod q) for i=k+1,...,k+j. When we restrict \exp_{\alpha} to arguments x such that some sequence of j consecutive shift bits of x is constant (i.e., not depending on x) we call it a 2^{-j}-fraction of \exp_{\alpha}. For groups of odd group order q we show that every two 2^{-j}-fractions of \exp_{\alpha} are equally one-way by a polynomial time transformation: Either they are all one-way or none of them. Our key theorem shows that arbitrary j consecutive shift bits of x are simultaneously secure when given \exp_{\alpha}(x) iff the 2^{-j}-fractions of \exp_{\alpha} are one-way. In particular this applies to the j least-significant bits of x and to the j most-significant bits of \frac{x}{q} \in [0,1). For one-way \exp_{\alpha} the individual bits of x are secure when given \exp_{\alpha}(x) by the method of Hastad, N\"aslund [HN98]. For groups of even order 2^{s}q we show that the j least-significant bits of \lfloor x/2^s\rfloor, as well as the j most-significant bits of \frac{x}{q} \in [0,1), are simultaneously secure iff the 2^{-j}-fractions of \exp_{\alpha'} are one-way for \alpha' := \alpha^{2^s}. We use and extend the models of generic algorithms of Nechaev (1994) and Shoup (1997). We determine the generic complexity of inverting fractions of \exp_{\alpha} for the case that \alpha has prime order q. As a consequence, arbitrary segments of (1-\varepsilon)\lg q consecutive shift bits of random x are for constant \varepsilon >0 simultaneously secure against generic attacks. Every generic algorithm using $t$ generic steps (group operations) for distinguishing bit strings of j consecutive shift bits of x from random bit strings has at most advantage O((\lg q) j\sqrt{t} (2^j/q)^{\frac14}).
Let G be a group of prime order q with generator g. We study hardcore subsets H is include in G of the discrete logarithm (DL) log g in the model of generic algorithms. In this model we count group operations such as multiplication, division while computations with non-group data are for free. It is known from Nechaev (1994) and Shoup (1997) that generic DL-algorithms for the entire group G must perform p2q generic steps. We show that DL-algorithms for small subsets H is include in G require m/ 2 + o(m) generic steps for almost all H of size #H = m with m <= sqrt(q). Conversely, m/2 + 1 generic steps are su±cient for all H is include in G of even size m. Our main result justifies to generate secret DL-keys from seeds that are only 1/2 * log2 q bits long.
We present a novel practical algorithm that given a lattice basis b1, ..., bn finds in O(n exp 2 *(k/6) exp (k/4)) average time a shorter vector than b1 provided that b1 is (k/6) exp (n/(2k)) times longer than the length of the shortest, nonzero lattice vector. We assume that the given basis b1, ..., bn has an orthogonal basis that is typical for worst case lattice bases. The new reduction method samples short lattice vectors in high dimensional sublattices, it advances in sporadic big jumps. It decreases the approximation factor achievable in a given time by known methods to less than its fourth-th root. We further speed up the new method by the simple and the general birthday method. n2
We enhance the security of Schnorr blind signatures against the novel one-more-forgery of Schnorr [Sc01] andWagner [W02] which is possible even if the discrete logarithm is hard to compute. We show two limitations of this attack. Firstly, replacing the group G by the s-fold direct product G exp(×s) increases the work of the attack, for a given number of signer interactions, to the s-power while increasing the work of the blind signature protocol merely by a factor s. Secondly, we bound the number of additional signatures per signer interaction that can be forged effectively. That fraction of the additional forged signatures can be made arbitrarily small.
We modify the concept of LLL-reduction of lattice bases in the sense of Lenstra, Lenstra, Lovasz [LLL82] towards a faster reduction algorithm. We organize LLL-reduction in segments of the basis. Our SLLL-bases approximate the successive minima of the lattice in nearly the same way as LLL-bases. For integer lattices of dimension n given by a basis of length 2exp(O(n)), SLLL-reduction runs in O(n.exp(5+epsilon)) bit operations for every epsilon > 0, compared to O(exp(n7+epsilon)) for the original LLL and to O(exp(n6+epsilon)) for the LLL-algorithms of Schnorr (1988) and Storjohann (1996). We present an even faster algorithm for SLLL-reduction via iterated subsegments running in O(n*exp(3)*log n) arithmetic steps.
We show that P(n)*(P(n)) for p = 2 with its geometrically induced structure maps is not an Hopf algebroid because neither the augmentation Epsilon nor the coproduct Delta are multiplicative. As a consequence the algebra structure of P(n)*(P(n)) is slightly different from what was supposed to be the case. We give formulas for Epsilon(xy) and Delta(xy) and show that the inversion of the formal group of P(n) is induced by an antimultiplicative involution Xi : P(n) -> P(n). Some consequences for multiplicative and antimultiplicative automorphisms of K(n) for p = 2 are also discussed.
The general subset sum problem is NP-complete. However, there are two algorithms, one due to Brickell and the other to Lagarias and Odlyzko, which in polynomial time solve almost all subset sum problems of sufficiently low density. Both methods rely on basis reduction algorithms to find short nonzero vectors in special lattices. The Lagarias-Odlyzko algorithm would solve almost all subset sum problems of density < 0.6463 . . . in polynomial time if it could invoke a polynomial-time algorithm for finding the shortest non-zero vector in a lattice. This paper presents two modifications of that algorithm, either one of which would solve almost all problems of density < 0.9408 . . . if it could find shortest non-zero vectors in lattices. These modifications also yield dramatic improvements in practice when they are combined with known lattice basis reduction algorithms.
Public key signature schemes are necessary for the access control to communication networks and for proving the authenticity of sensitive messages such as electronic fund transfers. Since the invention of the RSA scheme by Rivest, Shamir and Adleman (1978) research has focused on improving the e±ciency of these schemes. In this paper we present an efficient algorithm for generating public key signatures which is particularly suited for interactions between smart cards and terminals.
We present a novel parallel one-more signature forgery against blind Okamoto-Schnorr and blind Schnorr signatures in which an attacker interacts some times with a legitimate signer and produces from these interactions signatures. Security against the new attack requires that the following ROS-problem is intractable: find an overdetermined, solvable system of linear equations modulo with random inhomogenities (right sides). There is an inherent weakness in the security result of POINTCHEVAL AND STERN. Theorem 26 [PS00] does not cover attacks with 4 parallel interactions for elliptic curves of order 2200. That would require the intractability of the ROS-problem, a plausible but novel complexity assumption. Conversely, assuming the intractability of the ROS-problem, we show that Schnorr signatures are secure in the random oracle and generic group model against the one-more signature forgery.
We present a practical algorithm that given an LLL-reduced lattice basis of dimension n, runs in time O(n3(k=6)k=4+n4) and approximates the length of the shortest, non-zero lattice vector to within a factor (k=6)n=(2k). This result is based on reasonable heuristics. Compared to previous practical algorithms the new method reduces the proven approximation factor achievable in a given time to less than its fourthth root. We also present a sieve algorithm inspired by Ajtai, Kumar, Sivakumar [AKS01].
Let G be a Fuchsian group containing two torsion free subgroups defining isomorphic Riemann surfaces. Then these surface subgroups K and alpha-Kalpha exp(-1) are conjugate in PSl(2,R), but in general the conjugating element alpha cannot be taken in G or a finite index Fuchsian extension of G. We will show that in the case of a normal inclusion in a triangle group G these alpha can be chosen in some triangle group extending G. It turns out that the method leading to this result allows also to answer the question how many different regular dessins of the same type can exist on a given quasiplatonic Riemann surface.
We consider Schwarz maps for triangles whose angles are rather general rational multiples of pi. Under which conditions can they have algebraic values at algebraic arguments? The answer is based mainly on considerations of complex multiplication of certain Prym varieties in Jacobians of hypergeometric curves. The paper can serve as an introduction to transcendence techniques for hypergeometric functions, but contains also new results and examples.
The main subject of this survey are Belyi functions and dessins d'enfants on Riemann surfaces. Dessins are certain bipartite graphs on 2-mainfolds defining there are conformal and even an algebraic structure. In principle, all deeper properties of the resulting Riemann surfaces or algebraic curves should be encoded in these dessins, but the decoding turns out to be difficult and leads to many open problems. We emphasize arithmetical aspects like Galois actions, the relation to the ABC theorem in function filds and arithemtic questions in uniformization theory of algebraic curves defined over number fields.
The large conductance voltage- and Ca2+-activated potassium (BK) channel has been suggested to play an important role in the signal transduction process of cochlear inner hair cells. BK channels have been shown to be composed of the pore-forming alpha-subunit coexpressed with the auxiliary beta-1-subunit. Analyzing the hearing function and cochlear phenotype of BK channel alpha-(BKalpha–/–) and beta-1-subunit (BKbeta-1–/–) knockout mice, we demonstrate normal hearing function and cochlear structure of BKbeta-1–/– mice. During the first 4 postnatal weeks also, BKalpha–/– mice most surprisingly did not show any obvious hearing deficits. High-frequency hearing loss developed in BKalpha–/– mice only from ca. 8 weeks postnatally onward and was accompanied by a lack of distortion product otoacoustic emissions, suggesting outer hair cell (OHC) dysfunction. Hearing loss was linked to a loss of the KCNQ4 potassium channel in membranes of OHCs in the basal and midbasal cochlear turn, preceding hair cell degeneration and leading to a similar phenotype as elicited by pharmacologic blockade of KCNQ4 channels. Although the actual link between BK gene deletion, loss of KCNQ4 in OHCs, and OHC degeneration requires further investigation, data already suggest human BK-coding slo1 gene mutation as a susceptibility factor for progressive deafness, similar to KCNQ4 potassium channel mutations. © 2004, The National Academy of Sciences. Freely available online through the PNAS open access option.
Presentation at the AMS Southeastern Sectional Meeting 14-16 March 2003, and the Workshop Asymptotic Analysis, Stability, and Generalized Functions', 17-19 March 2003, Louisiana State University, Baton Rouge, Louisiana. See the corresponding papers "Mathematical Problems of Gauge Quantum Field Theory: A Survey of the Schwinger Model" and "Infinite Infrared Regularization and a State Space for the Heisenberg Algebra".
Presentation at the Università di Pisa, Pisa, Itlay 3 July 2002, the conference on Irreversible Quantum Dynamics', the Abdus Salam ICTP, Trieste, Italy, 29 July - 2 August 2002, and the University of Natal, Pietermaritzburg, South Africa, 14 May 2003. Version of 24 April 2003: examples added; 16 December 2002: revised; 12 Sptember 2002. See the corresponding papers "Zeno Dynamics of von Neumann Algebras", "Zeno Dynamics in Quantum Statistical Mechanics" and "Mathematics of the Quantum Zeno Effect"
Background: The existence of a constitutively expressed machinery for death in individual cells has led to the notion that survival factors repress this machinery and, if such factors are unavailable, cells die by default. In many cells, however, mRNA and protein synthesis inhibitors induce apoptosis, suggesting that in some cases transcriptional activity might actually impede cell death. To identify transcriptional mechanisms that interfere with cell death and survival, we combined gene trap mutagenesis with site-specific recombination (Cre/loxP system) to isolate genes from cells undergoing apoptosis by growth factor deprivation.
Results: From an integration library consisting of approximately 2 × 106 unique proviral integrations obtained by infecting the interleukin-3 (IL-3)-dependent hematopoietic cell line - FLOXIL3 - with U3Cre gene trap virus, we have isolated 125 individual clones that converted to factor independence upon IL-3 withdrawal. Of 102 cellular sequences adjacent to U3Cre integration sites, 17% belonged to known genes, 11% matched single expressed sequence tags (ESTs) or full cDNAs with unknown function and 72% had no match within the public databases. Most of the known genes recovered in this analysis encoded proteins with survival functions.
Conclusions: We have shown that hematopoietic cells undergoing apoptosis after withdrawal of IL-3 activate survival genes that impede cell death. This results in reduced apoptosis and improved survival of cells treated with a transient apoptotic stimulus. Thus, apoptosis in hematopoietic cells is the end result of a conflict between death and survival signals, rather than a simple death by default.
An excess of the proinflammatory substance IL-18 is present in joints of patients with rheumatoid arthritis (RA), and expression of IL-18 receptor (IL-18R) regulates IL-18 bioactivity in various cell types. We examined the expression of IL-18R alpha-chain and beta-chain and the biologic effects of IL-18 in fibroblast-like synoviocytes (FLS) after long-term culture. The presence of both IL-18R chains was a prerequisite for IL-18 signal transduction in FLS. However, all FLS cultures studied were either resistant or barely responsive to IL-18 stimulation as regards cell proliferation, expression of adhesion molecules ICAM-1 and vascular cell adhesion molecule (VCAM)-1, and the release of interstitial collagenase and stromelysin, IL-6 and IL-8, prostaglandin E2, or nitric oxide. We conclude that the presence of macrophages or IL-18R+ T cells that can respond directly to IL-18 is essential for the proinflammatory effects of IL-18 in synovitis in RA. Open Access: Published: 14 November 2001 © 2002 Möller et al., licensee BioMed Central Ltd (Print ISSN 1465-9905; Online ISSN 1465-9913)
Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is performed mainly in patients with high-risk or advanced hematologic malignancies and congenital or acquired aplastic anemias. In the context of the significant risk of graft failure after allo-HSCT from alternative donors and the risk of relapse in recipients transplanted for malignancy, the precise monitoring of posttransplant hematopoietic chimerism is of utmost interest. Useful molecular methods for chimerism quantification after allogeneic transplantation, aimed at distinguishing precisely between donor's and recipient's cells, are PCR-based analyses of polymorphic DNA markers. Such analyses can be performed regardless of donor's and recipient's sex. Additionally, in patients after sex-mismatched allo-HSCT, fluorescent in situ hybridization (FISH) can be applied. Methods: We compared different techniques for analysis of posttransplant chimerism, namely FISH and PCR-based molecular methods with automated detection of fluorescent products in an ALFExpress DNA Sequencer (Pharmacia) or ABI 310 Genetic Analyzer (PE). We used Spearman correlation test. Results: We have found high correlation between results obtained from the PCR/ALF Express and PCR/ABI 310 Genetic Analyzer. Lower, but still positive correlations were found between results of FISH technique and results obtained using automated DNA sizing technology. Conclusions: All the methods applied enable a rapid and accurate detection of post-HSCT chimerism.
Background: To investigate the occupational risk of tuberculosis (TB) infection in a low-incidence setting, data from a prospective study of patients with culture-confirmed TB conducted in Hamburg, Germany, from 1997 to 2002 were evaluated. Methods: M. tuberculosis isolates were genotyped by IS6110 RFLP analysis. Results of contact tracing and additional patient interviews were used for further epidemiological analyses. Results: Out of 848 cases included in the cluster analysis, 286 (33.7%) were classified into 76 clusters comprising 2 to 39 patients. In total, two patients in the non-cluster and eight patients in the cluster group were health-care workers. Logistic regression analysis confirmed work in the health-care sector as the strongest predictor for clustering (OR 17.9). However, only two of the eight transmission links among the eight clusters involving health-care workers had been detected previously. Overall, conventional contact tracing performed before genotyping had identified only 26 (25.2%) of the 103 contact persons with the disease among the clustered cases whose transmission links were epidemiologically verified. Conclusion: Recent transmission was found to be strongly associated with health-care work in a setting with low incidence of TB. Conventional contact tracing alone was shown to be insufficient to discover recent transmission chains. The data presented also indicate the need for establishing improved TB control strategies in health-care settings.
Introduction: ScFv(FRP5)-ETA is a recombinant antibody toxin with binding specificity for ErbB2 (HER2). It consists of an N-terminal single-chain antibody fragment (scFv), genetically linked to truncated Pseudomonas exotoxin A (ETA). Potent antitumoral activity of scFv(FRP5)-ETA against ErbB2-overexpressing tumor cells was previously demonstrated in vitro and in animal models. Here we report the first systemic application of scFv(FRP5)-ETA in human cancer patients.
Methods: We have performed a phase I dose-finding study, with the objective to assess the maximum tolerated dose and the dose-limiting toxicity of intravenously injected scFv(FRP5)-ETA. Eighteen patients suffering from ErbB2-expressing metastatic breast cancers, prostate cancers, head and neck cancer, non small cell lung cancer, or transitional cell carcinoma were treated. Dose levels of 2, 4, 10, 12.5, and 20 μg/kg scFv(FRP5)-ETA were administered as five daily infusions each for two consecutive weeks.
Results: No hematologic, renal, and/or cardiovascular toxicities were noted in any of the patients treated. However, transient elevation of liver enzymes was observed, and considered dose limiting, in one of six patients at the maximum tolerated dose of 12.5 μg/kg, and in two of three patients at 20 μg/kg. Fifteen minutes after injection, peak concentrations of more than 100 ng/ml scFv(FRP5)-ETA were obtained at a dose of 10 μg/kg, indicating that predicted therapeutic levels of the recombinant protein can be applied without inducing toxic side effects. Induction of antibodies against scFv(FRP5)-ETA was observed 8 days after initiation of therapy in 13 patients investigated, but only in five of these patients could neutralizing activity be detected. Two patients showed stable disease and in three patients clinical signs of activity in terms of signs and symptoms were observed (all treated at doses ≥ 10 μg/kg). Disease progression occurred in 11 of the patients.
Conclusion: Our results demonstrate that systemic therapy with scFv(FRP5)-ETA can be safely administered up to a maximum tolerated dose of 12.5 μg/kg in patients with ErbB2-expressing tumors, justifying further clinical development.
Background: The cosmopolitan moon jelly Aurelia is characterized by high degrees of morphological and ecological plasticity, and subsequently by an unclear taxonomic status. The latter has been revised repeatedly over the last century, dividing the genus Aurelia in as many as 12 or as little as two species. We used molecular data and phenotypic traits to unravel speciation processes and phylogeographic patterns in Aurelia.
Results: Mitochondrial and nuclear DNA data (16S and ITS-1/5.8S rDNA) from 66 world-wide sampled specimens reveal star-like tree topologies, unambiguously differentiating 7 (mtDNA) and 8 (ncDNA) genetic entities with sequence divergences ranging from 7.8 to 14% (mtDNA) and 5 to 32% (ncDNA), respectively. Phylogenetic patterns strongly suggest historic speciation events and the reconstruction of at least 7 different species within Aurelia. Both genetic divergences and life history traits showed associations to environmental factors, suggesting ecological differentiation forced by divergent selection. Hybridization and introgression between Aurelia lineages likely occurred due to secondary contacts, which, however, did not disrupt the unambiguousness of genetic separation.
Conclusions: Our findings recommend Aurelia as a model system for using the combined power of organismic, ecological, and molecular data to unravel speciation processes in cosmopolitan marine organisms.
© 2002 Schroth et al; licensee BioMed Central Ltd. Verbatim copying and redistribution of this article are permitted in any medium for any non-commercial purpose, provided this notice is preserved along with the article's original URL: http://www.biomedcentral.com/1471-2148/2/1
Dendritic cells (DC) are known to present exogenous protein Ag effectively to T cells. In this study we sought to identify the proteases that DC employ during antigen processing. The murine epidermal-derived DC line Xs52, when pulsed with PPD, optimally activated the PPD-reactive Th1 clone LNC.2F1 as well as the Th2 clone LNC.4k1, and this activation was completely blocked by chloroquine pretreatment. These results validate the capacity of XS52 DC to digest PPD into immunogenic peptides inducing antigen specific T cell immune responses. XS52 DC, as well as splenic DC and DCs derived from bone marrow degraded standard substrates for cathepsins B, C, D/E, H, J, and L, tryptase, and chymases, indicating that DC express a variety of protease activities. Treatment of XS52 DC with pepstatin A, an inhibitor of aspartic acid proteases, completely abrogated their capacity to present native PPD, but not trypsin-digested PPD fragments to Th1 and Th2 cell clones. Pepstatin A also inhibited cathepsin D/E activity selectively among the XS52 DC-associated protease activities. On the other hand, inhibitors of serine proteases (dichloroisocoumarin, DCI) or of cystein proteases (E-64) did not impair XS52 DC presentation of PPD, nor did they inhibit cathepsin D/E activity. Finally, all tested DC populations (XS52 DC, splenic DC, and bone marrow-derived DC) constitutively expressed cathepsin D mRNA. These results suggest that DC primarily employ cathepsin D (and perhaps E) to digest PPD into antigenic peptides.
Background: The neurophysiological and neuroanatomical foundations of persistent developmental stuttering (PDS) are still a matter of dispute. A main argument is that stutterers show atypical anatomical asymmetries of speech-relevant brain areas, which possibly affect speech fluency. The major aim of this study was to determine whether adults with PDS have anomalous anatomy in cortical speech-language areas. Methods: Adults with PDS (n = 10) and controls (n = 10) matched for age, sex, hand preference, and education were studied using high-resolution MRI scans. Using a new variant of the voxel-based morphometry technique (augmented VBM) the brains of stutterers and non-stutterers were compared with respect to white matter (WM) and grey matter (GM) differences. Results: We found increased WM volumes in a right-hemispheric network comprising the superior temporal gyrus (including the planum temporale), the inferior frontal gyrus (including the pars triangularis), the precentral gyrus in the vicinity of the face and mouth representation, and the anterior middle frontal gyrus. In addition, we detected a leftward WM asymmetry in the auditory cortex in non-stutterers, while stutterers showed symmetric WM volumes. Conclusions: These results provide strong evidence that adults with PDS have anomalous anatomy not only in perisylvian speech and language areas but also in prefrontal and sensorimotor areas. Whether this atypical asymmetry of WM is the cause or the consequence of stuttering is still an unanswered question. This article is available from: http://www.biomedcentral.com/1471-2377/4/23 © 2004 Jäncke et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
First paragraph (this article has no abstract) Persistent stimulation of nociceptors results in sensitization of nociceptive sensory neurons, which is associated with hyperalgesia and allodynia. The release of NO and subsequent synthesis of cGMP in the spinal cord are involved in this process. cGMP-dependent protein kinase I (PKG-I) has been suggested to act as a downstream target of cGMP, but its exact role in nociception hadn't been characterized yet. To further evaluate the NO/cGMP/PKG-I pathway in nociception we assessed the effects of PKG-I inhibiton and activaton in the rat formalin assay and analyzed the nociceptive behavior of PKG-I-/- mice. Open access article.
Background: In general shell-less slugs are considered to be slimy animals with a rather dull appearance and a pest to garden plants. But marine slugs usually are beautifully coloured animals belonging to the less-known Opisthobranchia. They are characterized by a large array of interesting biological phenomena, usually related to foraging and/or defence. In this paper our knowledge of shell reduction, correlated with the evolution of different defensive and foraging strategies is reviewed, and new results on histology of different glandular systems are included. Results: Based on a phylogeny obtained by morphological and histological data, the parallel reduction of the shell within the different groups is outlined. Major food sources are given and glandular structures are described as possible defensive structures in the external epithelia, and as internal glands. Conclusion: According to phylogenetic analyses, the reduction of the shell correlates with the evolution of defensive strategies. Many different kinds of defence structures, like cleptocnides, mantle dermal formations (MDFs), and acid glands, are only present in shell-less slugs. In several cases, it is not clear whether the defensive devices were a prerequisite for the reduction of the shell, or reduction occurred before. Reduction of the shell and acquisition of different defensive structures had an implication on exploration of new food sources and therefore likely enhanced adaptive radiation of several groups. © 2005 Wägele and Klussmann-Kolb; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited: http://www.frontiersinzoology.com/content/2/1/3/
Background: Tumor development remains one of the major obstacles following organ transplantation. Immunosuppressive drugs such as cyclosporine and tacrolimus directly contribute to enhanced malignancy, whereas the influence of the novel compound mycophenolate mofetil (MMF) on tumor cell dissemination has not been explored. We therefore investigated the adhesion capacity of colon, pancreas, prostate and kidney carcinoma cell lines to endothelium, as well as their beta1 integrin expression profile before and after MMF treatment. Methods: Tumor cell adhesion to endothelial cell monolayers was evaluated in the presence of 0.1 and 1 μM MMF and compared to unstimulated controls. beta1 integrin analysis included alpha1beta1 (CD49a), alpha2beta1 (CD49b), alpha3beta1 (CD49c), alpha4beta1 (CD49d), alpha5beta1 (CD49e), and alpha6beta1 (CD49f) receptors, and was carried out by reverse transcriptase-polymerase chain reaction, confocal microscopy and flow cytometry. Results: Adhesion of the colon carcinoma cell line HT-29 was strongly reduced in the presence of 0.1 μM MMF. This effect was accompanied by down-regulation of alpha3beta1 and alpha6beta1 surface expression and of alpha3beta1 and alpha6beta1 coding mRNA. Adhesion of the prostate tumor cell line DU-145 was blocked dose-dependently by MMF. In contrast to MMF's effects on HT-29 cells, MMF dose-dependently up-regulated alpha1beta1, alpha2beta1, alpha3beta1, and alpha5beta1 on DU-145 tumor cell membranes. Conclusion: We conclude that MMF possesses distinct anti-tumoral properties, particularly in colon and prostate carcinoma cells. Adhesion blockage of HT-29 cells was due to the loss of alpha3beta1 and alpha6beta1 surface expression, which might contribute to a reduced invasive behaviour of this tumor entity. The enhancement of integrin beta1 subtypes observed in DU-145 cells possibly causes re-differentiation towards a low-invasive phenotype.
Background: In rat, deafferentation of one labyrinth (unilateral labyrinthectomy) results in a characteristic syndrome of ocular and motor postural disorders (e.g., barrel rotation, circling behavior, and spontaneous nystagmus). Behavioral recovery (e.g., diminished symptoms), encompassing 1 week after unilateral labyrinthectomy, has been termed vestibular compensation. Evidence suggesting that the histamine H3 receptor plays a key role in vestibular compensation comes from studies indicating that betahistine, a histamine-like drug that acts as both a partial histamine H1 receptor agonist and an H3 receptor antagonist, can accelerate the process of vestibular compensation. Results: Expression levels for histamine H3 receptor (total) as well as three isoforms which display variable lengths of the third intracellular loop of the receptor were analyzed using in situ hybridization on brain sections containing the rat medial vestibular nucleus after unilateral labyrinthectomy. We compared these expression levels to H3 receptor binding densities. Total H3 receptor mRNA levels (detected by oligo probe H3X) as well as mRNA levels of the three receptor isoforms studied (detected by oligo probes H3A, H3B, and H3C) showed a pattern of increase, which was bilaterally significant at 24 h post-lesion for both H3X and H3C, followed by significant bilateral decreases in medial vestibular nuclei occurring 48 h (H3X and H3B) and 1 week post-lesion (H3A, H3B, and H3C). Expression levels of H3B was an exception to the forementioned pattern with significant decreases already detected at 24 h post-lesion. Coinciding with the decreasing trends in H3 receptor mRNA levels was an observed increase in H3 receptor binding densities occurring in the ipsilateral medial vestibular nuclei 48 h post-lesion. Conclusion: Progressive recovery of the resting discharge of the deafferentated medial vestibular nuclei neurons results in functional restoration of the static postural and occulomotor deficits, usually occurring within a time frame of 48 hours in rats. Our data suggests that the H3 receptor may be an essential part of pre-synaptic mechanisms required for reestablishing resting activities 48 h after unilateral labyrinthectomy.
Introduction: This open label, multicentre study was conducted to assess the times to offset of the pharmacodynamic effects and the safety of remifentanil in patients with varying degrees of renal impairment requiring intensive care.
Methods: A total of 40 patients, who were aged 18 years or older and had normal/mildly impaired renal function (estimated creatinine clearance ≥ 50 ml/min; n = 10) or moderate/severe renal impairment (estimated creatinine clearance <50 ml/min; n = 30), were entered into the study. Remifentanil was infused for up to 72 hours (initial rate 6–9 μg/kg per hour), with propofol administered if required, to achieve a target Sedation–Agitation Scale score of 2–4, with no or mild pain.
Results: There was no evidence of increased offset time with increased duration of exposure to remifentanil in either group. The time to offset of the effects of remifentanil (at 8, 24, 48 and 72 hours during scheduled down-titrations of the infusion) were more variable and were statistically significantly longer in the moderate/severe group than in the normal/mild group at 24 hours and 72 hours. These observed differences were not clinically significant (the difference in mean offset at 72 hours was only 16.5 min). Propofol consumption was lower with the remifentanil based technique than with hypnotic based sedative techniques. There were no statistically significant differences between the renal function groups in the incidence of adverse events, and no deaths were attributable to remifentanil use.
Conclusion: Remifentanil was well tolerated, and the offset of pharmacodynamic effects was not prolonged either as a result of renal dysfunction or prolonged infusion up to 72 hours.