Isotype-specific activation of cystic fibrosis transmembrane conductance regulator-chloride channels by cGMP-dependent protein kinase II

Type II cGMP-dependent protein kinase (cGKII) isolated from pig intestinal brush borders and type Iα cGK (cGKI) purified from bovine lung were compared for their ability to activate the cystic fibrosis transmembrane conductance regulator (CFTR)-Cl- channel in excised, inside-out membrane patches from NIH-3T3 fibroblasts and from a rat intestinal cell line (IEC-CF7) stably expressing recombinant CFTR. In both cell models, in the presence of cGMP and ATP, cGKII was found to mimic the effect of the catalytic subunit of cAMP- dependent protein kinase (cAK) on opening CFTR-Cl-channels, albeit with different kinetics (2-3-min lag time, reduced rate of activation). By contrast, cGKI or a monomeric cGKI catalytic fragment was incapable of opening CFTR-Cl- channels and also failed to potentiate cGKII activation of the channels. The cAK activation but not the cGKII activation was blocked by a cAK inhibitor peptide. The slow activation by cGKII could not be ascribed to counteracting protein phosphatases, since neither calyculin A, a potent inhibitor of phosphatase 1 and 2A, nor ATPγS (adenosine 5'-O- (thiotriphosphate)), producing stable thiophosphorylation, was able to enhance the activation kinetics. Channels preactivated by cGKII closed instantaneously upon removal of ATP and kinase but reopened in the presence of ATP alone. Paradoxically, immunoprecipitated CFTR or CF-2, a cloned R domain fragment of CFTR (amino acids 645-835) could be phosphorylated to a similar extent with only minor kinetic differences by both isotypes of cGK. Phosphopeptide maps of CF-2 and CFTR, however, revealed very subtle differences in site-specificity between the cGK isoforms. These results indicate that cGKII, in contrast to cGKIα, is a potential activator of chloride transport in CFTR-expressing cell types.</p

Heights of pre-special points of Shimura varieties

Let s be a special point on a Shimura variety, and x a pre-image of s in a fixed fundamental set of the associated Hermitian symmetric domain. We prove that the height of x is polynomially bounded with respect to the discriminant of the centre of the endomorphism ring of the corresponding ZZ -Hodge structure. Our bound is the final step needed to complete a proof of the André–Oort conjecture under the conjectural lower bounds for the sizes of Galois orbits of special points, using a strategy of Pila and Zannier

Key Rotation for Authenticated Encryption

A common requirement in practice is to periodically rotate the keys used to encrypt stored data. Systems used by Amazon and Google do so using a hybrid encryption technique which is eminently practical but has questionable security in the face of key compromises and does not provide full key rotation. Meanwhile, symmetric updatable encryption schemes (introduced by Boneh et al. CRYPTO 2013) support full key rotation without performing decryption: ciphertexts created under one key can be rotated to ciphertexts created under a different key with the help of a re-encryption token. By design, the tokens do not leak information about keys or plaintexts and so can be given to storage providers without compromising security. But the prior work of Boneh et al. addresses relatively weak confidentiality goals and does not consider integrity at all. Moreover, as we show, a subtle issue with their concrete scheme obviates a security proof even for confidentiality against passive attacks. This paper presents a systematic study of updatable Authenticated Encryption (AE). We provide a set of security notions that strengthen those in prior work. These notions enable us to tease out real-world security requirements of different strengths and build schemes that satisfy them efficiently. We show that the hybrid approach currently used in industry achieves relatively weak forms of confidentiality and integrity, but can be modified at low cost to meet our stronger confidentiality and integrity goals. This leads to a practical scheme that has negligible overhead beyond conventional AE. We then introduce re-encryption indistinguishability, a security notion that formally captures the idea of fully refreshing keys upon rotation. We show how to repair the scheme of Boneh et al., attaining our stronger confidentiality notion. We also show how to extend the scheme to provide integrity, and we prove that it meets our re- encryption indistinguishability notion. Finally, we discuss how to instantiate our scheme efficiently using off-the-shelf cryptographic components (AE, hashing, elliptic curves). We report on the performance of a prototype implementation, showing that fully secure key rotations can be performed at a throughput of approximately 116 kB/s

Topics on modular Galois representations modulo prime powers

This article surveys modularity, level raising and level lowering questions for two-dimensional representations modulo prime powers of the absolute Galois group of the rational numbers. It contributes some new results and describes algorithms and a database of modular forms orbits and higher congruences

Modular forms

Modular forms are functions with an enormous amount of symmetry that play a central role in number theory, connecting it with analysis and geometry. They have played a prominent role in mathematics since the 19th century and their study continues to flourish today. Modular forms formed the inspiration for Langlands' conjectures and play an important role in the description of the cohomology of varieties defined over number fields. This collection of up-to-date articles originated from the conference 'Modular Forms' held on the Island of Schiermonnikoog in the Netherlands. A broad range of topics is covered including Hilbert and Siegel modular forms, Weil representations, Tannakian categories and Torelli's theorem. This book is a good source for all researchers and graduate students working on modular forms or related areas of number theory and algebraic geometry. • Collection of articles by leaders in the field; presents the state of the art in modular forms • Topics covered include Siegel modular forms, Hecke eigenvalues of Hilbert modular forms, Weil representations, Tannakian categories and Torelli’s theorem • Ideal for academic researchers and graduate students in number theory and algebraic geometry; string theorists will also find the collection of interes

The André-Oort conjecture

The André-Oort conjecture is a problem in algebraic geometry from around 1990, with arithmetic, analytic and differential geometric aspects. Klingler, Ullmo and Yafaev, as well as Pila and Tsimerman have now shown that the Generalized Riemann Hypothesis implies the Andr´e-Oort conjecture. Both proofs appeared in the Annals ofMathematics in 2014. In this article Bas Edixhoven and Lenny Taelman describe the conjecture and these recent solutions