Reversal of β cell de-differentiation by a small molecule inhibitor of the TGFβ pathway

Dysfunction or death of pancreatic β cells underlies both types of diabetes. This functional decline begins with β cell stress and de-differentiation. Current drugs for type 2 diabetes (T2D) lower blood glucose levels but they do not directly alleviate β cell stress nor prevent, let alone reverse, β cell de-differentiation. We show here that Urocortin 3 (Ucn3), a marker for mature β cells, is down-regulated in the early stages of T2D in mice and when β cells are stressed in vitro. Using an insulin expression-coupled lineage tracer, with Ucn3 as a reporter for the mature β cell state, we screen for factors that reverse β cell de-differentiation. We find that a small molecule inhibitor of TGFβ receptor I (Alk5) protects cells from the loss of key β cell transcription factors and restores a mature β cell identity even after exposure to prolonged and severe diabetes. DOI: http://dx.doi.org/10.7554/eLife.02809.00

Evidence for microbial iron reduction in the methanic sediments of the oligotrophic southeastern Mediterranean continental shelf

© The Author(s), 2019. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Vigderovich, H., Liang, L., Herut, B., Wang, F., Wurgaft, E., Rubin-Blum, M., & Sivan, O. Evidence for microbial iron reduction in the methanic sediments of the oligotrophic southeastern Mediterranean continental shelf. Biogeosciences, 16(16), (2019): 3165-3181, doi: 10.5194/bg-16-3165-2019.Dissimilatory iron reduction is probably one of the oldest types of metabolisms that still participates in important biogeochemical cycles, such as those of carbon and sulfur. It is one of the more energetically favorable anaerobic microbial respiration processes and is usually coupled to the oxidation of organic matter. Traditionally this process is thought to be limited to the shallow part of the sedimentary column in most aquatic systems. However, iron reduction has also been observed in the methanic zone of many marine and freshwater sediments, well below its expected zone and occasionally accompanied by decreases in methane, suggesting a link between the iron and the methane cycles. Nevertheless, the mechanistic nature of this link (competition, redox or other) has yet to be established and has not been studied in oligotrophic shallow marine sediments. In this study we present combined geochemical and molecular evidences for microbial iron reduction in the methanic zone of the oligotrophic southeastern (SE) Mediterranean continental shelf. Geochemical porewater profiles indicate iron reduction in two zones, the uppermost part of the sediment, and the deeper zone, in the layer of high methane concentration. Results from a slurry incubation experiment indicate that the deep methanic iron reduction is microbially mediated. The sedimentary profiles of microbial abundance and quantitative PCR (qPCR) of the mcrA gene, together with Spearman correlation between the microbial data and Fe(II) concentrations in the porewater, suggest types of potential microorganisms that may be involved in the iron reduction via several potential pathways: H2 or organic matter oxidation, an active sulfur cycle, or iron-driven anaerobic oxidation of methane. We suggest that significant upward migration of methane in the sedimentary column and its oxidation by sulfate may fuel the microbial activity in the sulfate methane transition zone (SMTZ). The biomass created by this microbial activity can be used by the iron reducers below, in the methanic zone of the sediments of the SE Mediterranean.This study was supported by the joint grant of Israel Science Foundation and the National Natural Science Foundation of China (ISF-NSFC) (grant numbers 31661143022 (FW) and 2561/16 (OS)). Funding was provided to Hanni Vigderovich by the Mediterranean Sea Research Center of Israel

CDK2 limits the highly energetic secretory program of mature β cells by restricting PEP cycle-dependent KATP channel closure.

Hallmarks of mature β cells are restricted proliferation and a highly energetic secretory state. Paradoxically, cyclin-dependent kinase 2 (CDK2) is synthesized throughout adulthood, its cytosolic localization raising the likelihood of cell cycle-independent functions. In the absence of any changes in β cell mass, maturity, or proliferation, genetic deletion of Cdk2 in adult β cells enhanced insulin secretion from isolated islets and improved glucose tolerance in vivo. At the single β cell level, CDK2 restricts insulin secretion by increasing KATP conductance, raising the set point for membrane depolarization in response to activation of the phosphoenolpyruvate (PEP) cycle with mitochondrial fuels. In parallel with reduced β cell recruitment, CDK2 restricts oxidative glucose metabolism while promoting glucose-dependent amplification of insulin secretion. This study provides evidence of essential, non-canonical functions of CDK2 in the secretory pathways of quiescent β cells

Permuted Puzzles and Cryptographic Hardness

A permuted puzzle problem is defined by a pair of distributions $D_0,D_1$ over $S^n$. The problem is to distinguish samples from $D_0,D_1$, where the symbols of each sample are permuted by a single secret permutation $p$ of $[n]$. The conjectured hardness of specific instances of permuted puzzle problems was recently used to obtain the first candidate constructions of Doubly Efficient Private Information Retrieval (DE-PIR) (Boyle et al. & Canetti et al., TCC\u2717). Roughly, in these works the distributions $D_0,D_1$ over $F^n$ are evaluations of either a moderately low-degree polynomial or a random function. This new conjecture seems to be quite powerful, and is the foundation for the first DE-PIR candidates, almost two decades after the question was first posed by Beimel et al. (CRYPTO\u2700). While permuted puzzles are a natural and general class of problems, their hardness is still poorly understood. We initiate a formal investigation of the cryptographic hardness of permuted puzzle problems. Our contributions lie in three main directions: 1. Rigorous formalization. We formalize a notion of permuted puzzle distinguishing problems, extending and generalizing the proposed permuted puzzle framework of Boyle et al. (TCC\u2717). 2. Identifying hard permuted puzzles. We identify natural examples in which a one-time permutation provably creates cryptographic hardness, based on ``standard\u27\u27 assumptions. In these examples, the original distributions $D_0,D_1$ are easily distinguishable, but the permuted puzzle distinguishing problem is computationally hard. We provide such constructions in the random oracle model, and in the plain model under the Decisional Diffie-Hellman (DDH) assumption. We additionally observe that the Learning Parity with Noise (LPN) assumption itself can be cast as a permuted puzzle. 3. Partial lower bound for the DE-PIR problem. We make progress towards better understanding the permuted puzzles underlying the DE-PIR constructions, by showing that a toy version of the problem, introduced by Boyle et al. (TCC\u2717), withstands a rich class of attacks, namely those that distinguish solely via statistical queries

Certifying Trapdoor Permutations, Revisited

The modeling of trapdoor permutations has evolved over the years. Indeed, finding an appropriate abstraction that bridges between the existing candidate constructions and the needs of applications has proved to be challenging. In particular, the notions of certifying permutations (Bellare and Yung, 96), enhanced and doubly enhanced trapdoor permutations (Goldreich, 04, 08, 11, Goldreich and Rothblum, 13) were added to bridge the gap between the modeling of trapdoor permutations and needs of applications. We identify an additional gap in the current abstraction of trapdoor permutations: Previous works implicitly assumed that it is easy to recognize elements in the domain, as well as uniformly sample from it, even for illegitimate function indices. We demonstrate this gap by using the (Bitansky-Paneth-Wichs, 16) doubly-enhanced trapdoor permutation family to instantiate the Feige-Lapidot-Shamir (FLS) paradigm for constructing non-interactive zero-knowledge (NIZK) protocols, and show that the resulting proof system is unsound. To close the gap, we propose a general notion of certifiably injective doubly enhanced trapdoor functions (DECITDFs), which provides a way of certifying that a given key defines an injective function over the domain defined by it, even when that domain is not efficiently recognizable and sampleable. We show that DECITDFs suffice for instantiating the FLS paradigm; more generally, we argue that certifiable injectivity is needed whenever the generation process of the function is not trusted. We then show two very different ways to construct DECITDFs: One is via the traditional method of RSA/Rabin with the Bellare-Yung certification mechanism, and the other using indistinguishability obfuscation and injective pseudorandom generators. In particular the latter is the first candidate injective trapdoor function, from assumptions other than factoring, that suffices for the FLS paradigm. Finally we observe that a similar gap appears also in other paths proposed in the literature for instantiating the FLS paradigm, specifically via verifiable pseudorandom generators and verifiable pseudorandom functions. Closing the gap there can be done in similar ways to the ones proposed here

One-Message Zero Knowledge and Non-Malleable Commitments

We introduce a new notion of one-message zero-knowledge (1ZK) arguments that satisfy a weak soundness guarantee — the number of false statements that a polynomial-time non-uniform adversary can convince the verifier to accept is not much larger than the size of its non-uniform advice. The zero-knowledge guarantee is given by a simulator that runs in (mildly) super-polynomial time. We construct such 1ZK arguments based on the notion of multi-collision-resistant keyless hash functions, recently introduced by Bitansky, Kalai, and Paneth (STOC 2018). Relying on the constructed 1ZK arguments, subexponentially-secure time-lock puzzles, and other standard assumptions, we construct one-message fully-concurrent non-malleable commitments. This is the first construction that is based on assumptions that do not already incorporate non-malleability, as well as the first based on (subexponentially) falsifiable assumptions

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal