19 research outputs found
Structural Basis of Outstanding Multivalent Effects in Jack Bean α-Mannosidase Inhibition
Multivalent design of glycosidase inhibitors is a promising strategy for the treatment of diseases involving enzymatic hydrolysis of glycosidic bonds in carbohydrates. An essential prerequisite for successful applications is the atomicâlevel understanding of how outstanding binding enhancement occurs with multivalent inhibitors. Herein we report the first highâresolution crystal structures of the Jack bean αâmannosidase (JBαâman) in apo and inhibited states. The threeâdimensional structure of JBαâman in complex with the multimeric cyclopeptoidâbased inhibitor displaying the largest binding enhancements reported so far provides decisive insight into the molecular mechanisms underlying multivalent effects in glycosidase inhibition.Instituto de FĂsica de LĂquidos y Sistemas BiolĂłgico
A First-Order SCA Resistant AES without Fresh Randomness
Since the advent of Differential Power Analysis (DPA) in the late 1990s protecting embedded devices against Side-Channel Analysis (SCA) attacks has been a major research effort. Even though many different first-order secure masking schemes are available today, when applied to the AES S-box they all require fresh random bits in every evaluation. As the quality criteria for generating random numbers on an embedded device are not well understood, an integrated Random Number Generator (RNG) can be the weak spot of any protected implementation and may invalidate an otherwise secure implementation. We present a new construction based on Threshold Implementations and Changing of the Guards to realize a first-order secure AES with zero per-round randomness. Hence, our design does not need a built-in RNG, thereby enhancing security and reducing the overhead
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Nightside clouds and disequilibrium chemistry on the hot Jupiter WASP-43b
Hot Jupiters are among the best-studied exoplanets, but it is still poorly understood how their chemical composition and cloud properties vary with longitude. Theoretical models predict that clouds may condense on the nightside and that molecular abundances can be driven out of equilibrium by zonal winds. Here we report a phase-resolved emission spectrum of the hot Jupiter WASP-43b measured from 5âÎŒm to 12âÎŒm with the JWSTâs Mid-Infrared Instrument. The spectra reveal a large dayânight temperature contrast (with average brightness temperatures of 1,524â±â35âK and 863â±â23âK, respectively) and evidence for water absorption at all orbital phases. Comparisons with three-dimensional atmospheric models show that both the phase-curve shape and emission spectra strongly suggest the presence of nightside clouds that become optically thick to thermal emission at pressures greater than ~100âmbar. The dayside is consistent with a cloudless atmosphere above the mid-infrared photosphere. Contrary to expectations from equilibrium chemistry but consistent with disequilibrium kinetics models, methane is not detected on the nightside (2Ï upper limit of 1â6âppm, depending on model assumptions). Our results provide strong evidence that the atmosphere of WASP-43b is shaped by disequilibrium processes and provide new insights into the properties of the planetâs nightside clouds. However, the remaining discrepancies between our observations and our predictive atmospheric models emphasize the importance of further exploring the effects of clouds and disequilibrium chemistry in numerical models.Peer reviewe
Nightside clouds and disequilibrium chemistry on the hot Jupiter WASP-43b
Hot Jupiters are among the best-studied exoplanets, but it is still poorly
understood how their chemical composition and cloud properties vary with
longitude. Theoretical models predict that clouds may condense on the nightside
and that molecular abundances can be driven out of equilibrium by zonal winds.
Here we report a phase-resolved emission spectrum of the hot Jupiter WASP-43b
measured from 5-12 m with JWST's Mid-Infrared Instrument (MIRI). The
spectra reveal a large day-night temperature contrast (with average brightness
temperatures of 152435 and 86323 Kelvin, respectively) and evidence
for water absorption at all orbital phases. Comparisons with three-dimensional
atmospheric models show that both the phase curve shape and emission spectra
strongly suggest the presence of nightside clouds which become optically thick
to thermal emission at pressures greater than ~100 mbar. The dayside is
consistent with a cloudless atmosphere above the mid-infrared photosphere.
Contrary to expectations from equilibrium chemistry but consistent with
disequilibrium kinetics models, methane is not detected on the nightside
(2 upper limit of 1-6 parts per million, depending on model
assumptions).Comment: 61 pages, 13 figures, 4 tables. This preprint has been submitted to
and accepted in principle for publication in Nature Astronomy without
significant change
Nightside clouds and disequilibrium chemistry on the hot Jupiter WASP-43b
Hot Jupiters are among the best-studied exoplanets, but it is still poorly understood how their chemical composition and cloud properties vary with longitude. Theoretical models predict that clouds may condense on the nightside and that molecular abundances can be driven out of equilibrium by zonal winds. Here we report a phase-resolved emission spectrum of the hot Jupiter WASP-43b measured from 5-12 ÎŒm with JWST's Mid-Infrared Instrument (MIRI). The spectra reveal a large day-night temperature contrast (with average brightness temperatures of 1524±35 and 863±23 Kelvin, respectively) and evidence for water absorption at all orbital phases. Comparisons with three-dimensional atmospheric models show that both the phase curve shape and emission spectra strongly suggest the presence of nightside clouds which become optically thick to thermal emission at pressures greater than ~100 mbar. The dayside is consistent with a cloudless atmosphere above the mid-infrared photosphere. Contrary to expectations from equilibrium chemistry but consistent with disequilibrium kinetics models, methane is not detected on the nightside (2Ï upper limit of 1-6 parts per million, depending on model assumptions)
Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs
Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population
Bambus[4,6]urils as Dual Scaffolds for Multivalent Iminosugar Presentation and Ion Transport: Access to Unprecedented Glycosidase-Directed Anion Caging Agents
Bambusurils, BU[4] and BU[6], were used for the first time as multivalent scaffolds to link glycosidases inhibitors derived from 1-deoxynojirimycin (DNJ). Two linear DNJ ligands having six or nine carbon alkyl azido linkers or a trivalent DNJ dendron were grafted onto octapropargylated BU[4] and dodecapropargylated BU[6] using copper-catalyzed cycloaddition (CuAAC) to yield corresponding neoglycobambus[4] and neoglycobambus[6]urils bearing 8 to 24 iminosugars. The inhibition potencies of neoglycoBU[4], neoglycoBU[6] and neoglycoBU[6] caging anions were evaluated against Jack Bean α-mannosidase and compared to monovalent DNJ derivatives. Strong affinity enhancements per inhibitory head were obtained for the clusters holding trivalent dendrons with inhibitory constants in the nanomolar range (Ki = 24 nM for BU[4] with 24 DNJ units). Interestingly, the anion (bromide or iodide) encapsulated inside the cavity of BU[6] does not modify the inhibition potency of neoglycoBU[6], opening the way to water-soluble glycosidase-directed anion caging agents that may find applications in important fields such as bio(in)organic chemistry or oncology
Hybrid Multivalent Jack Bean α-Mannosidase Inhibitors: The First Example of Gold Nanoparticles Decorated with Deoxynojirimycin Inhitopes
Among carbohydrate-processing enzymes, Jack bean α-mannosidase (JBα-man) is the glycosidase with the best responsiveness to the multivalent presentation of iminosugar inhitopes. We report, in this work, the preparation of water dispersible gold nanoparticles simultaneously coated with the iminosugar deoxynojirimycin (DNJ) inhitope and simple monosaccharides (ÎČ-d-gluco- or α-d-mannosides). The display of DNJ at the gold surface has been modulated (i) by using an amphiphilic linker longer than the aliphatic chain used for the monosaccharides and (ii) by presenting the inhitope, not only in monomeric form, but also in a trimeric fashion through combination of a dendron approach with glyconanotechnology. The latter strategy resulted in a strong enhancement of the inhibitory activity towards JBα-man, with a Ki in the nanomolar range (Ki = 84 nM), i.e., more than three orders of magnitude higher than the monovalent reference compound
Structural Basis of Outstanding Multivalent Effects in Jack Bean α-Mannosidase Inhibition
Multivalent design of glycosidase inhibitors is a promising strategy for the treatment of diseases involving enzymatic hydrolysis of glycosidic bonds in carbohydrates. An essential prerequisite for successful applications is the atomic-level understanding of how outstanding binding enhancement occurs with multivalent inhibitors. Herein we report the first high-resolution crystal structures of the Jack bean α-mannosidase (JBα-man) in apo and inhibited states. The three-dimensional structure of JBα-man in complex with the multimeric cyclopeptoid-based inhibitor displaying the largest binding enhancements reported so far provides decisive insight into the molecular mechanisms underlying multivalent effects in glycosidase inhibition
Construction of giant glycosidase inhibitors from iminosugar-substituted fullerene macromonomers
An ultra-fast synthetic procedure based on grafting of twelve fullerene macromonomers onto a fullerene hexa-adduct core was used for the preparation of a giant molecule with 120 peripheral iminosugar residues. The inhibition profile of this giant iminosugar ball was evaluated against various glycosidases. In the particular case of the Jack bean α-mannosidase, a dramatic enhancement of the glycosidase inhibitory effect was observed for the giant molecule with 120 peripheral subunits as compared to that of the corresponding mono- and dodecavalent model compounds.We acknowledge the financial support from the Spanish Ministerio de EconomĂa y Competitividad (MINECO; contracts SAF2016-76083-R and CTQ2015-64425-C2-1-R), the Junta de AndalucĂa (contract FQM2012-1467), the CITIUS, the Biomolecular Interactions Platform (CicCartuja), the CNRS, the University of Strasbourg, the International Center for Frontier Research in Chemistry and the LabEx âChimie des SystĂšmes Complexesâ