Hydroxamic acids as potent inhibitors of Fe(II) and Mn(II) E. coli methionine aminopeptidase: biological activities and X-ray structures of oxazole hydroxamate-EcMetAP-Mn complexes

New series of acids and hydroxamic acids linked to five-membered heterocycles including furan, oxazole, 1,2,4- or 1,3,4-oxadiazole, and imidazole were synthesized and tested as inhibitors against the Fe(II) , Co(II) , and Mn(II) forms of E. coli methionine aminopeptidase (MetAP) and as antibacterial agents against wild-type and acrAB E. coli strains. 2-Aryloxazol-4-ylcarboxylic acids appeared as potent and selective inhibitors of the Co(II) MetAP form, with IC(50) values in the micromolar range, whereas 5-aryloxazol-2-ylcarboxylic acid regioisomers and 5-aryl-1,2,4-oxadiazol-3-ylcarboxylic acids were shown to be inefficient against all forms of EcMetAP. Regardless of the heterocycle, all the hydroxamic acids are highly potent inhibitors and are selective for the Mn(II) and Fe(II) forms, with IC(50) values between 1 and 2 μM. One indole hydroxamic acid that we previously reported as a potent inhibitor of E. coli peptide deformylase also demonstrated efficiency against EcMetAP. To gain insight into the positioning of the oxazole heterocycle with reversed substitutions at positions 2 and 5, X-ray crystal structures of EcMetAP-Mn complexed with two such oxazole hydroxamic acids were solved. Irrespective of the [metal]/[apo-MetAP] ratio, the active site consistently contains a dinuclear manganese center, with the hydroxamate as bridging ligand. Asp 97, which adopts a bidentate binding mode to the Mn2 site in the holoenzyme, is twisted in both structures toward the hydroxamate bridging ligand to favor the formation of a strong hydrogen bond. Most of the compounds show weak antibacterial activity against a wild-type E. coli strain. However, increased antibacterial activity was observed mainly for compounds with a 2-substituted phenyl group in the presence of the nonapeptide polymyxin B and phenylalanine-arginine-β-naphthylamide as permeabilizer and efflux pump blocker, respectively, which boost the intracellular uptake of the inhibitors.     

Synchronization in networks of identical linear systems

The paper investigates the synchronization of a network of identical linear state-space models under a possibly time-varying and directed interconnection structure. The main result is the construction of a dynamic output feedback coupling that achieves synchronization if the decoupled systems have no exponentially unstable mode and if the communication graph is uniformly connected. The result can be interpreted as a generalization of classical consensus algorithms. Stronger conditions are shown to be sufficient–but to some extent, also necessary–to ensure synchronization with the diffusive static output coupling often considered in the literature.     

Autonomous rigid body attitude synchronization

Control laws to synchronize attitudes in a swarm of fully actuated rigid bodies, in the absence of a common reference attitude or hierarchy in the swarm, are proposed in [Smith, T. R., Hanssmann, H., & Leonard, N.E. (2001). Orientation control of multiple underwater vehicles with symmetry-breaking potentials. In Proc. 40th IEEE conf. decision and control (pp. 4598-4603); Nair, S., Leonard, N. E. (2007). Stable synchronization of rigid body networks. Networks and Heterogeneous Media, 2(4), 595-624]. The present paper studies two separate extensions with the same energy shaping approach: (i) locally synchronizing the rigid bodies’ attitudes, but without restricting their final motion and (ii) relaxing the communication topology from undirected, fixed and connected to directed, varying and uniformly connected. The specific strategies that must be developed for these extensions illustrate the limitations of attitude control with reduced information.     

The Leukotriene Receptor Antagonist Montelukast Attenuates Neuroinflammation and Affects Cognition in Transgenic 5xFAD Mice

Alzheimer’s disease (AD) is the most common form of dementia. In particular, neuroinflammation, mediated by microglia cells but also through CD8+ T-cells, actively contributes to disease pathology. Leukotrienes are involved in neuroinflammation and in the pathological hallmarks of AD. In consequence, leukotriene signaling—more specifically, the leukotriene receptors—has been recognized as a potential drug target to ameliorate AD pathology. Here, we analyzed the effects of the leukotriene receptor antagonist montelukast (MTK) on hippocampal gene expression in 5xFAD mice, a commonly used transgenic AD mouse model. We identified glial activation and neuroinflammation as the main pathways modulated by MTK. The treatment increased the number of Tmem119+ microglia and downregulated genes related to AD-associated microglia and to lipid droplet-accumulating microglia, suggesting that the MTK treatment targets and modulates microglia phenotypes in the disease model compared to the vehicle. MTK treatment further reduced infiltration of CD8+T-cells into the brain parenchyma. Finally, MTK treatment resulted in improved cognitive functions. In summary, we provide a proof of concept for MTK to be a potential drug candidate for AD and provide novel modes of action via modulation of microglia and CD8+ T-cells. Of note, 5xFAD females showed a more severe pathology, and in consequence, MTK treatment had a more pronounced effect in the females compared to the males. The effects on neuroinflammation, i.e., microglia and CD8+ T-cells, as well as the effects on cognitive outcome, were dose-dependent, therefore arguing for the use of higher doses of MTK in AD clinical trials compared to the approved asthma dose.     

Temperature stability of a pure metakaolin based K-geopolymer: Part 1. Variations in the amorphous mineral network

The thermal behavior of a model MK based K-geopolymer (Si/Al = 1.38 and K/Al = 0.68; obtained by alkaline activation of a very pure metakaolin) was investigated between room temperature and 1400°C in order to evaluate its potentiality for high-temperature applications. The purpose of our study was to monitor the behavior of a geopolymer during a temperature rise in order to better understand its variations with respect to temperature. The works from the present paper focus only variations in the internal structure of the mineral matrix. The results presented here show that the amorphous mineral matrix is preserved up to 900°C. The results also show that there is a densification of the internal structure of tetrahedral network during heating, due to changes in the Q³ environments in fully-connected Q⁴ for both silicates and aluminates. Thus, our work provides a new more precise vision of the 3D geopolymeric mineral matrix for which the silicoaluminous network is not exclusively composed of Q⁴ entities, contrary to what is frequently encountered in the literature before.     

Minimizing the Two-Round Even–Mansour Cipher

The r-round (iterated) Even–Mansour cipher (also known as key-alternating cipher) defines a block cipher from r fixed public n-bit permutations \(P_1,\ldots ,P_r\) as follows: Given a sequence of n-bit round keys \(k_0,\ldots ,k_r\), an n-bit plaintext x is encrypted by xoring round key \(k_0\), applying permutation \(P_1\), xoring round key \(k_1\), etc. The (strong) pseudorandomness of this construction in the random permutation model (i.e., when the permutations \(P_1,\ldots ,P_r\) are public random permutation oracles that the adversary can query in a black-box way) was studied in a number of recent papers, culminating with the work of Chen and Steinberger (EUROCRYPT 2014), who proved that the r-round Even–Mansour cipher is indistinguishable from a truly random permutation up to \(\mathcal {O}(2^{\frac{rn}{r+1}})\) queries of any adaptive adversary (which is an optimal security bound since it matches a simple distinguishing attack). All results in this entire line of work share the common restriction that they only hold under the assumption that the round keys \(k_0,\ldots ,k_r\) and the permutations \(P_1,\ldots ,P_r\) are independent. In particular, for two rounds, the current state of knowledge is that the block cipher \(E(x)=k_2\oplus P_2(k_1\oplus P_1(k_0\oplus x))\) is provably secure up to \(\mathcal {O}(2^{2n/3})\) queries of the adversary, when \(k_0\), \(k_1\), and \(k_2\) are three independent n-bit keys, and \(P_1\) and \(P_2\) are two independent random n-bit permutations. In this paper, we ask whether one can obtain a similar bound for the two-round Even–Mansour cipher from just one n-bit key and one n-bit permutation. Our answer is positive: When the three n-bit round keys \(k_0\), \(k_1\), and \(k_2\) are adequately derived from an n-bit master key k, and the same permutation P is used in place of \(P_1\) and \(P_2\), we prove a qualitatively similar \(\widetilde{\mathcal {O}}(2^{2n/3})\) security bound (in the random permutation model). To the best of our knowledge, this is the first “beyond the birthday bound” security result for AES-like ciphers that does not assume independent round keys.     

Modeling of an Inductively Coupled Plasma for the Synthesis of Nanoparticles

Among other methods, inductively coupled plasma (ICP) torches can be used for the synthesis of nanoparticles. In this process, the precursor material is vaporized in the first step in the plasma core. In the second step, nucleation and condensation occur in the synthesis chamber where the plasma gets colder and high-purity nanoparticles are synthesized, the growth of which is stopped by gas quenching. From their low velocity and high temperature, induction plasmas are particularly adapted for this application. Numerical modeling is a good way to achieve a better knowledge and understanding of the process since non-intrusive diagnostics are fairly difficult to implement. In the present article, a two-dimensional model of an ICP torch was developed and validated on the basis of comparisons with data obtained by some other authors. Finally, the current frequency (13.56 MHz), pressure level (0.04 MPa), and gas flow rates were adjusted for the specific conditions of nanoparticles synthesis. This article is an invited paper selected from presentations at the 2007 International Thermal Spray Conference and has been expanded from the original presentation. It is simultaneously published in Global Coating Solutions, Proceedings of the 2007 International Thermal Spray Conference, Beijing, China, May 14-16, 2007, Basil R. Marple, Margaret M. Hyland, Yuk-Chiu Lau, Chang-Jiu Li, Rogerio S. Lima, and Ghislain Montavon, Ed., ASM International, Materials Park, OH, 2007.     

Infrared multiphoton dissociation tandem charge detection-mass spectrometry of single megadalton electrosprayed ions

This work presents the implementation of tandem mass spectrometry for experiments on single electrosprayed ions from compounds of megadalton (MDa) molecular weight, using two charge detection devices. The first mass spectrometry stage (first charge detection device) combined with an ion gate allows both mass-to-charge ratio and charge selections of the megadalton ion of interest. The second stage is based on an electrostatic ion trap and consists of an image charge detection tube mounted between two ion mirrors. Single MDa ions can be stored for several dozen milliseconds. During the trapping time, single ions can be irradiated by a continuous wavelength CO(2) laser. We observe stepwise changes in the charge of a single trapped ion owing to multiphoton activation. Illustration of infrared multiphoton dissociation tandem mass spectrometry are given for single megadalton ions of poly(ethylene oxide)s and DNAs.     

On global optimization articles in SMO

Recent discussions in the editorial committee of the SMO Journal, following a forum article (Sigmund, Struct Multidisc Optim 43(5):589–596, 2011) on non-gradient methods in topology optimization, have shown that an analysis of global optimization contributions to SMO might be useful.