Structure–Activity Relationships in NHC–Silver Complexes as Antimicrobial Agents

: Silver has a long history of antimicrobial activity and received an increasing interest in last decades owing to the rise in antimicrobial resistance. The major drawback is the limited duration of its antimicrobial activity. The broad-spectrum silver containing antimicrobial agents are well represented by N-heterocyclic carbenes (NHCs) silver complexes. Due to their stability, this class of complexes can release the active Ag+ cations in prolonged time. Moreover, the properties of NHC can be tuned introducing alkyl moieties on N-heterocycle to provide a range of versatile structures with different stability and lipophilicity. This review presents designed Ag complexes and their biological activity against Gram-positive, Gram-negative bacteria and fungal strains. In particular, the structure-activity relationships underlining the major requirements to increase the capability to induce microorganism death are highlighted here. Moreover, some examples of encapsulation of silver-NHC complexes in polymer-based supramolecular aggregates are reported. The targeted delivery of silver complexes to the infected sites will be the most promising goal for the future

NMR Structure and CD Titration with Metal Cations of Human Prion α2-Helix-Related Peptides

The 173–195 segment corresponding to the helix 2 of the C-globular prion protein domain could be one of several “spots” of intrinsic conformational flexibility. In fact, it possesses chameleon conformational behaviour and gathers several disease-associated point mutations. We have performed spectroscopic studies on the wild-type fragment 173–195 and on its D178N mutant dissolved in trifluoroethanol to mimic the in vivo system, both in the presence and in the absence of metal cations. NMR data showed that the structure of the D178N mutant is characterized by two short helices separated by a kink, whereas the wild-type peptide is fully helical. Both peptides retained these structural organizations, as monitored by CD, in the presence of metal cations. NMR spectra were however not in favour of the formation of definite ion-peptide complexes. This agrees with previous evidence that other regions of the prion protein are likely the natural target of metal cation binding

Reactivity of S- or Se- containing model peptides with environmental relevant Hg ions: LC-MS/MS study

Selenium (Se) is an essential element being present in the form of the naturally occurring amino acid selenocysteine (Sec), 25 human proteins involved in different cellular pathways contain Sec. As the most potent intracellular soft Lewis base, selenocysteine (SeCys) is able to bind electron poor soft acids as heavy metals, of awareness for environmental and human toxicology, Hg ions bind Se by means of higher equilibrium constants than sulfur (ca. 106 times), therefore these values compensate the lower cellular abundance (105 times) of selenols compared to thiols[2]. In this communication we present a comparative reactivity study of Hg(I) and Hg(II) compounds with model peptides: vasopressin (AVP) hormone with antidiuretic and vasopressor actions and its Sec containing analogs. These peptides were synthesized either by standard solid phase peptide Fmoc or Boc protocols. The metal ion interaction with these peptides was investigated by RP- LC coupled with electrospray MS/MS detection (LC-MS/MS). We observed mono, bis and bridged peptide metallations as detailed in the Scheme. Taking into consideration the stability of Se-Hg bonds, our results support the hypothesis of a binding preference of Hg to Sec residues in selenoproteins

Conformational Ensembles Explored Dynamically from Disordered Peptides Targeting Chemokine Receptor CXCR4

This work reports on the design and the synthesis of two short linear peptides both containing a few amino acids with disorder propensity and an allylic ester group at the C-terminal end. Their structural properties were firstly analyzed by means of experimental techniques in solution such as CD and NMR methods that highlighted peptide flexibility. These results were further confirmed by MD simulations that demonstrated the ability of the peptides to assume conformational ensembles. They revealed a network of transient and dynamic H-bonds and interactions with water molecules. Binding assays with a well-known drug-target, i.e., the CXCR4 receptor, were also carried out in an attempt to verify their biological function and the possibility to use the assays to develop new specific targets for CXCR4. Moreover, our data indicate that these peptides represent useful tools for molecular recognition processes in which a flexible conformation is required in order to obtain an interaction with a specific target

Intrinsically disordered amphiphilic peptides as potential targets in drug delivery vehicles

Intrinsically disordered proteins/peptides play a crucial role in many physiological and pathological events and may assume a precise conformation upon binding to a specific target. Recently, we have described the conformational and functional properties of two linear ester peptides provided with the following sequences: Y-G-E-C-P-C-K-OAllyl (PepK) and Y-G-E-C-P-C-E-OAllyl (PepE). Both peptides are characterized by the presence of the ‘‘CPC’’ motif together with a few amino acids able to promote disorder. The CPC sequence is a binding motif for the CXCR4 receptor that represents a well-known target for cancer therapies. In this paper, we report on synthetic amphiphilic peptides that consist of lipophilic derivatives of PepE and PepK bearing two stearic alkyl chains and/or an ethoxylic spacer. These peptide amphiphiles form stable supramolecular aggregates; they present conformational features that are typical of intrinsically disordered molecules as shown by CD spectroscopy. Solution fluorescence and DLS studies have been performed to evaluate Critical Micellar Concentrations and the dimension of supramolecular aggregates. Moreover, preliminary in vitro cell-based assays have been conducted to investigate the molecular recognition processes involving the CXCR4 receptor. In the end, the results obtained have been compared with the previous data generated by the corresponding non-amphiphilic peptides (PepE and PepK)

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Juxtaposing BTE and ATE – on the role of the European insurance industry in funding civil litigation

One of the ways in which legal services are financed, and indeed shaped, is through private insurance arrangement. Two contrasting types of legal expenses insurance contracts (LEI) seem to dominate in Europe: before the event (BTE) and after the event (ATE) legal expenses insurance. Notwithstanding institutional differences between different legal systems, BTE and ATE insurance arrangements may be instrumental if government policy is geared towards strengthening a market-oriented system of financing access to justice for individuals and business. At the same time, emphasizing the role of a private industry as a keeper of the gates to justice raises issues of accountability and transparency, not readily reconcilable with demands of competition. Moreover, multiple actors (clients, lawyers, courts, insurers) are involved, causing behavioural dynamics which are not easily predicted or influenced. Against this background, this paper looks into BTE and ATE arrangements by analysing the particularities of BTE and ATE arrangements currently available in some European jurisdictions and by painting a picture of their respective markets and legal contexts. This allows for some reflection on the performance of BTE and ATE providers as both financiers and keepers. Two issues emerge from the analysis that are worthy of some further reflection. Firstly, there is the problematic long-term sustainability of some ATE products. Secondly, the challenges faced by policymakers that would like to nudge consumers into voluntarily taking out BTE LEI

Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan

This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good

Search for stop and higgsino production using diphoton Higgs boson decays

Results are presented of a search for a "natural" supersymmetry scenario with gauge mediated symmetry breaking. It is assumed that only the supersymmetric partners of the top-quark (stop) and the Higgs boson (higgsino) are accessible. Events are examined in which there are two photons forming a Higgs boson candidate, and at least two b-quark jets. In 19.7 inverse femtobarns of proton-proton collision data at sqrt(s) = 8 TeV, recorded in the CMS experiment, no evidence of a signal is found and lower limits at the 95% confidence level are set, excluding the stop mass below 360 to 410 GeV, depending on the higgsino mass