פרסומים

It is disconcerting and also alarming that today clinicians are still bewildered and helpless when trying to cope with life-threatening sequelae of severe microbial infections, which very often culminate in sepsis, septic shock and death. According to CDC (the Centers for Disease Control and Prevention), the annual incidence of sepsis in the USA affects as many as 750,000 hospitalized patients and mortality rate is about 40% [1,2]. It was found in 2 complementary inpatient cohorts that up to 50% of hospital deaths were linked to sepsis [3]. Worldwide, sepsis is one of the common deadly diseases. It is one of the few conditions to strike with equal ferocity in resource-poor areas and in the developed world. Globally, 20 to 30 million patients are estimated to be afflicted every year. Every hour, about 1,000 people and each day around 24,000 people die from sepsis worldwide and sepsis is one of the least well known diseases. In the developing world, sepsis accounts for 60-80% of lost lives in childhood, with more than 6 million neonates and children affected by sepsis annually. Sepsis is responsible for >100,000 cases of maternal sepsis each year and in some countries is now a greater threat in pregnancy than bleeding or thromboembolism [4,5]. Screening the voluminous literature on sepsis treatment revealed unsuccessful efforts to save patients’ lives by administering antibiotics but only a signally-chosen antagonist at a time. The numbers of anti-inflammatory agents tested ineffectively over the years is phenomenal (see below) and today even the most promising activated protein C, the “miracle drug” was recently discontinued [6-9]. The initial reactions to infection are generalized pro-and anti-inflammatory responses. These usually starts by activation by microorganisms and some of their products of neutrophils, macrophages and monocytes, which are followed by toxic effects on vascular endothelial cells via pathogen recognition receptors, leading to endothelial disruption. Why have all the therapeutic strategies tested invariably failed to cope with the sequelae of severe microbial infections and what future approaches might break the stalemate leading to a better understanding of the pathophysiology of the "horror autotoxicus" phenomena of sepsis? [10].Reviewing the “glorious history” of medical microbiology revealed that immunoglobulins rich in anti-toxins activities proved very effective to cope with those maladies where a single virulence agent, such as the toxin of diphtheria, tetanus and botulism, are the main pathogenetic virulence agents. Also, anti-viral vaccines are the hallmark of the prevention of many childes viral diseases and of viral hepatitis. On the other hand, no single major virulence factor is identified in the majority of Gram positives Gram negatives, fungal and Mycobacterial pathogens. Therefore, it stands to reason that cell and tissue damage inflicted by these microorganisms may be a result of a coordinated "cross-talk" (synergism) among host factors and a multiplicity of pro-inflammatory agents generated during the proliferation of bacteria, mainly in the blood stream. These may include: extracellular pore-forming and membrane-permeabilizing hemolysins, capsular polysaccharides, LPS (endotoxin), the membrane-associated lipoteichoic acid (LTA), the rigid cell-wall peptidoglycan (PPG), leukocyte-derived oxygen and nitrogen species, anti-microbial cationic peptides, phospholipases, cationic proteinases, growth factors, cytokines and chemokines and many others. All these agents might be generated in various stages of inflammation and infection by microbes and by the host response. Furthermore, certain life-saving antibiotics might also act as "double-edged swords" by enhancing the release of microbial products (LPS, LTA, PPG, capsular polysaccharides, intra cellular toxins), resulting from to the activation of nascent autolytic wall enzymes released leading to bacteriolysis [11,12].

The determination of the absolute configuration of chiral molecules is at the heart of asymmetric synthesis. Here we probe the spectroscopic limits for chiral discrimination with NMR spectroscopy in chiral aligned media and with vibrational circular dichroism spectroscopy of the sixfold-deuterated chiral neopentane. The study of this compound presents formidable challenges since its stereogenicity is only due to small mass differences. For this purpose, we selectively prepared both enantiomers of 2H6-1 through a concise synthesis utilizing multifunctional intermediates. While NMR spectroscopy in chiral aligned media could be used to characterize the precursors to 2H6-1, the final assignment could only be accomplished with VCD spectroscopy, despite the fleetingly small dichroic properties of 1. Both enantiomers were assigned by matching the VCD spectra with those computed with density functional theory.

The determination of the absolute configuration of chiral molecules is at the heart of asymmetric synthesis. Here we probe the spectroscopic limits for chiral discrimination with NMR spectroscopy in chiral aligned media and with vibrational circular dichroism spectroscopy of the sixfold-deuterated chiral neopentane. The study of this compound presents formidable challenges since its stereogenicity is only due to small mass differences. For this purpose, we selectively prepared both enantiomers of ²H₆-1 through a concise synthesis utilizing multifunctional intermediates. While NMR spectroscopy in chiral aligned media could be used to characterize the precursors to ²H₆-1, the final assignment could only be accomplished with VCD spectroscopy, despite the fleetingly small dichroic properties of 1. Both enantiomers were assigned by matching the VCD spectra with those computed with density functional theory.

Disk-shaped nanoparticle aggregates organized in a hierarchical structure in a microphase separated block copolymer were prepared in a two-step process. First, a system comprising of polystyrene-block-poly(2-vinyl pyridine) and a palladium-pincer based surfactant was let to thermally equilibrate, resulting in the formation of structured material with hierarchically distributed concentrations of the palladium precursors. Then, in-situ reduction of the palladium precursors yielded the hierarchically organized nanocomposite. The importance of using an amphiphilic molecule for obtaining the hierarchical arrangement of the nanoparticle aggregates is demonstrated. Hierarchically arranged nanocomposites consisting of shape-controlled nanoparticle aggregates can potentially be useful as photonic materials with unique anisotropic optical response. (C) 2015 Elsevier Ltd. All rights reserved.

Indazoles is an important class of heterocyclic compounds having a wide range of biological and pharmaceutical applications. There is enormous potential in the synthesis of novel heterocyclic systems to be used as building blocks for the next generation of pharmaceuticals as anti-bacterial, anti-depressant and anti-inflammatory. Fused aromatic 1H and 2H-indazoles are well recognized for anti-hypertensive and anti-cancer properties. The present review focuses on novel routes of their synthesis and various biological activities.

Molecules capable of mimicking protein binding and/or functional sites present useful tools for a range of biomedical applications, including the inhibition of protein-ligand interactions. Such mimics of protein binding sites can currently be generated through structure-based design and chemical synthesis. Computational protein design could be further used to optimize protein binding site mimetics through rationally designed mutations that improve intermolecular interactions or peptide stability. Here, as a model for the study, we chose an interaction between human acetylcholinesterase (hAChE) and its inhibitor fasciculin-2 (Fas) because the structure and function of this complex is well understood. Structure-based design of mimics of the hAChE binding site for Fas yielded a peptide that binds to Fas at micromolar concentrations. Replacement of hAChE residues known to be essential for its interaction with Fas with alanine, in this peptide, resulted in almost complete loss of binding to Fas. Computational optimization of the hAChE mimetic peptide yielded a variant with slightly improved affinity to Fas, indicating that more rounds of computational optimization will be required to obtain peptide variants with greatly improved affinity for Fas. CD spectra in the absence and presence of Fas point to conformational changes in the peptide upon binding to Fas. Furthermore, binding of the optimized hAChE mimetic peptide to Fas could be inhibited by hAChE, providing evidence for a hAChE-specific peptide-Fas interaction.

Phage therapy has been proven to be more effective, in some cases, than conventional antibiotics, especially regarding multidrug-resistant biofilm infections. The objective here was to isolate an anti-Enterococcus faecalis bacteriophage and to evaluate its efficacy against planktonic and biofilm cultures. E. faecalis is an important pathogen found in many infections, including endocarditis and persistent infections associated with root canal treatment failure. The difficulty in E. faecalis treatment has been attributed to the lack of anti-infective strategies to eradicate its biofilm and to the frequent emergence of multidrug-resistant strains. To this end, an anti-E. faecalis and E. faecium phage, termed EFDG1, was isolated from sewage effluents. The phage was visualized by electron microscopy. EFDG1 coding sequences and phylogeny were determined by whole genome sequencing (GenBank accession number KP339049), revealing it belongs to the Spounavirinae subfamily of the Myoviridae phages, which includes promising candidates for therapy against Gram-positive pathogens. This analysis also showed that the EFDG1 genome does not contain apparent harmful genes. EFDG1 antibacterial efficacy was evaluated in vitro against planktonic and biofilm cultures, showing effective lytic activity against various E. faecalis and E. faecium isolates, regardless of their antibiotic resistance profile. In addition, EFDG1 efficiently prevented ex vivo E. faecalis root canal infection. These findings suggest that phage therapy using EFDG1 might be efficacious to prevent E. faecalis infection after root canal treatment.

Phage therapy has been proven to be more effective, in some cases, than conventional antibiotics, especially regarding multidrug-resistant biofilm infections. The objective here was to isolate an anti-Enterococcus faecalis bacteriophage and to evaluate its efficacy against planktonic and biofilm cultures. E. faecalis is an important pathogen found in many infections, including endocarditis and persistent infections associated with root canal treatment failure. The difficulty in E. faecalis treatment has been attributed to the lack of anti-infective strategies to eradicate its biofilm and to the frequent emergence of multidrug-resistant strains. To this end, an anti-E. faecalis and E. faecium phage, termed EFDG1, was isolated from sewage effluents. The phage was visualized by electron microscopy. EFDG1 coding sequences and phylogeny were determined by whole genome sequencing (GenBank accession number KP339049), revealing it belongs to the Spounavirinae subfamily of the Myoviridae phages, which includes promising candidates for therapy against Gram-positive pathogens. This analysis also showed that the EFDG1 genome does not contain apparent harmful genes. EFDG1 antibacterial efficacy was evaluated in vitro against planktonic and biofilm cultures, showing effective lytic activity against various E. faecalis and E. faecium isolates, regardless of their antibiotic resistance profile. In addition, EFDG1 efficiently prevented ex vivo E. faecalis root canal infection. These findings suggest that phage therapy using EFDG1 might be efficacious to prevent E. faecalis infection after root canal treatment.

Non-Boolean computations implementing operations on multi-valued variables beyond base 2 allow enhanced computational complexity. We introduce DNA as a functional material for ternary computing, and in particular demonstrate the use of three-valued oligonucleotide inputs to construct a 3 x 3 multiplication table. The system consists of two three-valued inputs of -1; 0; + 1 and a fluorophore/quencher functional hairpin acting as computational and reporter module. The interaction of the computational hairpin module with the different values of the inputs yields a 3 x 3 multiplication matrix consisting of nine nanostructures that are read out by three distinct fluorescence intensities. By combining three different hairpin computational modules, each modified with a different fluorophore/quencher pair, and using different sets of inputs, the parallel operation of three multiplication tables is demonstrated.