Designing Dual Transglutaminase 2/Histone Deacetylase Inhibitors Effective at Halting Neuronal Death

In recent years there has been a clear consensus that neurodegenerative conditions can be better treated through concurrent modulation of different targets. Herein we report that combined inhibition of transglutaminase 2 (TG2) and histone deacetylases (HDACs) synergistically protects against toxic stimuli mediated by glutamate. Based on these findings, we designed and synthesized a series of novel dual TG2–HDAC binding agents. Compound 3 [(E)‐N‐hydroxy‐5‐(3‐(4‐(3‐oxo‐3‐(pyridin‐3‐yl)prop‐1‐en‐1‐yl)phenyl)thioureido)pentanamide] emerged as the most interesting of the series, being able to inhibit TG2 and HDACs both in vitro (TG2 IC₅₀=13.3±1.5 μm , HDAC1 IC₅₀=3.38±0.14 μm , HDAC6 IC₅₀=4.10±0.13 μm ) and in cell‐based assays. Furthermore, compound 3 does not exert any toxic effects in cortical neurons up to 50 μm and protects neurons against toxic insults induced by glutamate (5 mm ) with an EC₅₀ value of 3.7±0.5 μm .     

Mono and Bifunctional Catalysts for Styrene Oxide Isomerization or Hydrogenation

Abstract  

Styrene oxide can be effectively isomerized to phenyl-acetaldehyde (98%) over amorphous silica alumina catalysts under very mild liquid phase conditions. On the other hand, a copper catalyst prepared using a silica zirconia support gave up to 80% yield in the hydrogenation of styrene oxide to 2-phenyl-ethanol.     

Expression of urokinase plasminogen activator receptor in resting and activated bovine neutrophils

Changes in urokinase-plasminogen activator (u-PA) and u-PA receptor (u-PAR) expression at the protein and mRNA level in resting neutrophils and in neutrophils activated by phorbol myristate acetate (PMA) were examined. Low amounts of u-PA were found intracellularly or membrane-bound in resting neutrophils. However, incubation of resting neutrophils with purified exogenous u-PA (10 IU/ml) revealed extensive binding of u-PA to cell membranes. Excess amino-terminal fragment of the u-PA molecule, a proteolytically inactive fragment of u-PA (amino acids 1-135) blocked binding of exogenous u-PA to the cell membrane. These results, collectively, indicate that the binding of u-PA is specific and that resting neutrophils have unoccupied u-PA receptors on their cell membrane. Addition of PMA led to an increase (P < 0.01) in total cell-associated, membrane-bound u-PA activity and u-PA mRNA expression by bovine neutrophils. In contrast. PMA increased u-PAR mRNA levels but this was accompanied by a decrease (2.5-fold; P < 0.01) in free, unoccupied u-PA binding sites. No significant effects on total cell-associated or membrane-bound u-PA were found when neutrophils were treated with 4-phorbol 12,13 didecanoate, a phorbol ester that does not activate protein kinase C (PKC). Furthermore, addition of 1-(5-isoquinolinesylphonyl)-2-methlylpiperazine dihydrochloride (H-7), a potent PKC inhibitor, blocked the effect of PMA on total cell-associated u-PA activity. Thus, PKC plays a role in the modulation of u-PA and u-PAR by PMA in bovine neutrophils.     

Characterization of microstructured optical fibers for wideband dispersion compensation

Microstructured optical fibers (MOFs) with small hole-to-hole spacing and large airholes are designed to compensate the anomalous dispersion and the dispersion slope of single-mode fibers. The geometrical parameters that characterize triangular MOFs are chosen to optimize the fiber length and the compensation over a wide wavelength range. A proper design of the photonic crystal fiber geometry allows us to achieve dispersion values of approximately -1700 ps nm(-1) km(-1) at 1550 nm and to compensate the dispersion of standard fibers within +/- 0.5 ps nm(-1) km(-1) over a 100-nm range. The MOF dispersion properties have been studied by means of a numerical simulator for modal analysis based on the finite-element method.     

Role of NEU3 Overexpression in the Prediction of Efficacy of EGFR-Targeted Therapies in Colon Cancer Cell Lines

The epidermal growth factor receptor (EGFR), through the MAP kinase and PI3K-Akt-mTOR axis, plays a pivotal role in colorectal cancer (CRC) pathogenesis. The membrane-associated NEU3 sialidase interacts with and desialylates EGFR by promoting its dimerization and downstream effectors’ activation. Among the targeted therapies against EGFR, the monoclonal antibody cetuximab is active only in a subgroup of patients not carrying mutations in the MAP kinase pathway. In order to better understand the EGFR-NEU3 interplay and the mechanisms of pharmacological resistance, we investigated the role of NEU3 deregulation in cetuximab-treated CRC cell lines transiently transfected with NEU3 using Western blot analysis. Our results indicate that NEU3 overexpression can enhance EGFR activation only if EGFR is overexpressed, indicating the existence of a threshold for NEU3-mediated EGFR activation. This enhancement mainly leads to the constitutive activation of the MAP kinase pathway. Consequently, we suggest that the evaluation of NEU3 expression cannot entirely substitute the evaluation of EGFR because EGFR-negative cases cannot be stimulated by NEU3. Furthermore, NEU3-mediated hyperactivation of EGFR is counterbalanced by the administration of cetuximab, hypothesizing that a combined treatment of NEU3- and EGFR-targeted therapies may represent a valid option for CRC patients, which must be investigated in the future.     

Implementation of a real option in a sustainable supply chain: an empirical study of alkaline battery recycling

Green supply chain management (GSCM) has emerged as a key approach for enterprises seeking to become environmentally sustainable. This paper aims to evaluate and describe the advantages of a GSCM approach by analysing practices and performance consequences in the battery recycling sector. It seeks to integrate works in supply chain management (SCM), environmental management, performance management and real option (RO) theory into one framework. In particular, life cycle assessment (LCA) is applied to evaluate the environmental impact of a battery recycling plant project, and life cycle costing (LCC) is applied to evaluate its economic impact. Firms, also understanding the relevance of GSCM, have often avoided applying the green principles because of the elevated costs that such management involved. Such costs could also seem superior to the potential advantages since standard performance measurement systems are internally and business focused; for these reasons, we consider all the possible value deriving also by uncertainty associated to a green project using the RO theory. This work is one of the few and pioneering efforts to investigate GSCM practices in the battery recycling sector.     

Enhancing cultural recommendations through social and linked open data

In this article, we describe a hybrid recommender system (RS) in the artistic and cultural heritage area, which takes into account the activities on social media performed by the target user and her friends, and takes advantage of linked open data (LOD) sources. Concretely, the proposed RS (1) extracts information from Facebook by analyzing content generated by users and their friends; (2) performs disambiguation tasks through LOD tools; (3) profiles the active user as a social graph; (4) provides her with personalized suggestions of artistic and cultural resources in the surroundings of the user’s current location. The last point is performed by integrating collaborative filtering algorithms with semantic technologies in order to leverage LOD sources such as DBpedia and Europeana. Based on the recommended points of cultural interest, the proposed system is also able to suggest to the active user itineraries among them, which meet her preferences and needs and are sensitive to her physical and social contexts as well. Experimental results on real users showed the effectiveness of the different modules of the proposed recommender.

     

Easy detectable isocyanate in the reaction with gelatin

Gelatin reactivity with isocyanate was studied by using the easy detectable 1-naphthyl-isocyanate (NphI). Four different NphI/gelatin feed ratios were investigated with NphI molar amount ranging between 1/10 and 1/1 with respect to the possible reactive groups of gelatin. The reactions were carried out at 45 °C in DMSO as solvent, under nitrogen atmosphere. Modified gelatin samples were characterized by IR, UV–VIS, fluorescence spectroscopies as well as by proton and DOSY NMR. Spectroscopy results allow to evidence the presence of both bonded and unbonded naphthyl derivatives in the gelatin samples. Unbonded species were present particularly at the highest NphI/gelatin feed ratio and their formation was correlated to the increasing competition of the reaction with water since the amount of available reactive groups on gelatin was comparable or smaller than the amount of residuum water in dry gelatin.     

An IR molding system for direct shaping of thermoplastics

A new molding technique is proposed to directly mold small parts from thermoplastic pellets. A small molding machine was designed and fabricated: the mold consisted of a transparent glass and a metallic frame; an infrared (IR) lamp provided the heat for the pellet melting. Molding tests were carried out by using three commercial thermoplastics and two metallic molds. Molding time and IR lamp power were changed to extract a moldability window for each combination of material and metallic mold. In the best process conditions, a high quality of the samples was obtained in terms of mold filling and surface aesthetics. POLYM. ENG. SCI., 2010. © 2010 Society of Plastics Engineers     

Potential Mechanisms Linking Atherosclerosis and Increased Cardiovascular Risk in COPD: Focus On Sirtuins

The development of atherosclerosis is a multi-step process, at least in part controlled by the vascular endothelium function. Observations in humans and experimental models of atherosclerosis have identified monocyte recruitment as an early event in atherogenesis. Chronic inflammation is associated with ageing and its related diseases (e.g., atherosclerosis and chronic obstructive pulmonary disease). Recently it has been discovered that Sirtuins (NAD⁺-dependent deacetylases) represent a pivotal regulator of longevity and health. They appear to have a prominent role in vascular biology and regulate aspects of age-dependent atherosclerosis. Many studies demonstrate that SIRT1 exhibits anti-inflammatory properties in vitro (e.g., fatty acid-induced inflammation), in vivo (e.g., atherosclerosis, sustainment of normal immune function in knock-out mice) and in clinical studies (e.g., patients with chronic obstructive pulmonary disease). Because of a significant reduction of SIRT1 in rodent lungs exposed to cigarette smoke and in lungs of patients with chronic obstructive pulmonary disease (COPD), activation of SIRT1 may be a potential target for chronic obstructive pulmonary disease therapy. We review the inflammatory mechanisms involved in COPD-CVD coexistence and the potential role of SIRT1 in the regulation of these systems.