Design,Synthesis, and Biological Evaluation of Tetrahydro‐β‐carboline Derivatives as Selective Sub‐Nanomolar Gelatinase Inhibitors

Targeting matrix metalloproteinases (MMPs) is a pursued strategy for treating several pathological conditions, such as multiple sclerosis and cancer. Herein, a series of novel tetrahydro‐β‐carboline derivatives with outstanding inhibitory activity toward MMPs are present. In particular, compounds 9 f , 9 g , 9 h and 9 i show sub‐nanomolar IC₅₀ values. Interestingly, compounds 9 g and 9 i also provide remarkable selectivity toward gelatinases; IC₅₀=0.15 nm for both toward MMP‐2 and IC₅₀=0.63 and 0.58 nm , respectively, toward MMP‐9. Molecular docking simulations, performed by employing quantum mechanics based partial charges, shed light on the rationale behind binding involving specific interactions with key residues of S1′ and S3′ domains. Taken together, these studies indicate that tetrahydro‐β‐carboline represents a promising scaffold for the design of novel inhibitors able to target MMPs and selectively bias gelatinases, over the desirable range of the pharmacokinetics spectrum.     

Analysis of the advection–diffusion mixing by the mapping method formalism in 3D open‐flow devices

This article extends the analysis of laminar mixing driven by a chaotic flow in the presence of diffusion to three‐dimensional open‐flow devices by means of the mapping‐matrix method. The extended formulation of the mapping matrix recently proposed by Gorodetskyi et al. (2012) allows inclusion of the molecular diffusion in the mixing process. This provides an efficient numerical tool for understanding the interplay between a chaotic advective field and diffusion, especially for high Péclet numbers. As a prototypical open‐flow device we consider the partitioned‐pipe mixer. Results deriving from the application of the extended mapping method are compared with Galerkin simulations, and a close agreement is found. Short‐term properties in the evolution of the concentration and the effect of axial diffusion are also addressed. © 2013 American Institute of Chemical Engineers AIChE J, 60: 387–407, 2014     

Evidence for a role of the membrane-proximal region of herpes simplex virus type 1 glycoprotein H in membrane fusion and virus inhibition

We have identified a putative membrane-interacting domain preceding the transmembrane domain of the Herpes simplex virus type 1 (HSV-1) glycoprotein H (gH). Peptides derived from this region interact strongly with membranes and show a high tendency to partition at the interface. This region is predicted to bind at the membrane interface by adopting an alpha helical structure. Peptides representing either the HSV-1 gH pretransmembrane region or a scrambled control with a different hydrophobic profile at the point of interface have been studied. The peptides derived from this domain of gH induce the fusion of liposomal membranes, adopt helical conformations in membrane mimetic environments and are able to inhibit HSV-1 infectivity. The pretransmembrane region appears to be a common feature in viral fusion proteins of several virus families, and such a feature might be related to their fusogenic function. The identification of membrane-interacting regions capable of modifying the biophysical properties of phospholipid membranes lends weight to the view that such domains might function directly in the fusion process and could facilitate the future development of HSV-1 entry inhibitors.     

Heparin induces an accumulation of atherogenic lipoproteins during hemodialysis in normolipidemic end‐stage renal disease patients

Dyslipidemias may account for the excess of cardiovascular mortality in end‐stage renal disease (ESRD). Lipoprotein studies in ESRD patients are usually relative to prehemodialysis samples even if significative changes may occur after dialysis. In this study, we aimed to investigate the effects of ESRD on triglyceride‐rich lipoproteins (TRL) subpopulations distribution and acute change following hemodialytic procedures, including the relative contribution of heparin administration. We selected a group of normolipidemic male middle‐aged ESRD patients free of any concomitant disease affecting lipoprotein remnant metabolism compared with controls. We separated TRL subfractions according to density and apoE content and evaluated the changes of these particles after hemodialytic procedures with or without heparin. ESRD subjects had higher TRL subfractions, with the exception of apoE‐rich particles, lower high‐density lipoprotein (HDL) largest subclasses, and a smaller low‐density lipoprotein peak particle size than controls. After a hemodialytic standard procedure with heparin, we demonstrated a significant reduction of triglyceride, an increase of HDL‐cholesterol levels, and a raise of small very‐low‐density lipoprotein, intermediate‐density lipoproteins (IDL), apoE‐rich particles, and non‐HDL‐cholesterol levels. When hemodialysis was performed without heparin, no significant changes were observed. In the absence of concomitant hyperlipidemic triggers, ESRD patients show significant lipoprotein abnormalities before dialysis, but without any increased remnant particles concentrations. We speculate that hemodialysis, in particular heparin administration during this procedure, leads to a massive atherogenic TRLs production because of the acute stimulation of the dysfunctional lipolytic system not followed by an efficient removal, determining a recurrent lipoprotein remnant accumulation.     

Innovative Anti Crash Absorber for a Crashworthy Landing Gear

This paper defines an innovative concept to anti-crash absorber in composite material to be integrated on the landing gear as an energy-absorbing device in crash conditions to absorb the impact energy. A composite cylinder tube in carbon fiber material is installed coaxially to the shock absorber cylinder and, in an emergency landing gear condition, collapses in order to enhance the energy absorption performance of the landing system. This mechanism has been developed as an alternative solution to a high-pressure chamber installed on the Agusta A129 CBT helicopter, which can be considered dangerous when the helicopter operates in hard and/or crash landing. The characteristics of the anti-crash device are presented and the structural layout of a crashworthy landing gear adopting the developed additional energy absorbing stage is outlined. Experimental and numerical results relevant to the material characterization and the force peaks evaluation of the system development are reported. The anti-crash prototype was designed, analysed, optimized, made and finally the potential performances of a landing gear with the additional anti-crash absorber system are tested by drop test and then correlated with a similar test without the anti-crash system, showing that appreciable energy absorbing capabilities and efficiencies can be obtained in crash conditions.     

A local approximation based multi-objective optimization algorithm with applications

Optimization techniques are useful tools to the design of complex systems. Especially in case of multiple conflicting performance indexes, the knowledge of the tradeoffs by means of Pareto optimality can help the designer to achieve the best solution. Due to the increasing power of the computing tools, more and more accurate and time consuming models are used. In this case, the Pareto set computation can be a hard task (the Pareto set can be nonconvex, nonlinearities and discontinuities can occur) and the efficiency and the accuracy become crucial features for an optimization algorithm. In this paper an optimization algorithm based on local approximation of the objective and constraints functions is presented and tested with some well known test functions. The optimal design of the suspension system of a ground vehicle is performed by the new algorithm in order to reach the best tradeoff by means of road holding, comfort, working space and cornering behavior. The numerical results show that the proposed algorithm has good accuracy and high efficiency if compared to some widely used methods. The results are explained providing some general observations on the efficiency of local approximation based algorithm an other well known algorithms.     

Parallel-local anodic oxidation of silicon surfaces by soft stamps

We investigate the fabrication of nanometric patterns on silicon surfaces by using the parallel-local anodic oxidation technique with soft stamps. This method yields silicon oxide nanostructures 15?nm high, namely at least five times higher than the nanostructures made with local anodic oxidation using atomic force microscopy, and thanks to the size of the stamp enables one to pattern the surface across a centimetre length scale. To implement this technique, we built a machine to bring the metallized polydimethylsiloxane stamp in contact with the silicon surface, subsequently inserted in a sealed chamber with controlled relative humidity. The oxide nanostructures are fabricated when a bias voltage of 36?V is applied between the stamp and the silicon for 2?min, with a relative humidity of 90%. The flexibility of the stamp enables a homogeneous conformal contact with the silicon surface, resulting in an excellent reproducibility of the process. Moreover, by means of two subsequent oxidations with the same stamp and just rotating the sample, we are able to fabricate complex nanostructures. Finally, a detailed study of the oxidation mechanism, also using a finite element analysis, has been performed to understand the underlying mechanism.     

Quality-by-control of intensified continuous filtration-drying of active pharmaceutical ingredients

Continuous manufacturing and closed-loop quality control are emerging technologies that are pivotal for next-generation pharmaceutical modernization. We develop a process control framework for a continuous carousel for integrated filtration-drying of crystallization slurries. The proposed control system includes model-based monitoring and control routines, such as state estimation and real-time optimization, implemented in a hierarchical, three-layer quality-by-control (QbC) framework. We implement the control system in ContCarSim, a publicly available carousel simulator. We benchmark the proposed control system against simpler methods, comprising a reduced subset of the elements of the overall control system, and against open-loop operation (the current standard in pharmaceutical manufacturing). The proposed control system demonstrates superior performance in terms of higher consistency in product quality and increased productivity, proving the benefits of closed-loop control and of model-based techniques in pharmaceutical manufacturing. This study represents a step forward toward end-to-end continuous pharmaceutical processing, and in the evolution of quality-by-design toward quality-by-control.