Development of the First Oral Bioprecursors of Bis‐alkylguanidine Antimalarial Drugs

Plasmodium falciparum is responsible of the most severe form of malaria, and new targets and novel chemotherapeutic scaffolds are needed to fight emerging multidrug‐resistant strains of this parasite. Bis‐alkylguanidines have been designed to mimic choline, resulting in the inhibition of plasmodial de novo phosphatidylcholine biosynthesis. Despite potent in vitro antiplasmodial and in vivo antimalarial activities, a major drawback of these compounds for further clinical development is their low oral bioavailability. To solve this issue, various modulations were performed on bis‐alkylguanidines. The introduction of N‐disubstituents on the guanidino motif improved both in vitro and in vivo activities. On the other hand, in vivo pharmacological evaluation in a mouse model showed that the N‐hydroxylated derivatives constitute the first oral bioprecursors in bis‐alkylguanidine series. This study paves the way for bis‐alkylguanidine‐based oral antimalarial agents targeting plasmodial phospholipid metabolism.     

Poly(ethylene terephthalate)/poly(ethylene glycol‐co‐1,3/1,4‐cyclohexanedimethanol terephthalate)/clay nanocomposites: Mechanical properties,optical transparency,and barrier properties

Poly(ethylene terephthalate) (PET)/clay, PET/poly(ethylene glycol‐co‐1,3/1,4‐cyclohexanedimethanol terephthalate) (PETG), and PET/PETG/clay nanocomposites were fabricated using the twin‐screw extrusion technique. The spherulitic morphologies, thermomechanical, mechanical, and gas‐barrier properties, as well as the effect of clay on the transparency of the resulting nanocomposites were identified. The clay induced the heterogeneous nucleation of the nanocomposites during the cold crystallization process, thereby increasing the crystallinities and melting temperatures of the resulting nanocomposites. The incorporation of clay increased the storage moduli, Young's moduli, impact strengths, and barrier properties of the PET, PETG, and PET/PETG blend. Regarding the optical transparency, the inclusion of clay can make the crystallizable PET matrix crystalline opaque. However, the amorphous PETG maintained its transparency. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 39869.     

Anticancer and Toxic Properties of Cyclotides are Dependent on Phosphatidylethanolamine Phospholipid Targeting

Cyclotides, ultrastable disulfide‐rich cyclic peptides, can be engineered to bind and inhibit specific cancer targets. In addition, some cyclotides are toxic to cancer cells, though not much is known about their mechanisms of action. Here we delineated the potential mode of action of cyclotides towards cancer cells. A novel set of analogues of kalata B1 (the prototypic cyclotide) and kalata B2 and cycloviolacin O2 were examined for their membrane‐binding affinity and selectivity towards cancer cells. By using solution‐state NMR, surface plasmon resonance, flow cytometry and bioassays we show that cyclotides are toxic against cancer and non‐cancerous cells and their toxicity correlates with their ability to target and disrupt lipid bilayers that contain phosphatidylethanolamine phospholipids. Our results suggest that the potential of cyclotides as anticancer therapeutics might best be realised by combining their amenability to epitope engineering with their ability to bind cancer cell membranes.     

Combination of multiphoton and reflective confocal imaging of cornea

We combine reflective confocal microscopy with multiphoton microscopy to form a minimally invasive technique to observe the cornea. The two imaging modalities allow detection of complementary information from the cornea. The autofluorescence signal shows the cytoplasm of epithelial cells, and the second harmonic generation signal is used to detect collagen, found mostly in the stroma of the cornea. The reflective confocal imaging allows detection of epithelial cells and keratocytes in the stroma. The system is first tested on bovine cornea. Assessment of the result on the bovine eye will be used to evaluate the potential of the system as a technique for in vivo clinical application.     

Computer aided manufacturing planning for mass customization: part 2, automated setup planning

Setup planning plays a crucial role in CAPP to ensure product quality while maintaining acceptable manufacturing cost. The tasks of setup planning include identifying manufacturing features and corresponding manufacturing processes, determining the number of setups, part orientation, locating datum and process sequence in each setup, and selecting machine tools and fixtures. An automated setup planning technique and system has been developed based on not only the tolerance analysis, but also the manufacturing resource capability analysis. The automated setup planning is divided into two levels: setup planning in single part level and in machine station level. Algorithms for setup generation and process sequencing have been developed and a case study of setup planning is presented.     

Gap-flow patterns behind twin-cylinders at low Reynolds number

The flow structures, drag coefficients (C _d ) and vortex shedding characteristics around a single square cylinder and twin side-by-side square cylinders were experimentally investigated with various Reynolds numbers (Re) and gap ratios (g*) in a vertical water tunnel. The Reynolds number (Re) and gap ratio (g*) were 178 < Re < 892 and 0 ≤ g* ≤ 2.5, respectively. The flow patterns and vortex shedding frequency were determined using the particle tracking flow visualization (PTFV). The flow structures, velocity properties, and drag coefficients were calculated using the particle image velocimetry (PIV). The topological flow patterns of vortex evolution processes were plotted and analyzed based on critical point theory. Furthermore, the flow structures behind twin side-by-side square cylinders were classified into three modes — single vortex-street mode, gap-flow mode and couple vortex-streets mode. The maximum C _d occurred in the single vortex-street mode, and the minimum C _d occurred in the gap-flow mode. The highest Strouhal number (St) occurred in the single vortex-street mode, and the lowest St occurred in the gap-flow mode.     

Experimental analyses to investigate the feasibility and effectiveness in using heat pipe-embedded drills

This paper presents an experimental investigation to verify the feasibility and effectiveness of heat pipe cooling in drilling operations. The basic idea is to insert a heat pipe at the center of the drill tool with the evaporator close to the drill tip and the condenser at the end of the drill. Consequently, the heat generated at the tool–chip interface can be removed by convection heat transfer. Experimental studies were involved in three cases, including solid drill without coolant, solid drill with coolant, and heat pipe drill. Drilling tests were conducted on a CNC machining center with full immersion cutting. The cast iron square block was used as the workpiece, and the high-speed steel was chosen for the drill tool material. Flank wear is considered as the criterion for tool failure, and the wear was measured using a Hisomet II Toolmaker’s microscope. The tests were conducted until the drill was rejected when an average flank wear greater than 0.10?mm was recorded. The results demonstrate that using a heat pipe in the drilling process can effectively perform thermal management comparable to the flooding coolant cooling used pervasively in the manufacturing industry, extending the tool life of the drill.     

Experimental analyses to investigate the feasibility and effectiveness in using heat-pipe embedded end-mills

This study experimentally verifies the feasibility and effectiveness of heat-pipe cooling in end-milling operations. The basic idea is to embed a heat-pipe at the center of an end-mill with the evaporator close to the tool tip, and the condenser at the tool end. Thus, most of heat generated on the end-mill tip can be quickly removed dependent on convection heat transfer by means of heat-pipe. The end-milling experiments were carried out on a CNC vertical machining center under three different cooling conditions, including dry milling, fluid cooling, and heat-pipe cooling. The work material was AISI 1040 steel, and hard alloy was chosen for the cutting tool material. Flank wear is considered as the criterion for tool failure and the wear was measured using a Hisomet II Toolmaker's microscope. The tests were conducted until the end-mill was rejected when maximum flank wear equal to 0.30?mm was recorded. The results validate that heat-pipe-assisted cooling in end-milling processes can effectively perform thermal management comparable to the fluid cooling used pervasively in the manufacturing industry, increasing the service life of the end-mill.