The Critical Role of Passive Permeability in Designing Successful Drugs

Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients.     

UPR: deadlock-free dynamic network reconfiguration by exploiting channel dependency graph compatibility

The Journal of Supercomputing - Deadlock-free dynamic network reconfiguration process is usually studied from the routing algorithm restrictions and resource reservation perspective. The dynamic...     

Formalization of Ring Theory in PVS

This paper presents a PVS development of relevant results of the theory of rings. The PVS theory includes complete proofs of the three classical isomorphism theorems for rings, and characterizations of principal, prime and maximal ideals. Algebraic concepts and properties are specified and formalized as generally as possible allowing in this manner their application to other algebraic structures. The development provides the required elements to formalize important algebraic theorems. In particular, the paper presents the formalization of the general algebraic-theoretical version of the Chinese remainder theorem (CRT) for the theory of rings, as given in abstract algebra textbooks, proved as a consequence of the first isomorphism theorem. Also, the PVS theory includes a formalization of the number-theoretical version of CRT for the structure of integers, which is the version of CRT found in formalizations. CRT for integers is obtained as a consequence of the general version of CRT for the theory of rings.

     

Bioinformatic characterization of the extracellular lipases from Kluyveromyces marxianus

Lipases are hydrolytic enzymes that break the ester bonds of triglycerides, generating free fatty acids and glycerol. Extracellular lipase activity has been reported for the nonconventional yeast Kluyveromyces marxianus, grown in olive oil as a substrate, and the presence of at least eight putative lipases has been detected in its genome. However, to date, there is no experimental evidence on the physiological role of the putative lipases nor their structural and catalytic properties. In this study, a bioinformatic analysis of the genes of the putative lipases from K. marxianus L-2029 was performed, particularly identifying and characterizing the extracellular expected enzymes, due to their biotechnological relevance. The amino acid sequence of 10 putative lipases, obtained by in silico translation, ranged between 389 and 773 amino acids. Two of the analysed putative proteins showed a signal peptide, 25 and 33 amino acids long for KmYJR107Wp and KmLIP3p, and a molecular weight of 44.53 and 58.23 kDa, respectively. The amino acid alignment of KmLIP3p and KmYJR107Wp with the crystallized lipases from a patatin and the YlLip2 lipase from Yarrowia lipolytica, respectively, revealed the presence of the hydrolase characteristic motifs. From the 3D models of putative extracellular K. marxianus L-2029 lipases, the conserved pentapeptide of each was determined, being GTSMG for KmLIP3p and GHSLG for KmYJR107Wp; besides, the genes of these two enzymes (LIP3 and YJR107W) are apparently regulated by oleate response elements. The phylogenetic analysis of all K. marxianus lipases revealed evolutionary affinities with lipases from abH15.03, abH23.01, and abH23.02 families.     

Tribological behaviour of a 3Y-TZP/Ta ceramic-metal biocomposite against ultrahigh molecular weight polyethylene (UHMWPE)

This study aims to evaluate the tribological behaviour of 3Y-TZP/Ta (20 vol%) ceramic-metal composites and 3Y-TZP monolithic ceramic prepared by spark plasma sintering (SPS) against ultrahigh molecular weight polyethylene (UHMWPE). According to the results of pin (UHMWPE)-on-flat wear test under dry conditions, the UHMWPE – 3Y-TZP/Ta system exhibited lower volume loss and friction coefficient than the UHMWPE – monolithic ceramic combination due to the presence of an autolubricating layer that provides sufficient lubrication for reducing the friction. Owing to the lubrication of the liquid media, under wet conditions obtained using simulated body fluid (SBF), similar behaviour is observed in both cases. Additionally, the ceramic and biocomposite materials were subjected to a low temperature degradation (LTD) process (often referred to as “ageing”) to evaluate the changes in the tribological behaviour after this treatment. In this particular case, the wear properties of the UHMWPE-biocomposite system were found to be less influenced by ageing in contrast to the case of the UHMWPE-zirconia monolithic material. In addition to their exceptional mechanical performance, 3Y-TZP/Ta composites also showed high resistance to low temperature degradation and good tribological properties, making them promising candidates for biomedical applications, especially for orthopaedic implants.     

Identification of vivianite,an unusual blue pigment,in a sixteenth century painting and its implications

Vivianite, a blue pigment employed in the past practically only in Northern and Central Europe, but with very limited use, was identified in an early sixteenth century painting, stylistically with Flemish features, from a church in Portugal. The identification of this iron phosphate mineral was made by SEM‐EDS based on the atomic ratio between phosphorus and iron in layers of blue paint (area analysis) and in particles of these same layers (spot analysis). This painting, about which there is no document to prove its authorship, becomes the first case, known in detail, of a sixteenth century painting containing vivianite. Moreover, this find and the presence of a chalk ground, also identified, strongly support the hypothesis of being a Flemish painting.     

Bibliometric analysis of the evolution of biochar research trends and scientific production

Clean Technologies and Environmental Policy - Biochar has caught great attention over the last decade, yielding a large number of publications in a broad range of disciplines. This scientometric...