Structural characterizations of lead anticancer compounds from the methanolic extract of <i>Jatropha tanjorensis</i>

LC/ESI/MS/MS data analysis on the phytoconstituents of methanolic extract of Jatropha tanjorensis leaves revealed the presence of abundant flavone glucosides (homoorientin, kaempferol-3-o-rutinoside, luteolin-7-o-glucoside, 6-C-pentosyl-8-C-hexosyl apigenin, naringin and vitexin), flavonol (kaempferol and kaempferide) and flavones (baicalein and diosmetin). We, herein, demonstrated that methanolic extract of J. tanjorensis possess DPPH free-radical scavenging activity (IC50 of 49.7 µg/mL), inhibition of  lipid peroxidation activity (IC50 of 189.6 µg/mL) and anticancer activity through MTT assay against EAC cells (IC50 of 14.57 µg/mL) and Caco-2 cells (IC50 of 21.0 µg/mL). In silico analysis indicated that cytotoxic activity of the methanolic extract of J. tanjorensis could be attributed to the presence of vitexin and 6-C-pentosyl-8-C-hexosyl apigenin as evidenced by exhaustive molecular docking studies carried out against 8 proteins of Bcl-2 family that play essential role in apoptosis. Moreover, drug-likeness properties of the leads and scopes to develop them as potent anticancer compounds are discussed

Identifying Opportunities for Virtual Reality Simulation in Surgical Education: A Review of the Proceedings from the Innovation, Design, and Emerging Alliances in Surgery (IDEAS) Conference: VR Surgery

To conduct a review of the state of virtual reality (VR) simulation technology, to identify areas of surgical education that have the greatest potential to benefit from it, and to identify challenges to implementation

Versatility of polyketide synthases in generating metabolic diversity

Polyketide synthases (PKSs) form a large family of multifunctional proteins involved in the biosynthesis of diverse classes of natural products. Architecturally at least three different types of PKSs have been discovered in the microbial world and recent years have revealed tremendous versatility of PKSs, both in terms of their structural and functional organization and in their ability to produce compounds other than typical secondary metabolites. Mycobacterium tuberculosis exploits polyketide biosynthetic enzymes to synthesize complex lipids, many of which are essential for its survival. The functional significance of the large repertoire of PKSs in Dictyostelium discoideum, perhaps in producing developmental regulating factors, is emerging. Recently determined structures of fatty acid synthases (FASs) and PKSs now provide an opportunity to delineate the mechanistic and structural basis of polyketide biosynthetic machinery

Fatty acyl-AMP ligases and polyketide synthases are unique enzymes of lipid biosynthetic machinery in Mycobacterium tuberculosis

The cell envelope of Mycobacterium tuberculosis (Mtb) possesses a repertoire of unusual lipids that are believed to play an important role in pathogenesis. In this review, we specifically focus on computational, biochemical and structural studies in lipid biosynthesis that have established functional role of polyketide synthases (PKSs) and fatty acyl-AMP ligases (FAALs). Mechanistic and structural studies with FAALs suggest that this group of proteins may have evolved from omnipresent fatty acyl-CoA ligases (FACLs). FAALs activate fatty acids as acyl-adenylates and transfer them on to the PKSs which then produce unusual acyl chains that are the components of mycobacterial lipids. FAALs are a newly discovered family of enzymes; whereas involvement of PKSs in lipid metabolism was not known prior to their discovery in Mtb. Since Mtb genome contains multiple homologs of FAALs and PKSs and owing to the conserved reaction mechanism and overlapping substrate specificity; there is tempting opportunity to develop 'systemic drugs' against these enzymes as anti-tuberculosis agents

Molecular basis of the functional divergence of fatty Acyl-AMP ligase biosynthetic Enzymes of mycobacterium tuberculosis

Activation of fatty acids as acyl-adenylates by fatty acyl-AMP ligases (FAALs) in Mycobacterium tuberculosis is a variant of a classical theme that involves formation of acyl-CoA (coenzyme A) by fatty acyl-CoA ligases (FACLs). Here, we show that FAALs and FACLs possess similar structural fold and substrate specificity determinants, and the key difference is the absence of a unique insertion sequence in FACL13 structure. A systematic analysis shows a conserved hydrophobic anchorage of the insertion motif across several FAALs. Strikingly, mutagenesis of two phenylalanine residues, which are part of the anchorage, to alanine converts FAAL32 to FACL32. This insertion-based in silico analysis suggests the presence of FAAL homologues in several other non-mycobacterial genomes including eukaryotes. The work presented here establishes an elegant mechanism wherein an insertion sequence drives the functional divergence of FAALs from canonical FACLs

Crystallization and preliminary X-ray crystallographic studies of the N-terminal domain of FadD28, a fatty-acyl AMP ligase from Mycobacterium tuberculosis

The crystallization and preliminary X-ray crystallographic studies of the N-terminal domain of FadD28, a fatty-acyl AMP ligase from M. tuberculosis, are reported

Review of research on friction riveting of polymer/metal light weight multi-material structures

The present transportation industry has been challenged by cost-saving requirements, ever-stronger environmental protection regulations and the significant growth of transport volume. One approach for tackling these challenges is the development of new improved transportation vehicles using new materials and innovative joining technologies. In the recent decade, the use of fiber-reinforced plastics-metal structures has increased significantly in bridge, automotive and aircraft structures, and friction riveting has evolved as a new and promising candidate for joining fiber-reinforced plastics to metals. Friction riveting bridges the gap between mechanical fastening and welding, and offers advantages such as short joining cycle times and a minimum of surface pre-treatment of the joining partners. The present work provides a comprehensive understanding of joining mechanism and behavior of friction riveted multi-material joint structures. Friction riveting has full potential to grow as an ecofriendly, economical and reliable joining method for developing polymer-metal multi-material structures

Quantitative Attack Tree Analysis via Priced Timed Automata

The success of a security attack crucially depends on the resources available to an attacker: time, budget, skill level, and risk appetite. Insight in these dependencies and the most vulnerable system parts is key to providing effective counter measures. This paper considers attack trees, one of the most prominent security formalisms for threat analysis. We provide an effective way to compute the resources needed for a successful attack, as well as the associated attack paths. These paths provide the optimal ways, from the perspective of the attacker, to attack the system, and provide a ranking of the most vulnerable system parts. By exploiting the priced timed automaton model checker Uppaal CORA, we realize important advantages over earlier attack tree analysis methods: we can handle more complex gates, temporal dependencies between attack steps, shared subtrees, and realistic, multi-parametric cost structures. Furthermore, due to its compositionality, our approach is flexible and easy to extend. We illustrate our approach with several standard case studies from the literature, showing that our method agrees with existing analyses of these cases, and can incorporate additional data, leading to more informative results

A novel tunnel in mycobacterial type III polyketide synthase reveals the structural basis for generating diverse metabolites

The superfamily of plant and bacterial type III polyketide synthases (PKSs) produces diverse metabolites with distinct biological functions. PKS18, a type III PKS from Mycobacterium tuberculosis, displays an unusual broad specificity for aliphatic long-chain acyl-coenzyme A (acyl-CoA) starter units (C6-C20) to produce tri- and tetraketide pyrones. The crystal structure of PKS18 reveals a 20 &#197; substrate binding tunnel, hitherto unidentified in this superfamily of enzymes. This remarkable tunnel extends from the active site to the surface of the protein and is primarily generated by subtle changes of backbone dihedral angles in the core of the protein. Mutagenic studies combined with structure determination provide molecular insights into the structural elements that contribute to the chain length specificity of the enzyme. This first bacterial type III PKS structure underlines a fascinating example of the way in which subtle changes in protein architecture can generate metabolite diversity in nature