Ages and relative sizes of pre-2004 tsunamis in the Bay of Bengal inferred from geologic evidence in the Andaman and Nicobar Islands

Geologic evidence along the northern part of the 2004 Aceh-Andaman rupture suggests that this region generated as many as five tsunamis in the prior 2000years. We identify this evidence by drawing analogy with geologic records of land-level change and the tsunami in 2004 from the Andaman and Nicobar Islands (A&N). These analogs include subsided mangrove swamps, uplifted coral terraces, liquefaction, and organic soils coated by sand and coral rubble. The pre-2004 evidence varies in potency, and materials dated provide limiting ages on inferred tsunamis. The earliest tsunamis occurred between the second and sixth centuries A.D., evidenced by coral debris of the southern Car Nicobar Island. A subsequent tsunami, probably in the range A.D. 770-1040, is inferred from deposits both in A&N and on the Indian subcontinent. It is the strongest candidate for a 2004-caliber earthquake in the past 2000years. A&N also contain tsunami deposits from A.D. 1250 to 1450 that probably match those previously reported from Sumatra and Thailand, and which likely date to the 1390s or 1450s if correlated with well-dated coral uplift offshore Sumatra. Thus, age data from A&N suggest that within the uncertainties in estimating relative sizes of paleo-earthquakes and tsunamis, the 1000year interval can be divided in half by the earthquake or earthquakes of A.D. 1250-1450 of magnitude >8.0 and consequent tsunamis. Unlike the transoceanic tsunamis generated by full or partial rupture of the subduction interface, the A&N geology further provides evidence for the smaller-sized historical tsunamis of 1762 and 1881, which may have been damaging locally.

Synthesis and application of weight function for edge cracked semicircular disk (ECSD)

We analyze the utility of edge cracked semicircular disk (ECSD) for rapid assessment of fracture toughness using compressive loading. Continuing our earlier work on ECSD, a theoretical examination here leads to a novel way for synthesizing weight functions using two distinct form factors. The efficacy of ECSD mode-I weight function synthesized using displacement and form factor methods is demonstrated by comparing with finite element results. Theory of elasticity in conjunction with finite element method is utilized to analyze crack opening potency of ECSD under eccentric compression to explore newer configurations of ECSD for fracture testing.

Dinuclear zinc bis(thiosemicarbazone) complexes: Synthesis, in vitro anticancer activity, cellular uptake and DNA interaction study

Four dinucleating bis(thiosemicarbazone) ligands and their zinc complexes have been synthesized and characterized by multinuclear NMR (H-1 and C-13), IR, UV-Vis, ESI-MS and fluorescence spectroscopic techniques. Their purity was assessed by elemental analysis. Cytotoxicity was tested against five human cancer cell lines using the sulphorhodamine B (SRB) assay, where one of the complexes, 1,3-bis{biacetyl-2'-(4 `'-N-pyrrolidinylthiosemicarbazone)-3'-(4 `'-N-pyrrolidinylthiosemicarbazone) zinc(II)} propane (6), was found to be quite cytotoxic against MCF-7 (breast cancer) and HepG2 (hepatoma cancer) cell lines, with a potency similar to that of the well known anticancer drug adriamycin. It is evident from the cellular uptake studies that the uptake is same for the active complex 6 and the inactive complex 8 (1,6-bis{biacetyl- 2'-(4 `'-N-pyrrolidinylthiosemicarbazone)-3'-(4 `'-N-pyrrolidinylthiosemicarbazone) zinc(II)} hexane) in MCF-7 and HepG2 cell lines. In vitro DNA binding and cleavage studies revealed that all complexes bind with DNA through electrostatic interaction, and cause no significant cleavage of DNA. (C) 2'13 Elsevier B. V. All rights reserved.

Beyond classical dynamic structural plasticity using mesh-free modelling techniques

The problem of modelling the transient response of an elastic-perfectly-plastic cantilever beam, carrying an impulsively loaded tip mass, is,often referred to as the Parkes cantilever problem 25]; The permanent deformation of a cantilever struck transversely at its tip, Proc. R. Soc. A., 288, pp. 462). This paradigm for classical modelling of projectile impact on structures is re-visited and updated using the mesh-free method, smoothed particle hydrodynamics (SPH). The purpose of this study is to investigate further the behaviour of cantilever beams subjected to projectile impact at its tip, by considering especially physically real effects such as plastic shearing close to the projectile, shear deformation, and the variation of the shear strain along the length and across the thickness of the beam. Finally, going beyond macroscopic structural plasticity, a strategy to incorporate physical discontinuity (due to crack formation) in SPH discretization is discussed and explored in the context of tip-severance of the cantilever beam. Consequently, the proposed scheme illustrates the potency for a more refined treatment of penetration mechanics, paramount in the exploration of structural response under ballistic loading. The objective is to contribute to formulating a computational modelling framework within which transient dynamic plasticity and even penetration/failure phenomena for a range of materials, structures and impact conditions can be explored ab initio, this being essential for arriving at suitable tools for the design of armour systems. (C) 2014 Elsevier Ltd. All rights reserved.

Phenyl carbohydrazone conjugated 2-oxoindoline as a new scaffold that augments the DNA and BSA binding affinity and anti-proliferative activity of a 1,10-phenanthroline based copper(II) complex

A new type of copper(II) complex, CuL(phen)(2)](NO3) (CuIP), where L ((E)-N'-(2-oxoindolin-3-ylidene) benzohydrazide) is a N donor ligand and phen is the N, N-donor heterocyclic 1,10-phenanthroline, has been synthesized. The phenyl carbohydrazone conjugated isatin-based ligand L and CuIP were characterized by elemental analysis, infrared, UV-Vis, H-1 and C-13 NMR and ESI-mass spectral data, as well as single-crystal X-ray diffraction. The interaction of calf thymus DNA (CT DNA) with L and CuIP has been investigated by absorption, fluorescence and viscosity titration methods. The complex CuIP displays better binding affinity than the ligand L. The observed DNA binding constant (K-b = 4.15(+/- 0.18) x 10(5) M-1) and binding site size (s = 0.19), viscosity data together with molecular docking studies of CuIP suggest groove binding and/or a partial intercalative mode of binding to CT DNA. In addition, CuIP shows good binding propensity to the bovine serum albumin (BSA) protein, giving a K-BSA value of 1.25(+/- 0.24) x 10(6) M-1. In addition, the docking studies on DNA and human serum albumin (HSA) CuIP interactions are consistent with the consequence of binding experiments. The in vitro anti-proliferative study establishes the anticancer potency of the CuIP against the human cervical (HeLa) and breast (MCF7) cancer cells; noncancer breast epithelial (MCF10a) cells have also been investigated. CuIP shows better cytotoxicity and sensitivity towards cancer cells over noncancer ones than L under identical conditions, with the appearance of apoptotic bodies. (C) 2014 Elsevier B.V. All rights reserved.

Anthrapyrazolone analogues intercept inflammatory JNK signals to moderate endotoxin induced septic shock

Severe sepsis or septic shock is one of the rising causes for mortality worldwide representing nearly 10% of intensive care unit admissions. Susceptibility to sepsis is identified to be mediated by innate pattern recognition receptors and responsive signaling pathways of the host. The c-Jun N-terminal Kinase (JNK)-mediated signaling events play critical role in bacterial infection triggered multi-organ failure, cardiac dysfunction and mortality. In the context of kinase specificities, an extensive library of anthrapyrazolone analogues has been investigated for the selective inhibition of c-JNK and thereby to gain control over the inflammation associated risks. In our comprehensive biochemical characterization, it is observed that alkyl and halogen substitution on the periphery of anthrapyrazolone increases the binding potency of the inhibitors specifically towards JNK. Further, it is demonstrated that hydrophobic and hydrophilic interactions generated by these small molecules effectively block endotoxin-induced inflammatory genes expression in in vitro and septic shock in vivo, in a mouse model, with remarkable efficacies. Altogether, the obtained results rationalize the significance of the diversity oriented synthesis of small molecules for selective inhibition of JNK and their potential in the treatment of severe sepsis.

Antimicrobial Peptides with Potential for Biofilm Eradication: Synthesis and Structure Activity Relationship Studies of Battacin Peptides

We report on the first chemical syntheses and structureactivity analyses of the cyclic lipopeptide battacin which revealed that conjugation of a shorter fatty acid, 4-methyl-hexanoic acid, and linearization of the peptide sequence improves antibacterial activity and reduces hemolysis of mouse blood cells. This surprising finding of higher potency in linear lipopeptides than their cyclic counterparts is economically beneficial. This novel lipopeptide was membrane lytic and exhibited antibiofilm activity against Pseudomonas aeruginosa, Staphylococcus aureus, and, for the first time, Pseudomonas syringe pv. actinidiae. The peptide was unstructured in aqueous buffer and dimyristoylphosphatidylcholine-polymerized diacetylene vesicles, with 12% helicity induced in 50% v/v of trifluoroethanol. Our results indicate that a well-defined secondary structure is not essential for the observed antibacterial activity of this novel lipopeptide. A truncated pentapeptide conjugated to 4-methyl hexanoic acid, having similar potency against Gram negative and Gram positive pathogens was identified through alanine scanning.

Synthesis, X-ray structure and in vitro cytotoxicity studies of Cu(I/II) complexes of thiosemicarbazone: special emphasis on their interactions with DNA

4-(p-X-phenyl)thiosemicarbazone of napthaldehyde {where X = Cl (HL1) and X = Br (HL2)}, thiosemicarbazone of quinoline-2-carbaldehyde (HL3) and 4-(p-fluorophenyl) thiosemicarbazone of salicylaldehyde (H2L4) and their copper(I) {Cu(HL1)(PPh3)(2)Br]center dot CH3CN (1) and Cu(HL2)(PPh3)(2)Cl]center dot DMSO (2)} and copper(II) {((Cu2L2Cl)-Cl-3)(2)(mu-Cl)(2)]center dot 2H(2)O (3) and Cu(L-4)(Py)] (4)} complexes are reported herein. The synthesized ligands and their copper complexes were successfully characterized by elemental analysis, cyclic voltammetry, NMR, ESI-MS, IR and UV-Vis spectroscopy. Molecular structures of all the Cu(I) and Cu(II) complexes have been determined by X-ray crystallography. All the complexes (1-4) were tested for their ability to exhibit DNA-binding and - cleavage activity. The complexes effectively interact with CT-DNA possibly by groove binding mode, with binding constants ranging from 10(4) to 10(5) M-1. Among the complexes, 3 shows the highest chemical (60%) as well as photo-induced (80%) DNA cleavage activity against pUC19 DNA. Finally, the in vitro antiproliferative activity of all the complexes was assayed against the HeLa cell line. Some of the complexes have proved to be as active as the clinical referred drugs, and the greater potency of 3 may be correlated with its aqueous solubility and the presence of the quinonoidal group in the thiosemicarbazone ligand coordinated to the metal.

Curcumin Pyrazole and its derivative (N-(3-Nitrophenylpyrazole) Curcumin inhibit aggregation, disrupt fibrils and modulate toxicity of Wild type and Mutant alpha-Synuclein

Accumulating evidence suggests that deposition of neurotoxic a-synuclein aggregates in the brain during the development of neurodegenerative diseases like Parkinson's disease can be curbed by anti-aggregation strategies that either disrupt or eliminate toxic aggregates. Curcumin, a dietary polyphenol exhibits anti-amyloid activity but the use of this polyphenol is limited owing to its instability. As chemical modifications in curcumin confiscate this limitation, such efforts are intensively performed to discover molecules with similar but enhanced stability and superior properties. This study focuses on the inhibitory effect of two stable analogs of curcumin viz. curcumin pyrazole and curcumin isoxazole and their derivatives against a-synuclein aggregation, fibrillization and toxicity. Employing biochemical, biophysical and cell based assays we discovered that curcumin pyrazole (3) and its derivative N-(3-Nitrophenylpyrazole) curcumin (15) exhibit remarkable potency in not only arresting fibrillization and disrupting preformed fibrils but also preventing formation of A11 conformation in the protein that imparts toxic effects. Compounds 3 and 15 also decreased neurotoxicity associated with fast aggregating A53T mutant form of a-synuclein. These two analogues of curcumin described here may therefore be useful therapeutic inhibitors for the treatment of a-synuclein amyloidosis and toxicity in Parkinson's disease and other synucleinopathies.

Synthesis of Novel Benzofuran-Gathered C-2,4,6-substituted Pyrimidine Derivatives Conjugated by Sulfonyl Chlorides: Orally Bioavailable, Selective, Effective Antioxidants and Antimicrobials Drug Candidates

In the present study, we have made an effort to develop the novel synthetic antioxidants and antimicrobials with improved potency. The novel benzofuran-gathered C-2,4,6-substituted pyrimidine derivatives 5a, 5b, 5c, 5d, 5e, 5f, 6a, 6b, 6c, 6d, 6e, 6f, 7a, 7b, 7c, 7d, 7e, 7f, 8a, 8b, 8c, 8d, 8e, 8f, 9a, 9b, 9c, 9d, 9e, 9f were synthesized by simple and efficient four-step reaction pathway. Initially, o-alkyl derivative of salicylaldehyde readily furnish corresponding 2-acetyl benzofuran 2 in good yield, upon the treatment with potassium tertiary butoxide in the presence of molecular sieves. Further, Claisen-Schmidt condensation with aromatic aldehydes via treatment with thiourea followed by coupling reaction with different sulfonyl chlorides afforded target compounds. The structures of newly synthesized compounds were confirmed by IR, H-1 NMR, C-13 NMR, mass, and elemental analysis and further screened for their antioxidant and antimicrobial activities. The results showed that the synthesized compounds 8b, 8e, 9b, and 9e produced significant antioxidant activity with 50% inhibitory concentration higher than that of reference, whereas compounds 7d and 7c produced dominant antimicrobial activity at concentrations 1.0 and 0.5mg/mL compared with standard Gentamicin and Nystatin, respectively.

First-in-Class Inhibitors of Sulfur Metabolism with Bactericidal Activity against Non-Replicating M-tuberculosis

Development of effective therapies to eradicate persistent, slowly replicating M. tuberculosis (Mtb) represents a significant challenge to controlling the global TB epidemic. To develop such therapies, it is imperative to translate information from metabolome and proteome adaptations of persistent Mtb into the drug discovery screening platforms. To this end, reductive sulfur metabolism is genetically and pharmacologically implicated in survival, pathogenesis, and redox homeostasis of persistent Mtb. Therefore, inhibitors of this pathway are expected to serve as powerful tools in its preclinical and clinical validation as a therapeutic target for eradicating persisters. Here, we establish a first functional HTS platform for identification of APS reductase (APSR) inhibitors, a critical enzyme in the assimilation of sulfate for the biosynthesis of cysteine and other essential sulfur-containing molecules. Our HTS campaign involving 38?350 compounds led to the discovery of three distinct structural classes of APSR inhibitors. A class of bioactive compounds with known pharmacology displayed potent bactericidal activity in wild-type Mtb as well as MDR and XDR clinical isolates. Top compounds showed markedly diminished potency in a conditional Delta APSR mutant, which could be restored by complementation with Mtb APSR. Furthermore, ITC studies on representative compounds provided evidence for direct engagement of the APSR target. Finally, potent APSR inhibitors significantly decreased the cellular levels of key reduced sulfur-containing metabolites and also induced an oxidative shift in mycothiol redox potential of live Mtb, thus providing functional validation of our screening data. In summary, we have identified first-in-class inhibitors of APSR that can serve as molecular probes in unraveling the links between Mtb persistence, antibiotic tolerance, and sulfate assimilation, in addition to their potential therapeutic value.

Impossibilità di pensare Dio non esistente : il Proslogion di Anselmo d'Aosta come applicazione implicita dei moderni procedimenti di logica aletica

Resumen: La vera intenzione teologica di Anselmo d’Aosta nello scrivere il Proslogion e il vero significato del suo celebre unum argumentum vanno visti nella funzione che la ragione svolge necessariamente all’interno della vita di fede del cristiano. Anselmo, come Tommaso d’Aquino, non sostiene che l’esistenza di Dio sia un “articulus fidei” ma piuttosto uno dei “praeambula fidei”. La ragione naturale ha la certezza che Dio esiste, ancora prima della dimostrazione metafisica, e questo non fa che confermare l’assurdità di pensare che non esista il fondamento reale di tutte le cose esistenti.

La luz del intelecto agente en los principios de la razón práctica según San Alberto Magno

Resumen: La Antigone de Sófocles y el Corpus Hippocraticum delinean ya los rasgos propios del derecho natural. La ética de Aristóteles, luego, ofrece una primera noción explícita del derecho natural, que San Alberto Magno comenta en Super ethica. Sin embargo, en De inventione de Cicerón el teólogo alemán encuentra su definición de derecho natural: “lo que cierta fuerza innata introdujo”. En De bono V q. 1 San Alberto determina los alcances de esta definición y completa una presentación acabada de la noción de derecho natural. También advierte San Alberto que el hombre, con respecto a la ciencia del intelecto práctico, se encuentra doblemente en potencia. Primero, está en potencia de conocer los principios primeros de esta ciencia y, segundo, una vez conocidos éstos, se encuentra en potencia de inferir a partir de ellos las conclusiones de la ciencia práctica. Poseídas estas conclusiones, finalmente, el hombre está en potencia de aplicarlas en la acción práctica. Intrigado por el modo en que los primeros principios son conocidos, San Alberto advierte que el conocimiento de las nociones correspondientes a estos principios sólo accidentalmente debe ser atribuido al descubrimiento o determinación de los nombres con los que llamamos a estos principios. En verdad, es necesaria la intervención de la luz del intelecto agente para llevar al acto el conocimiento de los principios. En este punto el discurso de San Alberto retorna a la definición ciceroniana: aquella fuerza innata que introduce el derecho natural no es otra que la luz del intelecto agente.

Endocrine disruption in fish: An assessment of recent research and results

This report provides an assessment of recent investigations into endocrine disruption in fresh and saltwater species of fish. Most work to date has concen-trated on reproductive endocrine disruption. Laboratory studies have shown a variety of synthetic and natural chemicals including certain industrial intermediates, PAHs, PCBs, pesticides, dioxins, trace elements and plant sterols can interfere with the endocrine system in fish. The potency of most of these chemicals, however, is typically hundreds to thousands of times less than that of endog-enous hormones. Evidence of environmental endocrine disruption ranges from the presence of female egg proteins in males and reduced levels of endogenous hormones in both males and females, to gonadal histopathologies and intersex (presence of ovotestes) fish. Overt endocrine disruption in fish does not appear to be a ubiquitous environmental phenomenon, but rather more likely to occur near sewage treatment plants, pulp and paper mills, and in areas of high organic chemical contamination. However, more wide-spread endocrine disruption can occur in rivers with smaller flows and correspondingly large or numerous wastewater inputs. Some of the most severe examples of endocrine disruption in fish have been found adjacent to sewage treatment plants. Effects are thought to be caused prima-rily by natural and synthetic estrogens and to a lesser extent by the degradation products of alkylphenol poly-ethoxylate surfactants. Effects found in fish near pulp and paper mills include reduced levels of estrogens and androgens as well as masculinization of females, and has been linked to the presence of β-sitosterol, a plant sterol. Effects seen in areas of heavy industrial activity typically include depressed levels of estrogens and androgens as well as reduced gonadal growth, and may be linked to the presence of PAHs, PCBs, and possibly dioxins. At this time, however, there is no clear indication that large populations of fish are being seriously impacted as a result of endocrine disruption, although additional work is needed to address this possibility. (PDF contains 63 pages)

A Trifluoromethyl Analogue of Celecoxib Exerts Beneficial Effects in Neuroinflammation

15 p.