Design and Synthesis of New Benzimidazole-Carbazole Conjugates for the Stabilization of Human Telomeric DNA, Telomerase Inhibition, and Their Selective Action on Cancer Cells

Cell-permeable small molecules that enhance the stability of the G-quadruplex (G4) DNA structures are currently among the most intensively pursued ligands for inhibition of the telomerase activity. Herein we report the design and syntheses of four novel benzimidazole carbazole conjugates and demonstrate their high binding affinity to G4 DNA. Si nuclease assay confirmed the ligand mediated G-quadruplex DNA protection. Additional evidence from Telomeric Repeat Amplification Protocol (TRAP-LIG) assay demonstrated efficient telomerase inhibition activity by the ligands. Two of the ligands showed IC50 values in the sub-micromolar range in the TRAP-LIG assay, which are the best among the benzimidazole derivatives reported so far. The ligands also exhibited cancer cell selective nuclear internalization, nuclear condensation, fragmentation, and eventually antiproliferative activity in long-term cell viability assays. Annexin V-FITC/PI staining assays confirm that the cell death induced by the ligands follows an apoptotic pathway. An insight into the mode of ligand binding was obtained from the molecular dynamics simulations.

Functionality preservation with enhanced mechanical integrity in the nanocomposites of the metal-organic framework, ZIF-8, with BN nanosheets

Metal-organic frameworks (MOFs) and boron nitride both possess novel properties, the former associated with microporosity and the latter with good mechanical properties. We have synthesized composites of the imidazolate based MOF, ZIF-8, and few-layer BN in order to see whether we can incorporate the properties of both these materials in the composites. The composites so prepared between BN nanosheets and ZIF-8 have compositions ZIF-1BN, ZIF-2BN, ZIF-3BN and similar to ZIF-4BN. The composites have been characterized by PXRD, TGA, XPS, electron microscopy, IR, Raman and solid state NMR spectroscopy. The composites possess good surface areas, the actual value decreasing only slightly with the increase in the BN content. The CO2 uptake remains nearly the same in the composites as in the parent ZIF-8. More importantly, the addition of BN markedly improves the mechanical properties of ZIF-8, a feature that is much desired in MOFs. Observation of microporous features along with improved mechanical properties in a MOF is indeed noteworthy. Such manipulation of properties can be profitably exploited in practical applications.

Controlled synthesis of tunable nanoporous carbons for gas storage and supercapacitor application

A simple methodology has been developed for the synthesis of functional nanoporous carbon (NPC) materials using a metal-organic framework (IRMOF-3) that can act as a template for external carbon precursor (viz, sucrose) and also a self-sacrificing carbon source. The resultant graphitic NPC samples (abbreviated as NPC-0, NPC-150, NPC-300, NPC-500 and NPC-1000 based on sucrose loading) obtained through loading different amounts of sucrose exhibit tunable textural parameters. Among these, NPC-300 shows very high surface area (BET approximate to 3119 m(2)/g, Langmuir approximate to 4031 m(2)/g) with a large pore volume of 1.93 cm(3)/g. High degree of porosity coupled with polar surface functional groups, make NPC-300 remarkable candidate for the uptake of H-2 (2.54 wt% at 1 bar, and 5.1 wt% at 50 bar, 77 K) and CO2 (64 wt% at 1 bar, 195 K and 16.9 wt% at 30 bar, 298 K). As a working electrode in a supercapacitor cell, NPC-300 shows excellent reversible charge storage thus, demonstrating multifunctional usage of the carbon materials. (C) 2015 Elsevier Inc. All rights reserved.

New dimeric carbazole-benzimidazole mixed ligands for the stabilization of human telomeric G-quadruplex DNA and as telomerase inhibitors. A remarkable influence of the spacer

for selectively targeting cancer cells. Herein, we report the design and evolution of a new kind of carbazole-based benzimidazole dimers for their efficient telomerase inhibition activity. Spectroscopic titrations reveal the ligands high affinity toward the G4 DNA with significantly higher selectivity over duplex-DNA. The electrophoretic mobility shift assay shows that the ligands efficiently promote the formation of 04 DNA even at a lower concentration of the stabilizing K+ ions. The TRAP-LIG assay demonstrates the ligand's potential telomerase inhibition activity and also establishes that the activity proceeds via G4 DNA stabilization. An efficient nuclear internalization of the ligands in several common cancer cells (HeLa, HT1080, and A549) also enabled differentiation between normal HFF cells in co-cultures of cancer and normal ones. The ligands induce significant apoptotic response and antiproliferative activity toward cancer cells selectively when compared to the normal cells.

Redox-Active Metal-Organic Frameworks: Highly Stable Charge-Separated States through Strut/Guest-to-Strut Electron Transfer

Molecular organization of donor and acceptor chromophores in self-assembled materials is of paramount interest in the field of photovoltaics or mimicry of natural light-harvesting systems. With this in mind, a redox-active porous interpenetrated metal-organic framework (MOF), {Cd(bpdc)(bpNDI)]4.5H(2)ODMF}(n) (1) has been constructed from a mixed chromophoric system. The -oxo-bridged secondary building unit, {Cd-2(-OCO)(2)}, guides the parallel alignment of bpNDI (N,N-di(4-pyridyl)-1,4,5,8-naphthalenediimide) acceptor linkers, which are tethered with bpdc (bpdcH(2)=4,4-biphenyldicarboxylic acid) linkers of another entangled net in the framework, resulting in photochromic behaviour through inter-net electron transfer. Encapsulation of electron-donating aromatic molecules in the electron-deficient channels of 1 leads to a perfect donor-acceptor co-facial organization, resulting in long-lived charge-separated states of bpNDI. Furthermore, 1 and guest encapsulated species are characterised through electrochemical studies for understanding of their redox properties.

High aspect ratio, processable coordination polymer gel nanotubes based on an AIE-active LMWG with tunable emission

A new TPE based low molecular weight gelator (LMWG) which displays both AIE and MCIE phenomena in gel state has been synthesized. LMWG self-assembles to form 1D nanofibers which undergo morphology transformation to coordination polymer gel (CPG) nanotubes upon metal ion coordination. CPG shows enhanced mechanical stability along with tunable emission properties.

The Comovement between Monetary and Fiscal Policy Instruments during the Post-War Period in the U.S.

This paper empirically studies the dynamic relationship between monetary and fiscal policies by analyzing the comovements between the Fed funds rate and the primary deficit/output ratio. Simple economic thinking establishes that a negative correlation between Fed rate and deficit arises whenever the two policy authorities share a common stabilization objective. However, when budget balancing concerns lead to a drastic deficit reduction the Fed may reduce the Fed rate in order to smooth the impact of fiscal policy, which results in a positive correlation between these two policy instruments. The empirical results show (i) a significant negative comovement between Fed rate and deficit and (ii) that deficit and output gap Granger-cause the Fed funds rate during the post-Volcker era, but the opposite is not true.

Markov Switching Risk Premium and the term structure of interest rates. Empirical evidence from US post-war interest rates

This paper considers the basic present value model of interest rates under rational expectations with two additional features. First, following McCallum (1994), the model assumes a policy reaction function where changes in the short-term interest rate are determined by the long-short spread. Second, the short-term interest rate and the risk premium processes are characterized by a Markov regime-switching model. Using US post-war interest rate data, this paper finds evidence that a two-regime switching model fits the data better than the basic model. The estimation results also show the presence of two alternative states displaying quite different features.

The changing behaviour of the term structure of post-war US

Using U.S. interest rate data covering the period 1950:1-1992:7, this paper tests the rational expectations model of the term structure of interest rates. We show evidence that the rational expectations model of the term structure is supported by the data during the seventies and a period lasting from the mid-eighties to the end of the sample. However, during the …fties, sixties and a period that covers most of the Volcker’s office term (from September 1979 to April 1986) the term structure model is rejected by the data. Moreover, wefind evidence of regime changes in the short-term rate process and the term structure of interest rates. These regime switches roughly coincide with changes in the Federal Reserve chairman. The switches in monetary policy taking place when the chairmanship of the Federal Reserve changes therefore seem to play an important role in characterizing the term structure of interest rates.

Switching Regimes in the Term Structure of Interest Rates During U.S. Post-War: A case for the Lucas proof equilibrium?

Published as an article in: Studies in Nonlinear Dynamics & Econometrics, 2004, vol. 8, issue 1, pages 5.

Voyages and travels into Brasil and east-Indies : containing an exact description of the dutch Brasil and divers parts of the east-Indies, their provinces, cities, living creatures, and products, the manners, customs, habits and religion the inhabitants : with a particular account of all the remarkable passages that happened during the author's stay of nine years in Brasil, especially in relation to the revolt of the portugueses, and the intestine war carried on there from 1640 to 1649 : as also a most ample description of the most famous city of batavia in the east-Indies

Joan Nieuhoff, viajante alemão, nasceu em Usen, Vesfália, em 1618, e morreu em Madagascar, em 1672. Trabalhou na Companhia das Índias Orientais, foi nomeado agente em Batávia, em 1654. Em 1655, foi à China tratar da abertura dos portos daquele país ao comércio holandês. Governou o Ceilão de 1662 a 1667. Em 1672, desembarcando em Madagascar, foi morto pelos nativos.

A photographic record of a pre- and post-lake creation event from World War II at Valley, Isle of Anglesey, UK

The article compares a recent aerial photograph of the lowlands of the Isle of Anglesey area with a German surveillance photograph from 1941. The authors aim to infer the environmental changes made to this sand dune and lake system as a direct consequence of constructing the airfield. Part of Tywyn Trewan, the extensive sand dune system, was completely destroyed in order to create runways and the technical and domestic accommodation to house a strategic airfield. As part of the dredging, six new water bodies with a combined surface area of approximately 6 ha were created.

Humanism after the Spanish Civil War: Gernika (1945-53), a Humanities and Social Sciencesbasque magazine

Espainiako Gerra Zibilaren eta II. Mundu Gerrarren ostean Gerra Hotza heldu zen. Testuinguru larri horretan humanismoan ikusi zuten hainbatek zibilizazio-krisiari irtenbidea topatzeko bidea. Gernika aldizkariak (1945-53) bere burua humanistatzat zeukan. Bertako idazleek gai horren inguruan zer adierazi zuten jasotzen saiatu gara, euskarazko zein erdarazko artikuluetan agertzen diren iritziak sailkatuz.