Iron(III) Schiff base complexes of arginine and lysine as netropsin mimics showing AT-selective DNA binding and photonuclease activity

Iron(III) complexes [Fe(L)(2)]Cl (1-3), where L is monoanionic N-salicylidene-arginine (sal-argH for 1), hydroxynaphthylidene-arginine (nap-argH for 2) and N-salicylidene-lysine (sal-lysH for 3), were prepared and their DNA binding and photo-induced DNA cleavage activity studied. Complex 3 as its hexafluorophosphate salt [Fe(sal-lysH)(2)](PF6)center dot 6H(2)O (3a) was structurally characterized by single crystal Xray crystallography. The crystals belonged to the triclinic space group P-1. The complex has two tridentate ligands in FeN2O4 coordination geometry with two pendant cationic amine moieties. Complexes 1 and 2 with two pendant cationic guanidinium moieties are the structural models for the antitumor antibiotics netropsin. The complexes are stable and soluble in water. They showed quasi-reversible Fe(III)/Fe(II) redox couple near 0.6 V in H2O-0.1 M KCl. The high-spin 3d(5)-iron(III) complexes with mu(eff) value of similar to 5.9 mu(B) displayed ligand-to-metal charge transfer electronic band near 500 mm in Tris-HCl buffer. The complexes show binding to Calf Thymus (CT) DNA. Complex 2 showed better binding propensity to the synthetic oligomer poly(dA)center dot poly(dT) than to CT-DNA or poly(dG)center dot poly(dC). All the complexes displayed chemical nuclease activity in the presence of 3-mercaptopropionic acid as a reducing agent and cleaved supercoiled pUC19 DNA to its nicked circular form. They exhibited photo-induced DNA cleavage activity in UV-A light and visible light via a mechanistic pathway that involves the formation of reactive hydroxyl radical species. (C) 2010 Elsevier Inc. All rights reserved.

Investigation of inter-ion interactions in N,N,N',N'-tetramethylethylenediammonium dithiocyanate via experimental and theoretical charge density studies

The crystal structure of the N,N,N',N'-tetramethylethylenediammonium dithiocyanate salt has been examined by experimental charge density studies from high-resolution X-ray diffraction data. The corresponding results are compared with multipole refinements, using theoretical structure factors obtained from a periodic density functional theory calculation at the B3LYP level with a 6-31G** basis set. The salt crystallizes in space group P (1) over bar and contains only a single ion pair with an inversion center in the cation. The salt has thus one unique classical N+-H center dot center dot center dot(NCS)(-) hydrogen bond but also has six other weaker interactions: four C-H center dot center dot center dot S, one C-H center dot center dot center dot N, and one C-H center dot center dot center dot C-pi. The nature of all these interactions has been examined topologically using Bader's quantum theory of "atoms in molecules" and all eight of the Koch-Popelier criteria. The experimental and theoretical approaches agree well and both show that the inter-ion interactions, even in this simplest of systems, play an integrated and complex role in the packing of the ions in the crystal. Electrostatic potential maps are derived from experimental charge densities. This is the first time such a system has been examined in detail by these methods.

Digital Photography in the Diagnosis and Follow-up of Ocular Diseases

Purpose: The aim of the present study was to develop and test new digital imaging equipment and methods for diagnosis and follow-up of ocular diseases. Methods: The whole material comprised 398 subjects (469 examined eyes), including 241 patients with melanocytic choroidal tumours, 56 patients with melanocytic iris tumours, 42 patients with diabetes, a 52-year old patient with chronic phase of VKH disease, a 30-year old patient with an old blunt eye injury, and 57 normal healthy subjects. Digital 50° (Topcon TRC 50 IA) and 45° (Canon CR6-45NM) fundus cameras, a new handheld digital colour videocamera for eye examinations (MediTell), a new subtraction method using the Topcon Image Net Program (Topcon corporation, Tokyo, Japan), a new method for digital IRT imaging of the iris we developed, and Zeiss photoslitlamp with a digital camera body were used for digital imaging. Results: Digital 50° red-free imaging had a sensitivity of 97.7% and two-field 45° and 50° colour imaging a sensitivity of 88.9-94%. The specificity of the digital 45°-50° imaging modalities was 98.9-100% versus the reference standard and ungradeable images that were 1.2-1.6%. By using the handheld digital colour video camera only, the optic disc and central fundus located inside 20° from the fovea could be recorded with a sensitivity of 6.9% for detection of at least mild NPDR when compared with the reference standard. Comparative use of digital colour, red-free, and red light imaging showed 85.7% sensitivity, 99% specificity, and 98.2 % exact agreement versus the reference standard in differentiation of small choroidal melanoma from pseudomelanoma. The new subtraction method showed growth in four of 94 melanocytic tumours (4.3%) during a mean ±SD follow-up of 23 ± 11 months. The new digital IRT imaging of the iris showed the sphincter muscle and radial contraction folds of Schwalbe in the pupillary zone and radial structural folds of Schwalbe and circular contraction furrows in the ciliary zone of the iris. The 52-year-old patient with a chronic phase of VKH disease showed extensive atrophy and occasional pigment clumps in the iris stroma, detachment of the ciliary body with severe ocular hypotony, and shallow retinal detachment of the posterior pole in both eyes. Infrared transillumination imaging and fluorescein angiographic findings of the iris showed that IR translucence (p=0.53), complete masking of fluorescence (p=0.69), presence of disorganized vessels (p=0.32), and fluorescein leakage (p=1.0) at the site of the lesion did not differentiate an iris nevus from a melanoma. Conclusions: Digital 50° red-free and two-field 50° or 45° colour imaging were suitable for DR screening, whereas the handheld digital video camera did not fulfill the needs of DR screening. Comparative use of digital colour, red-free and red light imaging was a suitable method in the differentiation of small choroidal melanoma from different pseudomelanomas. The subtraction method may reveal early growth of the melanocytic choroidal tumours. Digital IRT imaging may be used to study changes of the stroma and posterior surface of the iris in various diseases of the uvea. It contributed to the revealment of iris atrophy and serous detachment of the ciliary body with ocular hypotony together with the shallow retinal detachment of the posterior pole as new findings of the chronic phase of VKH disease. Infrared translucence and angiographic findings are useful in differential diagnosis of melanocytic iris tumours, but they cannot be used to determine if the lesion is benign or malignant.

Parametrized actor-critic algorithms for finite-horizon MDPs

Due to their non-stationarity, finite-horizon Markov decision processes (FH-MDPs) have one probability transition matrix per stage. Thus the curse of dimensionality affects FH-MDPs more severely than infinite-horizon MDPs. We propose two parametrized 'actor-critic' algorithms to compute optimal policies for FH-MDPs. Both algorithms use the two-timescale stochastic approximation technique, thus simultaneously performing gradient search in the parametrized policy space (the 'actor') on a slower timescale and learning the policy gradient (the 'critic') via a faster recursion. This is in contrast to methods where critic recursions learn the cost-to-go proper. We show w.p 1 convergence to a set with the necessary condition for constrained optima. The proposed parameterization is for FHMDPs with compact action sets, although certain exceptions can be handled. Further, a third algorithm for stochastic control of stopping time processes is presented. We explain why current policy evaluation methods do not work as critic to the proposed actor recursion. Simulation results from flow-control in communication networks attest to the performance advantages of all three algorithms.

Gene modulation and immunoregulatory roles of Interferon gamma

Interferon-gamma (IFN gamma) is a central regulator of the immune response and signals via the Janus Activated Kinase (JAK)-Signal Transducer and Activator of Transcription (STAT) pathway. Phosphorylated STAT1 homodimers translocate to the nucleus, bind to Gamma Activating Sequence (GAS) and recruit additional factors to modulate gene expression. A bioinformatics analysis revealed that greater number of putative promoters of immune related genes and also those not directly involved in immunity contain GAS compared to response elements (RE) for Interferon Regulatory Factor (IRF)1, Nuclear factor kappa B (NF kappa B) and Activator Protein (AP)1. GAS is present in putative promoters of well known IFN gamma-induced genes, IRF1, GBP1, CXCL10, and other genes identified were TLR3, VCAM1, CASP4, etc. Analysis of three microarray studies revealed that the expression of asubset of only GAS containing immune genes were modulated by IFN gamma. As a significant correlation exists between GAS containing immune genes and IFN gamma-regulated gene expression, this strategy may identify novel IFN gamma-responsive immune genes. This analysis is integrated with the literature on the roles of IFN gamma in mediating a plethoraof functions: anti-microbial responses, antigen processing,inflammation, growth suppression, cell death, tumor immunity and autoimmunity. Overall, this review summarizes our present knowledge onIFN gamma mediated signaling and functions. (C) 2009 Elsevier Ltd. All rights reserved.

Solving MDPs using two-timescale simulated annealing with multiplicative weights

We develop extensions of the Simulated Annealing with Multiplicative Weights (SAMW) algorithm that proposed a method of solution of Finite-Horizon Markov Decision Processes (FH-MDPs). The extensions developed are in three directions: a) Use of the dynamic programming principle in the policy update step of SAMW b) A two-timescale actor-critic algorithm that uses simulated transitions alone, and c) Extending the algorithm to the infinite-horizon discounted-reward scenario. In particular, a) reduces the storage required from exponential to linear in the number of actions per stage-state pair. On the faster timescale, a 'critic' recursion performs policy evaluation while on the slower timescale an 'actor' recursion performs policy improvement using SAMW. We give a proof outlining convergence w.p. 1 and show experimental results on two settings: semiconductor fabrication and flow control in communication networks.

Kohdennetut liposomit syövän hoidossa

Suurin ongelma syöpätautien lääkehoidossa on sen aiheuttamat toksiset sivuvaikutukset. Tyypillisesti vain noin 1 % elimistöön annostellusta lääkeaineesta saavuttaa hoitoa tarvitsevat syöpäsolut, loppuosa lääkeaineesta jää vahingoittamaan elimistön terveitä soluja. Toksiset sivuvaikutukset rajoittavat lääkehoidon annoksen nostamista elimistössä riittävälle pitoisuudelle, mikä johtaa usein sairauden ennenaikaiseen pahenemiseen ja mahdollisen lääkeaineresistenssin kehittymiseen. Liposomien välittämä lääkeaineen kohdentaminen voidaan jakaa kahteen eri menetelmään: passiiviseen ja aktiiviseen kohdentamiseen. Liposomien passiivisen kohdentamisen tarkoituksena on lisätä sytotoksisen lääkeaineen paikallistumista pelkästään kasvainkudokseen. Passiivinen kohdentaminen perustuu liposomien kulkeutumiseen verenkierron mukana, jolloin liposomit kerääntyvät epänormaalisti muodostuneeseen kasvainkudokseen. Liposomien aktiivisella kohdentamisella pyritään parantamaan passiivisesti kohdentuvien liposomien terapeuttista tehokkuutta kohdentamalla lääkeaineen vaikutus pelkästään syöpäsoluihin. Aktiivisessa kohdennuksessa liposomin pintaan kiinnitetään ligandi, joka spesifisesti tunnistaa kohdesolun. Tämän pro gradu -tutkielman kirjallisen osion tarkoituksena oli tutustua syöpäkudokseen kohdennettujen liposomien ominaisuuksiin tehokkaan soluunoton ja sytotoksisuuden saavuttamiseksi. Kokeellisessa osiossa tutkittiin kohdennettujen liposomien soluunottoa ja sytotoksista vaikutusta ihmisen munasarjasta eristetyillä adenokarsinoomasoluilla (SKOV-3). Liposomit kohdennettiin setuksimabi (C225, Erbitux®) vasta-aineella, jonka on todettu olevan tietyissä syöpätyypeissä (mm. keuhko- ja kolorektaalisyövissä, pään ja kaulan syövissä sekä rinta-, munuais-, eturauhas-, haima- ja munasarjasyövissä) yli-ilmentyneen epidermaalisen kasvutekijäreseptoriperheen HER1-proteiinin (ErbB-1, EGFR, epidermal growth factor receptor) spesifinen ja selektiivinen inhibiittori. Afrikan viherapinan munuaisista lähtöisin olevaa CV-1 solulinjaa käytettiin kontrollina kuvaamaan elimistön normaaleja soluja. Kohdennettujen liposomien soluunottoa tutkittiin soluunottokokeilla, joissa käytettiin kontrollina kohdentamattomia pegyloituja liposomeja. Setuksimabi-vasta-aineen spesifinen sitoutuminen EGF-reseptoriin todettiin kilpailutuskokeilla. Doksorubisiinia sisältävien immunoliposomien sytotoksisuutta selvitettiin Alamar Blue™ -elävyystestillä. Lisäksi immunoliposomien säilyvyyttä seurattiin mittaamalla liposomien keskimääräinen halkaisija noin kahden viikon välein. Setuksimabi-vasta-aineella kohdennettujen liposomien soluunotto oli huomattavasti suurentunut SKOV-3 syöpäsoluissa ja doksorubisiinia sisältävät kohdennetut liposomit aiheuttivat voimakkaamman sytotoksisen vaikutuksen kuin kohdentamattomat liposomit. Kohdennettujen doksorubisiiniliposomien sytotoksisuus tuli kuitenkin esille viiveellä, mikä viittaa lääkeaineen hitaaseen vapautumiseen liposomista. Suurentunutta soluunottoa ja sytotoksista vaikutusta ei havaittu CV-1 solulinjassa. Kohdennettujen liposomien sovellusmahdollisuudet lääketieteessä ja syövän hoidossa ovat merkittävät. Tällä hetkellä liposomien kliininen käyttö rajoittuu passiivisesti kohdennettuihin liposomeihin (Doxil® (Am.),Caelyx® (Eur.)). Lupaavista solukokeista huolimatta kohdennettujen liposomien terapeuttinen käyttö tulevaisuudessa näyttää haasteelliselta.

A Device to Crystallize Organic Solids: Structure of Ciprofloxacin, Midazolam, and Ofloxacin as Targets

The crystal structure determination of the anhydrous form of any organic compound has been a challenge because of solvent incorporation during crystallization. A device to grow anhydrous forms of low melting organic solids based on vaporization and condensation by a gradient cooling technique has been designed. Its utility has been evaluated by growing anhydrous forms of ciprofloxacin, midazolam, and ofloxacin. Ciprofloxacin crystallizes in triclinic P (1) over bar, midazolam in monoclinic P2(1)/n, and ofloxacin in the C2/c space group. Comparative studies on the conformational features with solvated structure show no significant variation in the aromatic moieties.

SPSA algorithms with measurement reuse

Four algorithms, all variants of Simultaneous Perturbation Stochastic Approximation (SPSA), are proposed. The original one-measurement SPSA uses an estimate of the gradient of objective function L containing an additional bias term not seen in two-measurement SPSA. As a result, the asymptotic covariance matrix of the iterate convergence process has a bias term. We propose a one-measurement algorithm that eliminates this bias, and has asymptotic convergence properties making for easier comparison with the two-measurement SPSA. The algorithm, under certain conditions, outperforms both forms of SPSA with the only overhead being the storage of a single measurement. We also propose a similar algorithm that uses perturbations obtained from normalized Hadamard matrices. The convergence w.p. 1 of both algorithms is established. We extend measurement reuse to design two second-order SPSA algorithms and sketch the convergence analysis. Finally, we present simulation results on an illustrative minimization problem.

Crystal structures and photocatalysis of the triclinic polymorphs of BiNbO4 and BiTaO4

The high-temperature polymorphs of two photocatalytic materials, BiNbO4 and BiTaO4 were synthesized by the ceramic method. The crystal structures of these materials were determined by single-crystal X-ray diffraction. BiNbO4 and BiTaO4 crystallize into the triclinic system P (1) over bar (No. 2), with a = 5.5376(4) angstrom, b = 7.6184(3) angstrom, c = 7.9324(36) angstrom, alpha = 102.565(3)degrees, beta = 90.143(2)degrees, gamma = 92.788 (4)degrees, V = 326.21 (5) angstrom(3). Z = 4 and a = 5.931(1) angstrom, b = 7.672(2) angstrom, c = 7.786(2) angstrom, alpha = 102.94 (3)degrees, beta = 90.04(3)degrees gamma = 93.53(3)degrees, V = 344.59(1) angstrom(3) and Z = 4, respectively. The structures along the c-axis, consist of layers of [Bi2O2] units separated by puckered sheets of (Nb/Ta)O-6 octahedra. Photocatalytic studies on the degradation of dyes indicate selectivity of BiNbO4 towards aromatics containing quinonic and azo functional groups

Crystal structure and conformation study of N-methyl-t-3-methyl-r-2, c-6-diphenylpiperidin-4-one thiosemicarbazone

Thiosemicarbazones are having the ability to bind with metal and inhibit the enzyme ribonucleoside diphosphate reductase(RDR),an enzyme which is involved in the synthesis of DNA precursors in the mammalian cells.The title compound N-methyl-t-3-methyl-r-2, c-6-diphenylpiperidin-4-one thiosemicarbazone (NMMDPT), CCDC 218052, was prepared using Mannich reaction and characterized by X-ray diffraction methods.The crystal data are:C20H24N4S; M.W= 352.49, triclinic,space group P (1) over bar, a = 8.467(2)angstrom, b = 10.228(2)angstrom, c = 12.249(2)angstrom; lpha=92.595(3)degrees, beta=104.173(3)degrees, gamma=13.628(3)degrees; V=930.0(3)angstrom(3), Z=2, D-cal=1.259Mgm(-3),mu=0.184mm(-1),lambda (MoKalpha)=0.71073 angstrom, final R1 and wR2 are 0.0470 and 0.1052, respectively. The piperidine rings adopt chair conformation. The planar phenyl rings are oriented equatorially at 2,6-positions of the piperidine ring. The molecular packing can be viewed as dimers held together by two N-H...S types of intermolecular hydrogen bonds. Weak C-H...pi interactions also support the stability of the molecules in the crystal in addition to van der Waals forces. (c) 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

High-temperature superconductivity in bismuth-copper oxides of the type BimMnCupOx (M=Mg, Ca, Sr, Ba, Bi)

Several oxides of the Bi m M n Cu p O x family (m=2, 3;n=2, 3, 4;p=1, 2, 3 and M=alkaline earth or Bi), possessing structures similar to the Aurivillius family of oxides, show highT c superconductivity.

Polarization Caging in Diffusion-Controlled Electron Transfer Reactions in Solution

In some bimolecular diffusion-controlled electron transfer (ET) reactions such as ion recombination (IR), both solvent polarization relaxation and the mutual diffusion of the reacting ion pair may determine the rate and even the yield of the reaction. However, a full treatment with these two reaction coordinates is a challenging task and has been left mostly unsolved. In this work, we address this problem by developing a dynamic theory by combining the ideas from ET reaction literature and barrierless chemical reactions. Two-dimensional coupled Smoluchowski equations are employed to compute the time evolution of joint probability distribution for the reactant (P-(1)(X,R,t)) and the product (p((2))(X,R,t)), where X, as is usual in ET reactions, describes the solvent polarization coordinate and R is the distance between the reacting ion pair. The reaction is described by a reaction line (sink) which is a function of X and R obtained by imposing a condition of equal energy on the initial and final states of a reacting ion pair. The resulting two-dimensional coupled equations of motion have been solved numerically using an alternate direction implicit (ADI) scheme (Peaceman and Rachford, J. Soc. Ind. Appl. Math. 1955, 3, 28). The results reveal interesting interplay between polarization relaxation and translational dynamics. The following new results have been obtained. (i) For solvents with slow longitudinal polarization relaxation, the escape probability decreases drastically as the polarization relaxation time increases. We attribute this to caging by polarization of the surrounding solvent, As expected, for the solvents having fast polarization relaxation, the escape probability is independent of the polarization relaxation time. (ii) In the slow relaxation limit, there is a significant dependence of escape probability and average rate on the initial solvent polarization, again displaying the effects of polarization caging. Escape probability increases, and the average rate decreases on increasing the initial polarization. Again, in the fast polarization relaxation limit, there is no effect of initial polarization on the escape probability and the average rate of IR. (iii) For normal and barrierless regions the dependence of escape probability and the rate of IR on initial polarization is stronger than in the inverted region. (iv) Because of the involvement of dynamics along R coordinate, the asymmetrical parabolic (that is, non-Marcus) energy gap dependence of the rate is observed.