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.

Distal anterior cerebral artery aneurysms

Objective: Distal anterior cerebral artery (DACA) aneurysms represent about 6% of all intracranial aneurysms. So far, only small series on treatment of these aneurysms have been published. Our aim is to evaluate the anatomic features, microneurosurgical techniques, treatment results, and long-term outcome in patients treated for DACA aneurysms. Patients and methods: We analyzed the clinical and radiological data on 517 consecutive patients diagnosed with DACA aneurysm at two neurosurgical centers serving solely the Southern (Helsinki) and Eastern (Kuopio) Finland in 1936–2007, and used a defined subgroup of the whole study population in each part of the study. Detailed anatomic analysis was performed in 101 consecutive patients from 1998 to 2007. Treatment results were analyzed in 427 patients treated between 1980 to 2005, the era of CT imaging and microneurosurgery. Long-term treatment outcome of ruptured DACA aneurysm(s) was evaluated in 280 patients with a median follow-up of 10 years; no patients were lost to follow-up. Results: DACA aneurysms, found most often (83%) at the A3 segment of the anterior cerebral artery (ACA), were smaller (median 6 mm vs. 8 mm), more frequently associated with multiple aneurysms (35% vs. 18%), and presented more often with intracerebral hematomas (ICHs) (53% vs. 26%) than ruptured aneurysms in general. They were associated with anomalies of the ACA in 23% of the patients. Microsurgical treatment showed similar complication rates (treatment morbidity 15%, treatment mortality 0.4%) as for other ruptured aneurysms. At one year after subarachnoid hemorrhage (SAH), DACA aneurysms had equally favorable outcome (GOS≥4) as other ruptured aneurysms (74% vs. 69%) but their mortality was lower (13% vs. 24%). Factors predicting unfavorable outcome for ruptured DACA aneurysms were advanced age, Hunt&Hess≥3, rebleeding before treatment, ICH, intraventricular hemorrhage, and severe preoperative hydrocephalus. The cumulative relative survival ratio showed 16% excess mortality in patients with ruptured DACA aneurysm during the first three years after SAH compared to the matched general population. From the fourth year onwards, there was no excess mortality during the follow-up. There were four episodes of recurrent SAH, only one due to treated DACA aneurysm, with a 10-year cumulative risk of 1.4%. Conclusions: The special neurovascular features and frequent association with anterior cerebral artery anomalies must be taken into account when planning occlusive treatment of DACA aneurysms. Clipping of DACA aneurysms provides a long-lasting result, with very small rates of rebleeding. After surviving three years from rupture of DACA aneurysm, the long-term survival of these patients becomes similar to that of the matched general population.

Lung structure and function studied by synchrotron radiation

A novel method for functional lung imaging was introduced by adapting the K-edge subtraction method (KES) to in vivo studies of small animals. In this method two synchrotron radiation energies, which bracket the K-edge of the contrast agent, are used for simultaneous recording of absorption-contrast images. Stable xenon gas is used as the contrast agent, and imaging is performed in projection or computed tomography (CT) mode. Subtraction of the two images yields the distribution of xenon, while removing practically all features due to other structures, and the xenon density can be calculated quantitatively. Because the images are recorded simultaneously, there are no movement artifacts in the subtraction image. Time resolution for a series of CT images is one image/s, which allows functional studies. Voxel size is 0.1mm3, which is an order better than in traditional lung imaging methods. KES imaging technique was used in studies of ventilation distribution and the effects of histamine-induced airway narrowing in healthy, mechanically ventilated, and anaesthetized rabbits. First, the effect of tidal volume on ventilation was studied, and the results show that an increase in tidal volume without an increase in minute ventilation results a proportional increase in regional ventilation. Second, spiral CT was used to quantify the airspace volumes in lungs in normal conditions and after histamine aerosol inhalation, and the results showed large patchy filling defects in peripheral lungs following histamine provocation. Third, the kinetics of proximal and distal airway response to histamine aerosol were examined, and the findings show that the distal airways react immediately to histamine and start to recover, while the reaction and the recovery in proximal airways is slower. Fourth, the fractal dimensions of lungs was studied, and it was found that the fractal dimension is higher at the apical part of the lungs compared to the basal part, indicating structural differences between apical and basal lung level. These results provide new insights to lung function and the effects of drug challenge studies. Nowadays the technique is available at synchrotron radiation facilities, but the compact synchrotron radiation sources are being developed, and in relatively near future the method may be used at hospitals.

Nonlinear ensemble prediction of chaotic daily rainfall

The significance of treating rainfall as a chaotic system instead of a stochastic system for a better understanding of the underlying dynamics has been taken up by various studies recently. However, an important limitation of all these approaches is the dependence on a single method for identifying the chaotic nature and the parameters involved. Many of these approaches aim at only analyzing the chaotic nature and not its prediction. In the present study, an attempt is made to identify chaos using various techniques and prediction is also done by generating ensembles in order to quantify the uncertainty involved. Daily rainfall data of three regions with contrasting characteristics (mainly in the spatial area covered), Malaprabha, Mahanadi and All-India for the period 1955-2000 are used for the study. Auto-correlation and mutual information methods are used to determine the delay time for the phase space reconstruction. Optimum embedding dimension is determined using correlation dimension, false nearest neighbour algorithm and also nonlinear prediction methods. The low embedding dimensions obtained from these methods indicate the existence of low dimensional chaos in the three rainfall series. Correlation dimension method is done on th phase randomized and first derivative of the data series to check whether the saturation of the dimension is due to the inherent linear correlation structure or due to low dimensional dynamics. Positive Lyapunov exponents obtained prove the exponential divergence of the trajectories and hence the unpredictability. Surrogate data test is also done to further confirm the nonlinear structure of the rainfall series. A range of plausible parameters is used for generating an ensemble of predictions of rainfall for each year separately for the period 1996-2000 using the data till the preceding year. For analyzing the sensitiveness to initial conditions, predictions are done from two different months in a year viz., from the beginning of January and June. The reasonably good predictions obtained indicate the efficiency of the nonlinear prediction method for predicting the rainfall series. Also, the rank probability skill score and the rank histograms show that the ensembles generated are reliable with a good spread and skill. A comparison of results of the three regions indicates that although they are chaotic in nature, the spatial averaging over a large area can increase the dimension and improve the predictability, thus destroying the chaotic nature. (C) 2010 Elsevier Ltd. All rights reserved.

Stereochemical analysis of the antigenic tip of the V3 loop peptide of HIV-1 gp120

A novel multiple turn conformation has been observed for a segment GPGRAFY in the crystal structure of a complex of HIV-1 gp120 V3 loop peptide with the Fab fragment of a neutralizing antibody [Ghiara ct al. (1994) Science 264, 82-85]. A structural motif has been defined for the peptide segment, employing idealized backbone conformations characterized by ranges of virtual C-alpha torsion angles and bond angles. A search of 122 high-resolution protein crystal structures has permitted identification of 24 examples of similar structural motifs. Two major conformational families have been identified, which differ primarily in the conformation at residue 3. The observed conformation at residue 3 in family 1 is left-handed helical (alpha(L)) and that in family 2 is right-handed helical (alpha(R)). Of the 10 examples in family 1, 9 examples have Gly residues at position 3. Of the 12 examples in family 2, 7 examples have Asn/Asp at position 3. Computer modeling of the V3 loop tip sequence using the two backbone conformational families as starting points leads to minimum-energy conformations in which antigenically important side-chains occupy similar spatial arrangements. This stereochemical analysis of the V3 loop tip sequence suggests a rational basis for the design of synthetic analog peptides for use as viral antagonists or synthetic antigens. (C) Munksgaard 1995.

Synthesis, sintering and microstructural characterization of nanocrystalline Hydroxyapatite Composites

Nanocrystalline hydroxyapatite (HAp) exhibits better bioactivity and biocompatibility with enhanced mechanical properties compared to the microcrystalline counterpart. In the present work, nanocrystalline hydroxyapatite was synthesized by wet chemical method. Sintering was carried out with nanocrystalline alumina as additive, the content of alumina being varied from 10 to 30 wt% in the composite. For 20 and 30 wt % Al2O3, hydroxyapatite decomposed into tricalcium phosphate (TCP) above the sintering temperature of 1100 degrees C. The fracture toughness of nano HAp-nano Al2O3 composite is anisotropic in nature and reached a maximum value of 6.9 MPa m(1/2).

Detection,amplification and sequence homology of sodC in clinical isolates of Salmonella sp

Background & objectives: Periplasmic copper and zinc superoxide dismutase (Cu,Zn-SOD or SodC) is an important component of the antioxidant shield which protects bacteria from the phagocytic oxidative burst. Cu,Zn-SODs protect Gram-negative bacteria against oxygen damage which have also been shown to contribute to the pathogenicity of these bacterial species. We report the presence of SodC in drug resistant Salmonella sp. isolated from patients suffering from enteric fever. Further sodC was amplified, cloned into Escherichia coli and the nucleotide sequence and amino acid sequence homology were compared with the standard strain Salmonella Typhimurium 14028. Methods: Salmonella enterica serovar Typhi (S. Typhi) and Salmonellaenterica serovar Paratyphi (S. Paratyphi) were isolated and identified from blood samples of the patients. The isolates were screened for the presence of Cu, Zn-SOD by PAGE using KCN as inhibitor of Cu,Zn-SOD. The gene (sodC) was amplified by PCR, cloned and sequenced. The nucleotide and amino acid sequences of sodC were compared using CLUSTAL X.Results: SodC was detected in 35 per cent of the Salmonella isolates. Amplification of the genomic DNA of S. Typhi and S. Paratyphi with sodC specific primers resulted in 519 and 515 bp amplicons respectively. Single mutational difference at position 489 was observed between thesodC of S. Typhi and S. Paratyphi while they differed at 6 positions with the sodC of S. Typhimurium 14028. The SodC amino acid sequences of the two isolates were homologous but 3 amino acid difference was observed with that of standard strain S. Typhimurium 14028.Interpretation & conclusions: The presence of SodC in pathogenic bacteria could be a novel candidate as phylogenetic marker.

Oncolytic Adenoviruses with Radiation Therapy for Treatment of Prostate Cancer

Prostate cancer is the most common cancer in males. Although many patients with localized disease can be cured with surgery and radiotherapy, advanced disease and especially castration resistant metastatic disease remains incurable, with a median life expectancy of less than 18 months. Oncolytic adenoviruses (Ads) are a new promising treatment against cancer due to their innate capacity to kill cancer cells. Viral replication in tumor cells leads to oncolysis and production of a multiplicity of new virions that are capable of further destroying cancerous tissue. Oncolytic Ads can be modified for tumor targeted infection and replication and be armed with therapeutic transgenes to maximize the oncolytic effect. Worldwide, clinical trials with oncolytic Ads have demonstrated good safety while the antitumor efficacy remains to be improved. Importantly, the best responses have been reported when oncolytic adenoviruses have been combined with standard cancer treatments, such as chemotherapy and radiation. Further, a challenge in many virotherapy approaches has been the monitoring of virus replication in vivo. Reporter genes have been extensively used as transgenes to evaluate the biodistribution of the virus and activity of specific promoters. However, these techniques are often limited to preclinical evaluation and not amenable to human use. The aim of the thesis was to find and develop new oncolytic Ads with maximum efficacy against metastatic, castration resistant prostate cancer and study them in vitro and in vivo combined to different forms of radiation therapy. Using combination therapy, we were aiming for better antitumor efficacy with reduced side effects. Capsid modified Ads for enhanced transduction were studied. Serotype 3 targeted chimera, Ad5/3, was found to have enhanced infectivity for prostate cancer and was used for developing new viruses for the study. Correlation between Ad-encoded marker peptide secretion and simultaneous viral replication was evaluated and the effects of radiotherapy on viral replication were studied in detail. We found that the repair of double strand breaks caused by ionizing radiation was inhibited by adenoviral proteins and led to autophagic cell death. Both subcutaneous models and intrapulmonary tumor models mimicking metastatic, aggressive disease were used in vivo. Virus efficacy was evaluated by intratumoral injections. Also, intravenous administration was evaluated to study the effectiveness in metastatic disease. Oncolytic adenovirus treatment led to significant tumor growth control and increased the survival rate of the mice. These results were further improved when oncolytic Ads were combined with radiation therapy. Oncolytic Ads expressing human sodium/iodide transporter (hNIS) as a transgene were evaluated for their oncolytic potency and for the functionality of hNIS in vitro and in vivo. Monitoring of viral replication was also assessed using different imaging modalities relative to clinical use. SPECT imaging of tumor-bearing mice was evaluated and combined with simultaneous CT-scanning to obtain important anatomical information on biodistribution, also in a three-dimensional form. It was shown that hNIS-expressing adenoviruses could harbour a bi-functional transgene allowing for localization and imaging of viral replication. Targeted radiotherapy was applied by systemic radioiodide administration and resulted in iodide accumulation into Ad-infected tumor. The combination treatment showed significantly enhanced antitumor efficacy in mice bearing prostate cancer tumors. In summary, the results presented above aim to provide new treatment modalities for castration resistant prostate cancer. Molecular insights were provided for better understanding of the benefits of combined radiation therapy and oncolytic adenoviruses, which will hopefully facilitate the translation of the approach into clinical use for humans.

Association of methylenetetrahydrofolate reductase gene polymorphisms & colorectal cancer in India

Background & objectives: Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate metabolism and involved in DNA synthesis, DNA repair and DNA methylation. The two common functional polymorphisms of MTHFR, 677C -> T and 1298 A -> C have shown to impact several diseases including cancer. This case-control study was undertaken to analyse the association of the MTHFR gene polymorphisms 677 C -> T and 1298 A -> C and risk of colorectal cancer (CRC).Methods: One hundred patients with a confirmed histopathologic diagnosis of CRC and 86 age and gender matched controls with no history of cancer were taken for this study. DNA was isolated from peripheral blood samples and the genotypes were determined by PCR-RFLP. The risk association was estimated by compounding odds ratio (OR) with 95 per cent confidence interval (CI). Results: Genotype frequency of MTHFR 677 CC, CT and TT were 76.7, 22.1 and 1.16 per cent in controls, and 74,25 and 1.0 per cent among patients. The 'T' allele frequency was 12.21 and 13.5 per cent in controls and patients respectively. The genotype frequency of MTHFR 1298 AA, AC, and CC were 25.6, 58.1 and 16.3 per cent for controls and 22, 70 and 8 per cent for patents respectively. The 'C' allele frequency for 1298 A -> C was 43.0 and 45.3 per cent respectively for controls and patients. The OR for 677 CT was 1.18 (95% CI 0.59-2.32, P = 0.642), OR for 1298 AC was 1.68 (95% CI 0.92-3.08, P = 0.092) and OR for 1298 CC was 0.45(95% CI 0.18-1.12, P = 0.081). The OR for the combined heterozygous state (677 CT and 1298 AC) was 1.18(95% CI 0.52-2.64, P =0.697).Interpretation & conclusion: The frequency of the MTHFR 677 TT genotype is rare as compared to 1298 CC genotype in the population studied. There was no association between 677 C -> T and 1298 A -> C polymorphisms and risk of CRC either individually or in combination. The homozygous state for 1298 A -> C polymorphism appears to slightly lower risk of CRC. This needs to be confirmed with a larger sample size.

Methylenetetrahydrofolate reductase gene polymorphisms and risk of acute lymphoblastic leukemia in children

Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate metabolism and is involved in DNA synthesis, DNA repair and DNA methylation. Genetic polymorphisms of this enzyme have been shown to impact several diseases, including cancer. Leukemias are malignancies arising from rapidly proliferating hematopoietic cells having great requirement of DNA synthesis. This case-control study was undertaken to analyze the association of the MTHFR gene polymorphisms 677 C"T and 1298 A"C and the risk of acute lymphoblastic leukemia in children. Materials and Methods: Eighty-six patients aged below 15 years with a confirmed diagnosis of acute lymphoblastic leukemia (ALL) and 99 matched controls were taken for this study. Analysis of the polymorphisms was done using the polymerase chain reaction -restriction fragment length polymorphism (PCR-RFLP) method. Results: Frequency of MTHFR 677 CC and CT were 85.9% and 14.1% in the controls, and 84.9% and 15.1% in the cases. The 'T' allele frequency was 7% and 7.5% in cases and controls respectively. The frequency of MTHFR 1298 AA, AC, and CC were 28.3%, 55.6% and 16.1% for controls and 23.3%, 59.3% and 17.4% for cases respectively. The 'C' allele frequency for 1298 A→C was 43.9% and 47% respectively for controls and cases. The odds ratio (OR) for C677T was 1.08 (95% CI 0.48- 2.45, p = 0.851) and OR for A1298C was 1.29(95% CI 0.65-2.29, p = 0.46) and OR for 1298 CC was 1.31 (95% CI 0.53-3.26, p =0.56). The OR for the combined heterozygous status (677 CT and 1298 AC) was 1.94 (95% CI 0.58 -6.52, p = 0.286). Conclusion: The prevalence of 'T' allele for 677 MTHFR polymorphism was low in the population studied. There was no association between MTHFR 677 C→T and 1298 A→C gene polymorphisms and risk of ALL, which may be due to the small sample size.

On Using Projective Relations for Calibration and Estimation in a Structured-Light Scanner

For structured-light scanners, the projective geometry between a projector-camera pair is identical to that of a camera-camera pair. Consequently, in conjunction with calibration, a variety of geometric relations are available for three-dimensional Euclidean reconstruction. In this paper, we use projector-camera epipolar properties and the projective invariance of the cross-ratio to solve for 3D geometry. A key contribution of our approach is the use of homographies induced by reference planes, along with a calibrated camera, resulting in a simple parametric representation for projector and system calibration. Compared to existing solutions that require an elaborate calibration process, our method is simple while ensuring geometric consistency. Our formulation using the invariance of the cross-ratio is also extensible to multiple estimates of 3D geometry that can be analysed in a statistical sense. The performance of our system is demonstrated on some cultural artifacts and geometric surfaces.

Penetration of hydromagnetic energy deep into the magnetosphere

Magnetometer data, acquired on spacecraft and simultaneously at high and low latitudes on the ground, are compared in order to study the propagation characteristics of hydromagnetic energy deep into the magnetosphere. Single events provide evidence that wave energy at L ∼ 3 can at times be only one order of magnitude lower than at L ∼ 13. In addition, statistical analyses of the H-component groundbased data obtained during local daytime hours of 17 July-3 August 1985 show that wave amplitudes at L ∼ 3 are generally 10-30 times lower than at L ∼ 13. The L-dependence of near-equator magnetic field fluctuations measured on ISEE-2 show a sharp drop in energy near the magnetopause and a more gradual fall-off of energy deeper inside the magnetosphere. Such high levels of wave power deep in the magnetosphere have not been quantitatively understood previously. Our initial attempt is to calculate the decay length of an evanescent wave generated at a thick magnetopause boundary. Numerical calculations show that fast magnetosonic modes (called magnetopause and inner mode) can be generated under very restrictive conditions for the field and plasma parameters. These fast compressional modes may have their energy reduced by only one order of magnitude over a penetration depth of about 8RE. More realistic numerical simulations need to be carried out to see whether better agreement with the data can be attained.

An analytical model for the capacity estimation of combined VoIP and TCP file transfers over EDCA in an IEEE 802.11e WLAN

In this paper we develop and numerically explore the modeling heuristic of using saturation attempt probabilities as state dependent attempt probabilities in an IEEE 802.11e infrastructure network carrying packet telephone calls and TCP controlled file downloads, using Enhanced Distributed Channel Access (EDCA). We build upon the fixed point analysis and performance insights in [1]. When there are a certain number of nodes of each class contending for the channel (i.e., have nonempty queues), then their attempt probabilities are taken to be those obtained from saturation analysis for that number of nodes. Then we model the system queue dynamics at the network nodes. With the proposed heuristic, the system evolution at channel slot boundaries becomes a Markov renewal process, and regenerative analysis yields the desired performance measures.The results obtained from this approach match well with ns2 simulations. We find that, with the default IEEE 802.11e EDCA parameters for AC 1 and AC 3, the voice call capacity decreases if even one file download is initiated by some station. Subsequently, reducing the voice calls increases the file download capacity almost linearly (by 1/3 Mbps per voice call for the 11 Mbps PHY).

Reduction in magnetic field induced broadening of the resistive transition in laser‐deposited YBa2Cu3O7−x thin films on MgO

The magnetic field induced broadening of the normal to superconducting resistive transition of YBa2Cu3O7−x thin films laser deposited on (100) MgO substrates for field oriented parallel to the c axis is found to be significantly reduced in comparison with that found previously in single crystals and in films deposited on SrTiO3. This reduction in broadening is associated with a high density of defects which, while causing a slight decrease in Tc and an increase in the zero‐field transition width, seems to provide strong vortex pinning centers that reduce flux creep

Spectroscopic, microscopic and first rheological investigations in charge-transfer interaction induced organogels

This article describes two-component charge-transfer interaction mediated organogels (CT-gels) derived from anthracene carboxamides obtained from 2-amino 2-hydroxymethyl-1,3-propanediol (TRIS), and 2,3-dialkoxyanthracenes as donors, with 2,4,7-trinitrofluorenone (TNF) as the common acceptor. We demonstrate the versatility of TNF as an electron acceptor in the formation of these gels. The effect of subtle changes in the donor structure on the gelation ability has been investigated by varying the alkyl chain length in the dialkoxyanthracene donors, and by varying the position of the TRIS substituent in the anthracene carboxamide donors. Distinct differences have been observed in the nature of the CT-gels based on these two kinds of anthracene donors. It has been reported in the literature that 2,3-dialkoxyanthracenes form gels on their own in various aliphatic hydrocarbons and alcohols for linear alkyl chains bearing at least 6mcarbon atoms (C-6). In the present study, it is shown that themCT-complex of these molecules with TNF is able to gel many alcoholic and a few hydrocarbon solvents. Also, in the presence of TNF, the 2,3-dialkoxyanthracenes (C-4-C-5) which were non-gelators on their own at ambient temperatures, form CT-gels in a number of alcohols. The other series of gelators discussed, the anthracene carboxamides, require the mandatory presence of TNF to form gels. This donor-acceptor complex forms gels in various aliphatic alcohols. Interestingly, the formation of these CT-gels requires rapid cooling in most of the cases. Thermal stability studies with both types of CT-gels indicate an optimum stoichiometry of 1 : 1 between the donor and the acceptor. Dynamic rheological experiments reveal these gels as viscoelastic soft materials, with the mechanical strength of these gels depending on the amount of TNF present. This provides a means to tune the strength of the gel by varying the doping concentration of the acceptor.