Immune responses against hepatitis C virus genotype 3a virus-like particles in mice: A novel VLP prime-adenovirus boost strategy

Chronic hepatitis C virus (HCV) infection represents a major health threat to global population. In India, approximately 15-20% of cases of chronic liver diseases are caused by HCV infection. Although, new drug treatments hold great promise for HCV eradication in infected individuals, the treatments are highly expensive. A vaccine for preventing or treating HCV infection would be of great value, particularly in developing countries. Several preclinical trials of virus-like particle (VLP) based vaccine strategies are in progress throughout the world. Previously, using baculovirus based system, we have reported the production of hepatitis C virus-like particles (HCV-LPs) encoding structural proteins for genotype 3a, which is prevalent in India. In the present study, we have generated HCV-LPs using adenovirus based system and tried different immunization strategies by using combinations of both kinds of HCV-LPs with other genotype 3a-based immunogens. HCV-LPs and peptides based ELISAs were used to evaluate antibody responses generated by these combinations. Cell-mediated immune responses were measured by using T-cell proliferation assay and intracellular cytokine staining. We observed that administration of recombinant adenoviruses expressing HCV structural proteins as final booster enhances both antibody as well as T-cell responses. Additionally, reduction of binding of VLP and JFH1 virus to human hepatocellular carcinoma cells demonstrated the presence of neutralizing antibodies in immunized sera. Taken together, our results suggest that the combined regimen of VLP followed by recombinant adenovirus could more effectively inhibit HCV infection, endorsing the novel vaccine strategy. (C) 2015 Elsevier Ltd. All rights reserved.

Trans-dichlorooxovandium (IV) complex as a novel photoinducible DNA interstrand crosslinker for cancer therapy

Although DNA interstrand crosslinking (ICL) agents such as mitomycin C, cisplatin and psoralen serve as potent anticancer drugs, these agents are known to have dose-limiting toxic effects on normal cells. Moreover, tumor resistance to these agents has been reported. Here, we show that trans-dichlorooxovanadium (IV) complex of pyrenyl terpyridine (VDC) is a novel photoinducible DNA crosslinking agent. By a combination of in vitro and ex vivo experiments including plasmid-based assays, we find that VDC forms monoadducts on the DNA and can be activated by UV-A and visible light to generate DNA interstrand crosslinks. VDC efficiently activates Fanconi anemia (FA) pathway of DNA interstrand crosslink repair. Strikingly, photoinduction of VDC induces prolonged activation of cell cycle checkpoint and a high degree of cell death in homologous recombination (HR)/ICL repair defective cells. Moreover, VDC specifically targets cells that express pathological RAD51C mutants. These data imply that VDC can be potentially used for cancer therapy and suggest that tumors arising in patients with gene mutations in FA and HR repair pathway can be specifically targeted by a photoactivatable VDC.

Novel synergistic photocatalytic degradation of antibiotics and bacteria using V-N doped TiO2 under visible light: the state of nitrogen in V-doped TiO2

We report the synthesis of vanadium and nitrogen co-doped TiO2 for photocatalysis mainly emphasizing the state of nitrogen doping into TiO2 in the presence of vanadium ions. Considering the increase in antibiotic resistance developed by microbes due to the excess of pharmaceutical waste in the ecosystem, the photocatalytic activity was measured by degrading an antibiotic, chloramphenicol. A novel experiment was conducted by degrading the antibiotic and bacteria in each other's vicinity to focus on their synergistic photo-degradation by V-N co-doped TiO2. The catalysts were characterized using XRD, DRS, PL, TEM, BET and XPS analysis. Both interstitial and substitutional nitrogen doping were achieved with V-TiO2, showing high efficiency under visible light for antibiotic and bacterial degradation. In addition, the effect of doping concentration of nitrogen and vanadium in TiO2 and catalyst loading was studied thoroughly. Reusability experiments show that the prepared V-N co-doped TiO2 was stable for many cycles.

Novel Fe70Zr10Ni6Al4Si6B4 thick metallic glass coating produced by laser cladding

A novel multicomponent thick metallic glass coating has been synthesised by laser cladding. The maximum coating thickness was I mm. The clad cooling rate restrained the epitaxial growth of dendrites in the metallic glass coating. The metallic glass had high glass forming ability with a wide supercooled liquid region ranging from 59 to 70 K. The metallic glass coating also revealed high hardness and good corrosion resistance.

Body and Grotesque as Self-Disruption in Kerstin Hensel’s Gothic East(ern) German Novel Lärchenau (2008)

[EN] By analysing the novel Lärchenau and its -to a certain point- gothic features, this article interprets the elaboration of body in this novel as a site of the expression of power, but also as an alternative language. The grotesque dimension and the representation of the bodily numbness and pain as projections of historical awareness are key elements for the interpretation of Lärchenau in the context of Post-Unification Germany.

Neuroprotective Effect of Melatonin: A Novel Therapy against Perinatal Hypoxia-Ischemia

17 p.

Three-dimensional supercell simulation of novel semiconductor nanostructures

In this thesis we investigate atomic scale imperfections and fluctuations in the quantum transport properties of novel semiconductor nanostructures. For this purpose, we have developed a numerically efficient supercell model of quantum transport capable of representing potential variations in three dimensions. This flexibility allows us to examine new quantum device structures made possible through state-of-the-art semiconductor fabrication techniques such as molecular beam epitaxy and nanolithography. These structures, with characteristic dimensions on the order of a few nanometers, hold promise for much smaller, faster and more efficient devices than those in present operation, yet they are highly sensitive to structural and compositional variations such as defect impurities, interface roughness and alloy disorder. If these quantum structures are to serve as components of reliable, mass-produced devices, these issues must be addressed.

In Chapter 1 we discuss some of the important issues in resonant tunneling devices and mention some of thier applications. In Chapters 2 and 3, we describe our supercell model of quantum transport and an efficient numerical implementation. In the remaining chapters, we present applications.

In Chapter 4, we examine transport in single and double barrier tunneling structures with neutral impurities. We find that an isolated attractive impurity in a single barrier can produce a transmission resonance whose position and strength are sensitive to the location of the impurity within the barrier. Multiple impurities can lead to a complex resonance structure that fluctuates widely with impurity configuration. In addition, impurity resonances can give rise to negative differential resistance. In Chapter 5, we study interface roughness and alloy disorder in double barrier structures. We find that interface roughness and alloy disorder can shift and broaden the n = 1 transmission resonance and give rise to new resonance peaks, especially in the presence of clusters comparable in size to the electron deBroglie wavelength. In Chapter 6 we examine the effects of interface roughness and impurities on transmission in a quantum dot electron waveguide. We find that variation in the configuration and stoichiometry of the interface roughness leads to substantial fluctuations in the transmission properties. These fluctuations are reduced by an attractive impurity placed near the center of the dot.

Structurally engineered cytochromes c with novel ligand-binding properties

Semisynthesis of horse heart cytochrome c and site-directed mutagenesis of Saccharomyces cerevisiae (S. c.) iso-1-cytochrome c have been utilized to substitute Ala for the cytochrome c heme axial ligand Met80 to yield ligand-binding proteins (horse heart Ala80cyt c and S.c. Ala80cyt c) with spectroscopic properties remarkably similar to those of myoglobin. Both species of Fe(II)Ala80cyt c form exceptionally stable dioxygen complexes with autoxidation rates 10-30x smaller and O₂ binding constants ~ 3x greater than those of myoglobin. The resistance of O₂-Fe(II)Ala80cyt c to autoxidation is attributed in part to protection of the heme site from solvent as exhibited by the exceptionally slow rate of CO binding to the heme as well as the low quantum yield of CO photodissociation.

UV/vis, EPR, and paramagnetic NMR spectroscopy indicate that at pH 7 the Fe(III)Ala80cyt c heme is low-spin with axial His-OH^- coordination and that below pH ~6.5, Fe(III)Ala80cyt cis high-spin with His-H₂O heme ligation. Significant differences in the pH dependence of the ¹H NMR spectra of S.c. Fe(III)Ala80cyt c compared to wild-type demonstrate that the axial ligands influence the conformational energetics of cytochrome c.

¹H NMR spectroscopy has been utilized to determine the solution structure of the cyanide derivative of S.c. Fe(III)Ala80cyt c. 82% of the resonances in the ¹H NMR spectrum of S.c. CN-Fe(III)Ala80cyt c have been assigned through 1D and 2D experiments. The RMSD values after restrained energy minimization of the family of 17 structures obtained from distance geometry calculations are 0.68 ± 0.11 Å for the backbone and 1.32 ± 0.14 Å for all heavy atoms. The solution structure indicates that a tyrosine in the "distal" pocket of CN-Fe(III)Ala80cyt c forms a hydrogen bond with the Fe(III)-CN unit, suggesting that it may play a role analogous to that of the distal histidine in myoglobin in stabilizing the dioxygen adduct.

Creating dangerously: literature as an instrument of resistance in the works of Edwidge Danticat

O objetivo desta dissertação é discutir o lugar que o fazer literário ocupa no processo de resistência à poderes hegemônicos. Como fontes primárias centrais, foram escolhidos o romance histórico The Farming of Bones (1998) e a narrativa autobiográfica Brother, Im Dying (2007), ambos escritos pela autora haitiana-americana Edwidge Danticat. Em The Farming of Bones, Danticat reconstrói ficcionalmente o trágico e obscuro episódio ocorrido em 1937 quando o então ditador da República Dominicana, Rafael Trujillo, ordenou o extermínio de todos os haitianos que residiam e trabalhavam em cidades dominicanas próximas à fronteira com o Haiti. O silêncio por parte dos governos de ambos os países em torno do massacre ainda perdura. A publicação do romance histórico de Danticat 61 anos após tal ato de terrorismo de Estado se torna, desta forma, exemplo de como o fazer literário e o fazer histórico podem fundir-se. Em Brother, Im Dying, Danticat narra a história da vida e da morte de suas duas figuras paternas, seu pai Andre (Mira) Dantica e seu tio Joseph Dantica (que a criou dos 4 aos 12 anos, no Haiti). Joseph, sobrevivente de um câncer de laringe, foi pastor batista e fundador de uma igreja e uma escola no Haiti. Morreu dois dias depois de pedir asilo político nos EUA e ser detido na prisão Krome, em Miami. Mira, que migrara no início da ditadura de François Duvalier para os EUA, onde trabalhou como taxista, morreu vítima de fibrose pulmonar poucos meses depois de seu irmão mais velho. Edwidge Danticat recebeu a notícia de que o quadro de seu pai era irreversível no mesmo dia em que descobriu que está grávida de sua primeira filha. Com uma escrita que abrange tanto a narrativa de si quanto a narrativa do outro, além das esferas públicas e privadas, Danticat cria em Brother, Im Dying um locus de fazer auto/biográfico que dialoga com questões de diáspora, identidade cultural e memória. Os ensaios publicados em Create Dangerously (2010) e as várias entrevistas concedidas por Danticat também reforçam meu argumento que Edwidge Danticat exerce seu papel de artista engajada através de seu fazer principalmente, mas não exclusivamente literário. Desta forma, a autora constrói uma possibilidade de resistência ao discurso hegemônico que opera tanto em seu país de origem quanto em seu país de residência.

A Novel Scheduling Index Rule Proposal for QoE Maximization in Wireless Networks

This paper deals with the resource allocation problem aimed at maximizing users' perception of quality in wireless channels with time-varying capacity. First of all, we model the subjective quality-aware scheduling problem in the framework of Markovian decision processes. Then, given that the obtaining of the optimal solution of this model is unachievable, we propose a simple scheduling index rule with closed-form expression by using a methodology based on Whittle approach. Finally, we analyze the performance of the achieved scheduling proposal in several relevant scenarios, concluding that it outperforms the most popular existing resource allocation strategies.

Pseudohypoparathyroidism Type Ib Associated with Novel Duplications in the GNAS Locus

Context Pseudohypoparathyroidism type 1b (PHP-Ib) is characterized by renal resistance to PTH (and, sometimes, a mild resistance to TSH) and absence of any features of Albright's hereditary osteodystrophy. Patients with PHP-Ib suffer of defects in the methylation pattern of the complex GNAS locus. PHP-Ib can be either sporadic or inherited in an autosomal dominant pattern. Whereas familial PHP-Ib is well characterized at the molecular level, the genetic cause of sporadic PHP-Ib cases remains elusive, although some molecular mechanisms have been associated with this subtype. Objective The aim of the study was to investigate the molecular and imprinting defects in the GNAS locus in two unrelated patients with PHP-Ib. Design We have analyzed the GNAS locus by direct sequencing, Methylation-Specific Multiplex Ligation-dependent Probe Amplification, microsatellites, Quantitative Multiplex PCR of Short Fluorescent fragments and array-Comparative Genomic Hybridization studies in order to characterize two unrelated families with clinical features of PHP-Ib. Results We identified two duplications in the GNAS region in two patients with PHP-Ib: one of them, comprising similar to 320 kb, occurred 'de novo' in the patient, whereas the other one, of similar to 179 kb in length, was inherited from the maternal allele. In both cases, no other known genetic cause was observed. Conclusion In this article, we describe the to-our-knowledge biggest duplications reported so far in the GNAS region. Both are associated to PHP-Ib, one of them occurring 'de novo' and the other one being maternally inherited.

A novel heavily doped drift-auxiliary cathode lateral insulated gate transistor structure

A novel CMOS-compatible, heavily doped drift auxiliary cathode lateral insulated gate transistor (HDD-ACLIGT) structure is analyzed using two-dimensional device simulation techniques. Simulation results indicate that low on-resistance and a fast turn-off time of less than 50 ns can be achieved by incorporating an additional n+ region which is self-aligned to the gate between the p+ auxiliary cathode and the p well, together with an extended p buried layer in an anode-shorted modified lateral insulated gate transistor (MLIGT) structure. The on-state and its transient performance are analyzed in detail. The on-state performances of the HDD-ACLIGT and the MLIGT are compared and discussed. The results indicate that the HDD-ACLIGT structure is well suited for HVICs. The device is also well suited for integration with self-aligned digital CMOS.

A novel fusion gene, TRIMS-Cyclophilin A in the pig-tailed macaque determines its susceptibility to HIV-1 infection

Objective: In Old World monkeys, the tripartite motif Sec (TRIM5 alpha) protein confers resistance to HIV-1 infection following virus entry into host cells. However, the pig-tailed macaque (Macaca nemestrina) is an exception and is susceptible to HIV-1 in

A novel method for rapid comparative quantitative analysis of nuclear fuel cycles

One of the greatest obstacles facing the nuclear industry is that of sustainability, both in terms of the finite reserves of uranium ore and the production of highly radiotoxic spent fuel which presents proliferation and environmental hazards. Alternative nuclear technologies have been suggested as a means of delivering enhanced sustainability with proposals including fast reactors, the use of thorium fuel and tiered fuel cycles. The debate as to which is the most appropriate technology continues, with each fuel system and reactor type delivering specific advantages and disadvantages which can be difficult to compare fairly. This paper demonstrates a framework of performance metrics which, coupled with a first-order lumped reactor model to determine nuclide population balances, can be used to quantify the aforementioned pros and cons for a range of different fuel and reactor combinations. The framework includes metrics such as fuel efficiency, spent fuel toxicity and proliferation resistance, and relative cycle performance is analysed through parallel coordinate plots, yielding a quantitative comparison of disparate cycles. © 2011 Elsevier Ltd. All rights reserved.

The effect of remodelling and contractility of the actin cytoskeleton on the shear resistance of single cells: a computational and experimental investigation.

The biomechanisms that govern the response of chondrocytes to mechanical stimuli are poorly understood. In this study, a series of in vitro tests are performed, in which single chondrocytes are subjected to shear deformation by a horizontally moving probe. Dramatically different probe force-indentation curves are obtained for untreated cells and for cells in which the actin cytoskeleton has been disrupted. Untreated cells exhibit a rapid increase in force upon probe contact followed by yielding behaviour. Cells in which the contractile actin cytoskeleton was removed exhibit a linear force-indentation response. In order to investigate the mechanisms underlying this behaviour, a three-dimensional active modelling framework incorporating stress fibre (SF) remodelling and contractility is used to simulate the in vitro tests. Simulations reveal that the characteristic force-indentation curve observed for untreated chondrocytes occurs as a result of two factors: (i) yielding of SFs due to stretching of the cytoplasm near the probe and (ii) dissociation of SFs due to reduced cytoplasm tension at the front of the cell. In contrast, a passive hyperelastic model predicts a linear force-indentation curve similar to that observed for cells in which the actin cytoskeleton has been disrupted. This combined modelling-experimental study offers a novel insight into the role of the active contractility and remodelling of the actin cytoskeleton in the response of chondrocytes to mechanical loading.