On conduction mechanism in paramagnetic phase of Gd based manganites

Materials belonging to the family of manganites are technologically important since they exhibit colossal magneto resistance. A proper understanding of the transport properties is very vital in tailoring the properties. A heavy rare earth doped manganite like Gd0·7Sr0·3MnO3 is purported to be exhibiting unusual properties because of smaller ionic radius of Gd. Gd0·7Sr0·3MnO3 is prepared by a wet solid state reaction method. The conduction mechanism in such a compound has been elucidated by subjecting the material to low temperature d.c. conductivity measurement. It has been found that the low band width material follows a variable range hopping (VRH) model followed by a small polaron hopping (SPH) model. The results are presented here

The empirical study of the price mechanism in the Chinese housing market

In China, the history of the establishment of the private housing market is pretty short. Actually in less then two decades, the market has grown from almost the scratch to playing an important role in the economy. A great achievement! But many problems also exist. They need to be properly addressed and solved. Price problem---simply put, housing price is too high--- is one of them, and this paper is focused on it. Three basic questions are posed, i.e. (1) how to judge the housing affordability? (2) why the housing price is so high? (3) how to solve the housing price problem. The paper pays particular attention to answering the second question. Except the numerous news reports and surveys show that most of the ordinary city dwellers complained about the high housing price, the mathematical means, the four ratios, are applied to judge the housing affordability in Shanghai and Shenzhen. The results are very clear that the price problem is severe. So why? Something is wrong with the price mechanism. This research shows that mainly these five factors contribute to the price problem: the housing reform, the housing development model, the unbalanced housing market, the housing project financing and the poor governmental management. Finally the paper puts forward five suggestions to solve the housing price problem in first-hand private Chinese housing market. They include: the establishment of real estate information system, the creation of specific price management department, the government price regulation, the property tax and the legalization of "cushion money".

Protein Folding Simulations: Confinement, External Fields and Sequence Design

The present Thesis looks at the problem of protein folding using Monte Carlo and Langevin simulations, three topics in protein folding have been studied: 1) the effect of confining potential barriers, 2) the effect of a static external field and 3) the design of amino acid sequences which fold in a short time and which have a stable native state (global minimum). Regarding the first topic, we studied the confinement of a small protein of 16 amino acids known as 1NJ0 (PDB code) which has a beta-sheet structure as a native state. The confinement of proteins occurs frequently in the cell environment. Some molecules called Chaperones, present in the cytoplasm, capture the unfolded proteins in their interior and avoid the formation of aggregates and misfolded proteins. This mechanism of confinement mediated by Chaperones is not yet well understood. In the present work we considered two kinds of potential barriers which try to mimic the confinement induced by a Chaperon molecule. The first kind of potential was a purely repulsive barrier whose only effect is to create a cavity where the protein folds up correctly. The second kind of potential was a barrier which includes both attractive and repulsive effects. We performed Wang-Landau simulations to calculate the thermodynamical properties of 1NJ0. From the free energy landscape plot we found that 1NJ0 has two intermediate states in the bulk (without confinement) which are clearly separated from the native and the unfolded states. For the case of the purely repulsive barrier we found that the intermediate states get closer to each other in the free energy landscape plot and eventually they collapse into a single intermediate state. The unfolded state is more compact, compared to that in the bulk, as the size of the barrier decreases. For an attractive barrier modifications of the states (native, unfolded and intermediates) are observed depending on the degree of attraction between the protein and the walls of the barrier. The strength of the attraction is measured by the parameter $\epsilon$. A purely repulsive barrier is obtained for $\epsilon=0$ and a purely attractive barrier for $\epsilon=1$. The states are changed slightly for magnitudes of the attraction up to $\epsilon=0.4$. The disappearance of the intermediate states of 1NJ0 is already observed for $\epsilon =0.6$. A very high attractive barrier ($\epsilon \sim 1.0$) produces a completely denatured state. In the second topic of this Thesis we dealt with the interaction of a protein with an external electric field. We demonstrated by means of computer simulations, specifically by using the Wang-Landau algorithm, that the folded, unfolded, and intermediate states can be modified by means of a field. We have found that an external field can induce several modifications in the thermodynamics of these states: for relatively low magnitudes of the field ($<2.06 \times 10^8$ V/m) no major changes in the states are observed. However, for higher magnitudes than ($6.19 \times 10^8$ V/m) one observes the appearance of a new native state which exhibits a helix-like structure. In contrast, the original native state is a $\beta$-sheet structure. In the new native state all the dipoles in the backbone structure are aligned parallel to the field. The design of amino acid sequences constitutes the third topic of the present work. We have tested the Rate of Convergence criterion proposed by D. Gridnev and M. Garcia ({\it work unpublished}). We applied it to the study of off-lattice models. The Rate of Convergence criterion is used to decide if a certain sequence will fold up correctly within a relatively short time. Before the present work, the common way to decide if a certain sequence was a good/bad folder was by performing the whole dynamics until the sequence got its native state (if it existed), or by studying the curvature of the potential energy surface. There are some difficulties in the last two approaches. In the first approach, performing the complete dynamics for hundreds of sequences is a rather challenging task because of the CPU time needed. In the second approach, calculating the curvature of the potential energy surface is possible only for very smooth surfaces. The Rate of Convergence criterion seems to avoid the previous difficulties. With this criterion one does not need to perform the complete dynamics to find the good and bad sequences. Also, the criterion does not depend on the kind of force field used and therefore it can be used even for very rugged energy surfaces.

Theory of laser-induced ultrafast structural changes in solids

The present thesis is a contribution to the study of laser-solid interaction. Despite the numerous applications resulting from the recent use of laser technology, there is still a lack of satisfactory answers to theoretical questions regarding the mechanism leading to the structural changes induced by femtosecond lasers in materials. We provide here theoretical approaches for the description of the structural response of different solids (cerium, samarium sulfide, bismuth and germanium) to femtosecond laser excitation. Particular interest is given to the description of the effects of the laser pulse on the electronic systems and changes of the potential energy surface for the ions. Although the general approach of laser-excited solids remains the same, the potential energy surface which drives the structural changes is calculated with different theoretical models for each material. This is due to the difference of the electronic properties of the studied systems. We use the Falicov model combined with an hydrodynamic method to study photoinduced phase changes in cerium. The local density approximation (LDA) together with the Hubbard-type Hamiltonian (LDA+U) in the framework of density functional theory (DFT) is used to describe the structural properties of samarium sulfide. We parametrize the time-dependent potential energy surface (calculated using DFT+ LDA) of bismuth on which we perform quantum dynamical simulations to study the experimentally observed amplitude collapse and revival of coherent $A_{1g}$ phonons. On the basis of a time-dependent potential energy surface calculated from a non-orthogonal tight binding Hamiltonian, we perform molecular dynamics simulation to analyze the time evolution (coherent phonons, ultrafast nonthermal melting) of germanium under laser excitation. The thermodynamic equilibrium properties of germanium are also reported. With the obtained results we are able to give many clarifications and interpretations of experimental results and also make predictions.

India’s Carbon Governance: The Clean Development Mechanism

Carbon Governance systems – institutional arrangements in place for mitigating greenhouse gas emissions – are different in emerging countries. Indeed, carbon is the same everywhere but Carbon Governance isn’t: in Brazil, the financial community is actively interested in carbon trading, but Chinese banks have hardly any interest in it; and while the Chinese government takes an active interest in providing capacity to project developers, the Brazilian authorities see their role uniquely as guarantors of environmental integrity of emissions reductions projects. In the case of India, carbon governance offers specific features of patterns and interactions mostly because India strongly developed the Clean Development Mechanism and its market. This article proposes a study to the research and understanding of how exactly carbon governance works in the Indian case, knowing that India is the second largest host of CDM projects.

Structural insights into the allosteric activation mechanism of cGMP-dependent protein kinase I

Cyclic GMP-dependent protein kinase (PKG) is a key transducer in the NO-cGMP signaling pathway. In this line, PKG has been considered an important drug target for treating hypertensive cardiovascular and pulmonary diseases. However, the investigation of PKG’s allosteric activation mechanism has been hampered by a lack of structural information. One of the fundamental questions on the cGMP-dependent activation of PKG is how the enzyme can distinguish cGMP over cAMP and selectively respond to cGMP. To ensure proper signaling, PKG must have developed unique features to ensure its activation upon the right activation signal. In this thesis, the cGMP-selective activation mechanism of PKG was studied through determining crystal structures of three truncated constructs of the regulatory domain [CNB-A (92-227), CNB-B (271-369), and CNB-A/B (92-351)] of PKG Iβ in the absence or presence of cyclic nucleotides. Herein, two individual CNB domain structures with biochemical data revealed that the C-terminal CNB domain (CNB-B) is responsible for cGMP selectivity, while the N-terminal CNB-domain (CNB-A) has a higher binding affinity for both cGMP and cAMP without showing any selectivity. Based on these crystal structures, mutagenesis studies were performed in which the critical residues for cyclic nucleotide selectivity and activation were identified. Furthermore, we discovered that the conformational changes of the C-terminal helix of the CNB-B that bridges between the regulatory and catalytic domains including the hydrophobic capping interaction are crucial for PKG activation. In addition, to observe the global conformation of the activated R-domain, I solved a co-crystal structure of the CNB-A/B with cGMP. Although a monomeric construct was crystallized, the structure displays a dimer. Strikingly, the CNB-A domain and its bound cGMP provide a key interface for this dimeric interaction. Using small angle X-ray scattering (SAXS), the existence of the cGMP-mediated dimeric interface within the CNB domains was confirmed. Furthermore, measuring cGMP-binding affinities (EC50) of the dimeric interface mutants as well as determining activation constants (Ka) revealed that the interface formation is important for PKG activation. To conclude, this thesis study provides a new mechanistic insight in PKG activation along with a newly found interface that can be targeted for designing PKG-specific activity modulators.

The NAFTA investment dispute settlement mechanism and the admissibility of amicus curiae briefs by NGOs

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Molecular mechanism involved in the mutagenicity induced by Aflatoxin B1

The aflatoxin B1 (AFB1) is a mycotoxin that has been identified as the most potent hepatocarcinogen. The metabolite resulting from detoxification process of AFB1 in liver, has the ability to react with the genomic DNA, generating AFB1-DNA adducts; during DNA replication process, this adduct induced the G:C→T:A transversion. Polymorphism in genes encoding for enzymes involved in the activation and detoxification of AFB1 and DNA repair enzymes has been associated with the risk of hepatocellular carcinoma (HCC) development. Additionally, in populations of high exposure to aflatoxin and high prevalence of hepatitis B virus (HBV) infection, has been demonstrated a synergism between these two risk factors for the development of HCC.

The use of insect cells to identify potent and selective inhibitors of the replication of the Dengue and Chikungunya viruses and unravel their molecular mechanism of action

Dengue and Chikungunya viruses cause the most important arthropod-borne viral infections for humans. These viruses are predominant in tropical and subtropical regions. In addition, these viruses are predominant in tropical and subtropical regions. Dengue mortality rate is around 1.2 to 3.5% and deaths due to chikungunya fever are around 1 in 1000; however, half of chikungunya-infected patients evolve into a chronic state that can persist for months up to years. There are no antiviral drugs available for DENV and CHIKV treatment and prevention. Moreover, vector control strategies have failed so far. Thus, the development of potent inhibitors for a broad spectrum of RNA viruses is urgently needed. We established and characterized a new embryonic insect cell line from Culex quinquefasciatus mosquito. Also we established the flaviviruses and alphavirus replication, both in C6/36 and Lulo insect cell lines, as well as in Vero cell line. In addition we carried out a reference compound library and reference panel of assays and data for DENV, which provides a benchmark for further studies. During this study, a panel of 9 antiviral molecules, with proven in vitro anti-dengue virus activity and that act at different stages of the DENV life cycle, was selected. Finally, Favipiravir or T-705, was identified as inhibitor in vitro and in vivo of alphaviruses and the mutation K291R in nsP4, which is responsible of the polymerase activity, was found as the mode of action in CHIKV. Interestingly, lysine in motif F1 is also highly conserved in positive-stranded RNA viruses and this might explain the broad spectrum of T-705 antiviral activity.

Edexcel AS History: The Collapse of the Liberal State and the Triumph of Fascism in Italy, 1896-1943.

Esta guía ha sido escrita por un examinador y explica los requisitos de cada unidad, resume el contenido relevante de cada unidad e incluye una serie de preguntas y respuestas. Cumple los requisitos establecidos para aprobar el examen de historia del nivel Edexcel AS que pertenece al segundo ciclo de enseñanza secundaria. El tema principal del libro es el colapso del estado liberal y el triunfo del fascismo en Italia, 1896-1943, los temas secundarios son: Italia en 1896, el impacto de la Primera Guerra Mundial en Italia, la crisis económica y política de la posguerra, el aumento del fascismo en 1922, la creación del estado fascista, la política de Mussolini, y el impacto de la Segunda Guerra Mundial en Italia.

Self-deception as a mechanism for the maintenance of drug addiction

Resumen tomado de la publicaci??n

Destabilizing Mutations Alter the Hydrogen Exchange Mechanism in Ribonuclease A

The effect of strongly destabilizing mutations, I106A and V108G of Ribonuclease A (RNase A), on its structure and stability has been determined by NMR. The solution structures of these variants are essentially equivalent to RNase A. The exchange rates of the most protected amide protons in RNase A (35ºC), the I106A variant (35ºC), and the V108G variant (10ºC) yield stability values of 9.9, 6.0, and 6.8 kcal/mol, respectively, when analyzed assuming an EX2 exchange mechanism. Thus, the destabilization induced by these mutations is propagated throughout the protein. Simulation of RNase A hydrogen exchange indicates that the most protected protons in RNase A and the V108G variant exchange via the EX2 regime, whereas those of I106A exchange through a mixed EX1 1 EX2 process. It is striking that a single point mutation can alter the overall exchange mechanism. Thus, destabilizing mutations joins high temperatures, high pH and the presence of denaturating agents as a factor that induces EX1 exchange in proteins. The calculations also indicate a shift from the EX2 to the EX1 mechanism for less protected groups within the same protein. This should be borne in mind when interpreting exchange data as a measure of local stability in less protected regions

Pressure-jump-induced kinetics reveals a hydration dependent folding/unfolding mechanism of ribonuclease A

Pressure-jump (p-jump)-induced relaxation kinetics was used to explore the energy landscape of protein folding/unfolding of Y115W, a fluorescent variant of ribonuclease A. Pressure-jumps of 40MPa amplitude (5ms dead-time) were conducted both to higher (unfolding) and to lower (folding) pressure, in the range from 100 to 500MPa, between 30 and 50°C. Significant deviations from the expected symmetrical protein relaxation kinetics were observed. Whereas downward p-jumps resulted always in single exponential kinetics, the kinetics induced by upward p-jumps were biphasic in the low pressure range and monophasic at higher pressures. The relative amplitude of the slow phase decreased as a function of both pressure and temperature. At 50°C, only the fast phase remained. These results can be interpreted within the framework of a two-dimensional energy surface containing a pressure- and temperature-dependent barrier between two unfolded states differing in the isomeric state of the Asn-113–Pro-114 bond. Analysis of the activation volume of the fast kinetic phase revealed a temperature-dependent shift of the unfolding transition state to a larger volume. The observed compensation of this effect by glycerol offers an explanation for its protein stabilizing effect

Characterization and mechanism of action of the biological control agent Pantoea agglomerans EPS125

La soca EPS125 ha mostrat ser un efectiu agent de control biològic de diferents patògens fúngics de postcollita en diferents fruits. Degut a la seva elevada eficàcia, es va plantejar desenvolupar aquesta soca comercialment i per aquest motiu en el present treball es plantejà complementar la informació necessària pel seu registre. D'acord amb els resultats obtinguts mitjançant proves fenotípiques i genotípiques, la soca EPS125 queda inclosa dins l'espècie Pantoea agglomerans (Enterobacter agglomerans-Erwinia herbicola). En relació a la utilització de fonts de carboni, en el perfil i contingut d'àcids grassos cel·lulars i en el polimorfisme en la longitud dels fragments de macrorestricció genòmica (MRFLP), la soca EPS125 mostrà trets característics que la diferencien d'altres soques. Els dos marcadors moleculars (125.2 i 125.3) específics per la soca EPS125 dissenyats en el present treball mostraren ser semiespecífics per la seva detecció mitjançant la tècnica PCR i Real Time PCR. Quedant pendent l'anàlisi d'especificitat de l'ús combinat dels dos marcadors moleculars en una reacció PCR multiplex. P. agglomerans EPS125 ha mostrat ser molt efectiva en el control de Penicillium expansum en poma amb una dosi efectiva mitjana de 2.7x105 a 7x105 ufc/ml, i una ratio de 25-101 cèl·lules de la soca EPS125 per inactivar una espora del patogen segons el model de saturació hiperbòlica. Segons les aproximacions fenotípiques i estudis genotípics realitzats, sembla que els mecanismes de biocontrol utilitzats per la soca EPS125 contra P. expansum en poma estan directament relacionats amb la capacitat de formació de biofilm per aquesta soca.

Mechanism of action of cyclic antimicrobial peptides

This PhD thesis is the result of the combination of experimental and computational techniques with the aim of understanding the mechanism of action of de novo cyclic decapeptides with high antimicrobial activity. By experimental techniques the influence of the replacement of the phenylalanine for tryptophan residue in their antimicrobial activity was tested and the stability in human serum was also analyzed, in order to evaluate their potential therapeutic application as antitumor agents. On the other hand, the interaction amongst the peptide BPC194 c(KKLKKFKKLQ), the best candidate from the whole library of cyclic peptides, and a model anionic membrane was simulated. The results showed a structure-function relationship derived from the stable conformation of the peptides involved in the membrane permeabilization. As a result, a rational design was performed being BPC490 the peptide with best antimicrobial activity compared with the best active peptide from the original library.