Geometric quantum computation using fictitious spin-1/2 subspaces of strongly dipolar coupled nuclear spins

Geometric phases have been used in NMR to implement controlled phase shift gates for quantum-information processing, only in weakly coupled systems in which the individual spins can be identified as qubits. In this work, we implement controlled phase shift gates in strongly coupled systems by using nonadiabatic geometric phases, obtained by evolving the magnetization of fictitious spin-1/2 subspaces, over a closed loop on the Bloch sphere. The dynamical phase accumulated during the evolution of the subspaces is refocused by a spin echo pulse sequence and by setting the delay of transition selective pulses such that the evolution under the homonuclear coupling makes a complete 2 pi rotation. A detailed theoretical explanation of nonadiabatic geometric phases in NMR is given by using single transition operators. Controlled phase shift gates, two qubit Deutsch-Jozsa algorithm, and parity algorithm in a qubit-qutrit system have been implemented in various strongly dipolar coupled systems obtained by orienting the molecules in liquid crystal media.

A simple classical approach for the melting temperature of inert-gas nanoparticles

Like the metal and semiconductor nanoparticles, the melting temperature of free inert-gas nanoparticles decreases with decreasing size. The variation is linear with the inverse of the particle size for large nanoparticles and deviates from the linearity for small nanoparticles. The decrease in the melting temperature is slower for free nanoparticles with non-wetting surfaces, while the decrease is faster for nanoparticles with wetting surfaces. Though the depression of the melting temperature has been reported for inert-gas nanoparticles in porous glasses, superheating has also been observed when the nanoparticles are embedded in some matrices. By using a simple classical approach, the influence of size, geometry and the matrix on the melting temperature of nanoparticles is understood quantitatively and shown to be applicable for other materials. It is also shown that the classical approach can be applied to understand the size-dependent freezing temperature of nanoparticles.

Enantiodiscrimination and extraction of short and long range homo- and hetero-nuclear residual dipolar couplings by a spin selective correlation experiment

A two dimensional correlation experiment for the measurement of short and long range homo- and hetero- nuclear residual dipolar couplings (RDCs) from the broad and featureless proton NMR spectra including C-13 satellites is proposed. The method employs a single natural abundant C-13 spin as a spy nucleus to probe all the coupled protons and permits the determination of RDCs of negligible strengths. The technique has been demonstrated for the study of organic chiral molecules aligned in chiral liquid crystal, where additional challenge is to unravel the overlapped spectrum of enantiomers. The significant advantage of the method is demonstrated in better chiral discrimination using homonuclear RDCs as additional parameters. (C) 2010 Elsevier B.V. All rights reserved.

Molecular and Clinical Characteristics of Pituitary Adenoma Predisposition (PAP)

Pituitary adenomas are common benign neoplasms. Although most of them are sporadic, a minority occurs in familial settings. Heterozygous germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were found to underlie familial pituitary adenomas, a condition designated as pituitary adenoma predisposition (PAP). PAP confers incomplete penetrance of mostly growth hormone (GH) secreting adenomas in young patients, who often lack a family history of pituitary adenomas. This thesis work aimed to clarify the molecular and clinical characteristics of PAP. Applying the multiplex ligation-dependent probe amplification assay (MLPA), we found large genomic AIP deletions to account for a subset of PAP. Therefore, MLPA could be considered in PAP suspected patients with no AIP mutations found with conventional sequencing. We generated an Aip mouse model to examine pituitary tumorigenesis in vivo. The heterozygous Aip mutation conferred complete penetrance of pituitary adenomas that were mostly GH-secreting, rendering the phenotype of the Aip mouse similar to that of PAP patients. We suggest that AIP may function as a candidate gatekeeper gene in somatotrophs. To clarify molecular mechanisms of tumorigenesis, we elucidated the expression of AIP-related molecules in human and mouse pituitary tumors. The expression of aryl hydrocarbon receptor nuclear translocator (ARNT) was reduced in mouse Aip-deficient adenomas, and similar ARNT reduction was also evident in human AIP mutation positive adenomas. This suggests that in addition to participating in the hypoxia pathway, estrogen receptor signaling and xenobiotic response pathways, ARNT may play a role in AIP-related tumorigenesis. We also studied the characteristics and the response to therapy of PAP patients and found them to have an aggressive disease phenotype with young age at onset. Therefore, improvement in treatment outcomes of PAP patients would require their efficient identification and earlier diagnosis of the pituitary adenomas. The possible role of the RET proto-oncogene in tumorigenesis of familial AIP mutation negative pituitary adenomas was evaluated, but none of the found RET germline variants were considered pathogenic. Surprisingly, RET immunohistochemistry suggested possible underexpression of RET in AIP mutation positive pituitary adenomas an observation that merits further investigation.

Diabetic cardiomyopathy and post-infarct ventricular remodelling : Effects of levosimendan in a rodent model of type II diabetes

Type 2 diabetes is a risk factor for the development of cardiovascular disease. Recently, the term diabetic cardiomyopathy has been proposed to describe the changes in the heart that occur in response to chronic hyperglycemia and insulin resistance. Ventricular remodelling in diabetic cardiomyopathy includes left ventricular hypertrophy, increased interstitial fibrosis, apoptosis and diastolic dysfunction. Mechanisms behind these changes are increased oxidative stress and renin-angiotensin system activation. The diabetic Goto-Kakizaki rat is a non-obese model of type 2 diabetes that exhibits defective insulin signalling. Recently two interconnected stress response pathways have been discovered that link insulin signalling, longevity, apoptosis and cardiomyocyte hypertrophy. The insulin-receptor PI3K/Ak pathway inhibits proapoptotic FOXO3a in response to insulin signalling and the nuclear Sirt1 deacetylase inhibits proapoptotic p53 and modulates FOXO3a in favour of survival and growth. --- Levosimendan is a calcium sensitizing agent used for the management of acute decompensated heart failure. Levosimendan acts as a positive inotrope by sensitizing cardiac troponin C to calcium and exerts vasodilation by opening mitochondrial and sarcolemmal ATP-sensitive potassium channels. Levosimendan has been described to have beneficial effects in ventricular remodelling after myocardial infarction. The aims of the study were to characterize whether diabetic cardiomyopathy associates with cardiac dysfunction, cardiomyocyte apoptosis, hypertrophy and fibrosis in spontaneously diabetic Goto-Kakizaki (GK) rats, which were used to model type 2 diabetes. Protein expression and activation of the Akt FOXO3a and Sirt1 p53 pathways were examined in the development of ventricular remodelling in GK rats with and without myocardial infarction (MI). The third and fourth studies examined the effects of levosimendan on ventricular remodelling and gene expression in post-MI GK rats. The results demonstrated that diabetic GK rats develop both modest hypertension and features similar to diabetic cardiomyopathy including cardiac dysfunction, LV hypertrophy and fibrosis and increased apoptotic signalling. MI induced a sustained increase in cardiomyocyte apoptosis in GK rats together with aggravated LV hypertrophy and fibrosis. The GK rat myocardium exhibited decreased Akt- FOXO3a phosphorylation and increased nuclear translocation of FOXO3a and overproduction of the Sirt1 protein. Treatment with levosimendan decreased cardiomyocyte apoptosis, senescence and LV hypertrophy and altered the gene expression profile in GK rat myocardium. The findings indicate that impaired cardioprotection via Akt FOXO3a and p38 MAPK is associated with increased apoptosis, whereas Sirt1 functions in counteracting apoptosis and the development of LV hypertrophy in the GK rat myocardium. Overall, levosimendan treatment protects against post-MI ventricular remodelling and alters the gene expression profile in the GK rat myocardium.

Quenching of gA in the nuclear medium

The numerical values of gA are evaluated using quantum-chromodynamic sum rules. The nuclear medium effects are taken into account by modifying the chiral symmetry breaking correlation, . Our results indicate a quenching of gA in a nuclear medium. The physical reasons for this fundamental quenching are noted to be the same for the effective mass of the nucleon bound in a nucleus being less than its free space value.

Triacylglycerol synthesis in developing seeds of groundnut (Arachis hypogaea): Pathway and properties of enzymes of sn-Glycerol 3-phosphate formation

The enzymatic pathway for the synthesis of sn-glycerol 3-phosphate was investigated in developing groundnut seeds (Arachis hypogaea). Glycerol-3-phosphate dehydrogenase was not detected in this tissue but an active glycerokinase was demonstrated in the cytosolic fraction. It showed an optimum pH at 8.6 and positive cooperative interactions with both glycerol and ATP. Triosephosphate isomerase and glyceraldehyde-3-phosphate phosphatase were observed mainly in the cytosolic fraction while an active glyceraldehyde reductase was found mainly in the mitochondrial and microsomal fractions. The glyceraldehyde 3-phosphate phosphatase showed specificity and positive cooperativity with respect to glyceraldehyde 3-phosphate. The glyceraldehyde reductase was active toward glucose and fructose but not toward formaldehyde and showed absolute specificity toward NADPH. It is concluded that in the developing groundnut seed, sn-glycerol 3-phosphate is synthesized essentially by the pathway dihydroxyacetone phosphate ? glyceraldehyde 3-phosphate ?Pi glyceraldehyde ?NADPH glycerol ?ATP glycerol 3-phosphate. All the enyzmes of this pathway showed activity profiles commensurate with their participation in triacylglycerol synthesis which is maximal during the period 15�35 days after fertilization. Glycerokinase appears to be the rate-limiting enzyme in this pathway.

Hantavirus glycoprotein GN in virion assembly and regulation of interferon response

Hantaviruses have a tri-segmented negative-stranded RNA genome. The S segment encodes the nucleocapsid protein (N), M segment two glycoproteins, Gn and Gc, and the L segment the RNA polymerase. Gn and Gc are co-translationally cleaved from a precursor and targeted to the cis-Golgi compartment. The Gn glycoprotein consists of an external domain, a transmembrane domain and a C-terminal cytoplasmic domain. In addition, the S segment of some hantaviruses, including Tula and Puumala virus, have an open reading frame (ORF) encoding a nonstructural potein NSs that can function as a weak interferon antagonist. The mechanisms of hantavirus-induced pathogenesis are not fully understood but it is known that both hemorrhagic fever with renal syndrome (HFRS) and hantavirus (cardio) pulmonary syndrome (HCPS) share various features such as increased capillary permeability, thrombocytopenia and upregulation of TNF-. Several hantaviruses have been reported to induce programmed cell death (apoptosis), such as TULV-infected Vero E6 cells which is known to be defective in interferon signaling. Recently reports describing properties of the hantavirus Gn cytoplasmic tail (Gn-CT) have appeared. The Gn-CT of hantaviruses contains animmunoreceptor tyrosine-based activation motif (ITAM) which directs receptor signaling in immune and endothelial cells; and contain highly conserved classical zinc finger domains which may have a role in the interaction with N protein. More functions of Gn protein have been discovered, but much still remains unknown. Our aim was to study the functions of Gn protein from several aspects: synthesis, degradation and interaction with N protein. Gn protein was reported to inhibit interferon induction and amplication. For this reason, we also carried out projects studying the mechanisms of IFN induction and evasion by hantavirus. We first showed degradation and aggresome formation of the Gn-CT of the apathogenic TULV. It was reported earlier that the degradation of Gn-CT is related to the pathogenicity of hantavirus. We found that the Gn-CT of the apathogenic hantaviruses (TULV, Prospect Hill virus) was degraded through the ubiquitin-proteasome pathway, and TULV Gn-CT formed aggresomes upon treatment with proteasomal inhibitor. Thus the results suggest that degradation and aggregation of the Gn-CT may be a general property of most hantaviruses, unrelated to pathogenicity. Second, we investigated the interaction of TULV N protein and the TULV Gn-CT. The Gn protein is located on the Golgi membrane and its interaction with N protein has been thought to determine the cargo of the hantaviral ribonucleoprotein which is an important step in virus assembly, but direct evidence has not been reported. We found that TULV Gn-CT fused with GST tag expressed in bacteria can pull-down the N protein expressed in mammalian cells; a mutagenesis assay was carried out, in which we found that the zinc finger motif in Gn-CT and RNA-binding motif in N protein are indispensable for the interaction. For the study of mechanisms of IFN induction and evasion by Old World hantavirus, we found that Old World hantaviruses do not produce detectable amounts of dsRNA in infected cells and the 5 -termini of their genomic RNAs are monophosphorylated. DsRNA and tri-phosphorylated RNA are considered to be critical activators of innate immnity response by interacting with PRRs (pattern recognition receptors). We examined systematically the 5´-termini of hantavirus genomic RNAs and the dsRNA production by different species of hantaviruses. We found that no detectable dsRNA was produced in cells infected by the two groups of the old world hantaviruses: Seoul, Dobrava, Saaremaa, Puumala and Tula. We also found that the genomic RNAs of these Old World hantaviruses carry 5´-monophosphate and are unable to trigger interferon induction. The antiviral response is mainly mediated by alpha/beta interferon. Recently the glycoproteins of the pathogenic hantaviruses Sin Nombre and New York-1 viruses were reported to regulate cellular interferon. We found that Gn-CT can inhibit the induction of IFN activation through Toll-like receptor (TLR) and retinoic acid-inducible gene I-like RNA helicases (RLH) pathway and that the inhibition target lies at the level of TANK-binding kinase 1 (TBK-1)/ IKK epislon complex and myeloid differentiation primary response gene (88) (MyD88) / interferon regulatory factor 7 (IRF-7) complex.

Mode of action of antitumour antibiotics-III: Modulation of permeability of nuclear membrane in the presence of the antibiotics

The binding characteristics of the antibiotics to nuclei and their effect on the permeability of nuclear membrane with respect to histones and ribonucleic acids have been investigated. The binding constant for chromomycin A3 was found to be 1.4 × 104M?1 and number of binding sites was equal to 3.48 ± 1.08 × 1012 molecules/nuclei. The antibiotic chromomycin A3 enhanced the uptake of lysine-rich histone, actinomycin D decreased the uptake and ethidium bromide had no effect. Chromomycin A3 also enhanced the release of acid insoluble fraction containing RNA from the nuclei, actinomycin D and ethidium bromide inhibited the release of acid insoluble fraction containing RNA. The relevance of this finding to the role of nuclear envelope in understanding the mechanism of action of the antibiotic has been discussed.

Defining the pathway to insulin-like growth factor system targeting in cancer

The insulin-like growth factors (IGEs; IGF-1 and IGF-2) play central roles in cell growth, differentiation, survival, transformation and metastasis. The biologic effects of the IGFs are mediated by the IGF-1 receptor (IGF-1R), a receptor tyrosine kinase with homology to the insulin receptor (IR). Dysregulation of the ICE system is well recognized as a key contributor to the progression of multiple cancers, with IGF-1R activation increasing the tumorigenic potential of breast, prostate, lung, colon and head and neck squamous cell carcinoma (HNSCC). Despite this relationship, targeting the IGF-1R has only recently undergone development as a molecular cancer therapeutic. As it has taken hold, we are witnessing a robust increase and interest in targeting the inhibition of IGF-1R signaling. This is accentuated by the list of over 30 drugs, including monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) that are under evaluation as single agents or in combination therapies 1]. The ICE-binding proteins (IGFBPs) represent the third component of the ICE system consisting of a class of six soluble secretory proteins. They represent a unique class of naturally occurring ICE-antagonists that bind to and sequester IGF-1 and IGF-2, inhibiting their access to the IGF-1R. Due to their dual targeting of the IGFs without affecting insulin action, the IGFBPs are an untapped ``third'' class of IGF-1R inhibitors. in this commentary, we highlight some of the significant aspects of and prospects for targeting the IGF-1R and describe what the future may hold. (C) 2010 Elsevier Inc. All rights reserved.

Conformations of synthetic alamethicin fragments. Evidence for 310 helical folding from 270-MHz hydrogen-1 nuclear magnetic resonance and circular dichroism studies

IH NMR studies at 270 MHz on the synthetic alamethicin fragments Z-Aib-Pro-Aib-Ala-Aib-Ala-OMe (1-6), Boc-Gln-Aib-Val-Aib-Gly-Leu-Aib-OMe (7-1 3), Boc-Leu-Aib-Pro-Val-Aib-OMe (1 2-16), and Boc-Gly-Leu- Aib-Pro-Val-Aib-OMe (1 1-16) have been carried out in CDC13 and (CD3)2S0. The intramolecularly hydrogen bonded amide hydrogens in these peptides have been delineated by using solvent titration experiments and temperature coefficientsof NH chemical shifts in (CD3)+30. All the peptides adopt highly folded structures, characterized by intramolecular 4 - 1 hydrogen bonds. The 1-6 fragment adopts a 310 helical conformation with four hydrogen bonds, in agreement with earlier studies (Rao, Ch. P., Nagaraj, R., Rao, C. N. R., & Balaram, P. (1980) Biochemistry 19, 425-4311. The 7-13

Conformations of dehydrophenylalanyl containing peptides. Nuclear Overhauser effect study of two acyclic

Two isomeric, acyclic tetrapeptides containing a Z-dehydrophenylalanine residue (Δz-Phe) at position 2 or 3, Boc-Leu-Ala-Δz-Phe-Leu-OMe (1) and Boc-Leu-Δz-Phe-Ala-Leu-OMe (2), have been synthesized and their solution conformations investigated by 270MHz 1H n.m.r. spectroscopy. In peptide 1 the Leu(4) NH group appears to be partially shielded from solvent, while in peptide 2 both Ala(3) and Leu(4) NH groups show limited solvent accessibility. Extensive difference nuclear Overhauser effect (n.O.e.) studies establish the occurrence of several diagnostic inter-residue n.O.e.s (CαjH ⇆ Ni+1H and NiH ⇆ Ni+1H) between backbone protons. The simultaneous observation of “mutually exclusive” n.O.e.s suggests the presence of multiple solution conformations for both peptides. In peptide 1 the n.O.e. data are consistent with a dynamic equilibrium between an -Ala-Δz-Phe- Type II β-turn structure and a second species with Δz-Phe adopting a partially extended conformation with Ψ values of ± 100° to ± 150°. In peptide 2 the results are compatible with an equilibrium between a highly folded consecutive β-turn structure for the -Leu-Δz-Phe-Ala- segment and an almost completely extended conformation.

Hyperfine effects in the nuclear magnetic resonance of paramagnetic molecules

Paramagnetic, or open-shell, systems are often encountered in the context of metalloproteins, and they are also an essential part of molecular magnets. Nuclear magnetic resonance (NMR) spectroscopy is a powerful tool for chemical structure elucidation, but for paramagnetic molecules it is substantially more complicated than in the diamagnetic case. Before the present work, the theory of NMR of paramagnetic molecules was limited to spin-1/2 systems and it did not include relativistic corrections to the hyperfine effects. It also was not systematically expandable. --- The theory was first expanded by including hyperfine contributions up to the fourth power in the fine structure constant α. It was then reformulated and its scope widened to allow any spin state in any spatial symmetry. This involved including zero-field splitting effects. In both stages the theory was implemented into a separate analysis program. The different levels of theory were tested by demonstrative density functional calculations on molecules selected to showcase the relative strength of new NMR shielding terms. The theory was also tested in a joint experimental and computational effort to confirm assignment of 11 B signals. The new terms were found to be significant and comparable with the terms in the earlier levels of theory. The leading-order magnetic-field dependence of shielding in paramagnetic systems was formulated. The theory is now systematically expandable, allowing for higher-order field dependence and relativistic contributions. The prevailing experimental view of pseudocontact shift was found to be significantly incomplete, as it only includes specific geometric dependence, which is not present in most of the new terms introduced here. The computational uncertainty in density functional calculations of the Fermi contact hyperfine constant and zero-field splitting tensor sets a limit for quantitative prediction of paramagnetic shielding for now.

Dipolar cross-correlation effects in the nuclear overhauser experiments of weakly and strongly coupled spins

The effect of dipolar cross correlation in 1H---1H nuclear Overhauser effect experiments is investigated by detailed calculation in an ABX spin system. It is found that in weakly coupled spin systems, the cross-correlation effects are limited to single-quantum transition probabilities and decrease in magnitude as ωτc increases. Strong coupling, however, mixes the states and the cross correlations affect the zero-quantum and double-quantum transition probabilities as well. The effect of cross correlation in steady-state and transient NOE experiments is studied as a function of strong coupling and ωτc. The results for steady-state NOE experiments are calculated analytically and those for transient NOE experiments are calculated numerically. The NOE values for the A and B spins have been calculated by assuming nonselective perturbation of all the transitions of the X spin. A significant effect of cross correlation is found in transient NOE experiments of weakly as well as strongly coupled spins when the multiplets are resolved. Cross correlation manifests itself largely as a multiplet effect in the transient NOE of weakly coupled spins for nonselective perturbation of all X transitions. This effect disappears for a measuring pulse of 90° or when the multiplets are not resolved. For steady-state experiments, the effect of cross correlation is analytically zero for weakly coupled spins and small for strongly coupled spins.