402 research outputs found
A Closed-Form Solution of the Multi-Period Portfolio Choice Problem for a Quadratic Utility Function
In the present paper, we derive a closed-form solution of the multi-period
portfolio choice problem for a quadratic utility function with and without a
riskless asset. All results are derived under weak conditions on the asset
returns. No assumption on the correlation structure between different time
points is needed and no assumption on the distribution is imposed. All
expressions are presented in terms of the conditional mean vectors and the
conditional covariance matrices. If the multivariate process of the asset
returns is independent it is shown that in the case without a riskless asset
the solution is presented as a sequence of optimal portfolio weights obtained
by solving the single-period Markowitz optimization problem. The process
dynamics are included only in the shape parameter of the utility function. If a
riskless asset is present then the multi-period optimal portfolio weights are
proportional to the single-period solutions multiplied by time-varying
constants which are depending on the process dynamics. Remarkably, in the case
of a portfolio selection with the tangency portfolio the multi-period solution
coincides with the sequence of the simple-period solutions. Finally, we compare
the suggested strategies with existing multi-period portfolio allocation
methods for real data.Comment: 38 pages, 9 figures, 3 tables, changes: VAR(1)-CCC-GARCH(1,1) process
dynamics and the analysis of increasing horizon are included in the
simulation study, under revision in Annals of Operations Researc
Molecular Dynamics Simulations Suggest Ligand’s Binding to Nicotinamidase/Pyrazinamidase
The research on the binding process of ligand to pyrazinamidase (PncA) is crucial for elucidating the inherent relationship between resistance of Mycobacterium tuberculosis and PncA’s activity. In the present study, molecular dynamics (MD) simulation methods were performed to investigate the unbinding process of nicotinamide (NAM) from two PncA enzymes, which is the reverse of the corresponding binding process. The calculated potential of mean force (PMF) based on the steered molecular dynamics (SMD) simulations sheds light on an optimal binding/unbinding pathway of the ligand. The comparative analyses between two PncAs clearly exhibit the consistency of the binding/unbinding pathway in the two enzymes, implying the universality of the pathway in all kinds of PncAs. Several important residues dominating the pathway were also determined by the calculation of interaction energies. The structural change of the proteins induced by NAM’s unbinding or binding shows the great extent interior motion in some homologous region adjacent to the active sites of the two PncAs. The structure comparison substantiates that this region should be very important for the ligand’s binding in all PncAs. Additionally, MD simulations also show that the coordination position of the ligand is displaced by one water molecule in the unliganded enzymes. These results could provide the more penetrating understanding of drug resistance of M. tuberculosis and be helpful for the development of new antituberculosis drugs
Gating at the Mouth of the Acetylcholine Receptor Channel: Energetic Consequences of Mutations in the αM2-Cap
Gating of nicotinic acetylcholine receptors from a C(losed) to an O(pen) conformation is the initial event in the postsynaptic signaling cascade at the vertebrate nerve-muscle junction. Studies of receptor structure and function show that many residues in this large, five-subunit membrane protein contribute to the energy difference between C and O. Of special interest are amino acids located at the two transmitter binding sites and in the narrow region of the channel, where C↔O gating motions generate a low↔high change in the affinity for agonists and in the ionic conductance, respectively. We have measured the energy changes and relative timing of gating movements for residues that lie between these two locations, in the C-terminus of the pore-lining M2 helix of the α subunit (‘αM2-cap’). This region contains a binding site for non-competitive inhibitors and a charged ring that influences the conductance of the open pore. αM2-cap mutations have large effects on gating but much smaller effects on agonist binding, channel conductance, channel block and desensitization. Three αM2-cap residues (αI260, αP265 and αS268) appear to move at the outset of channel-opening, about at the same time as those at the transmitter binding site. The results suggest that the αM2-cap changes its secondary structure to link gating motions in the extracellular domain with those in the channel that regulate ionic conductance
The PI-3 kinase-Akt-MDM2-survivin signaling axis in high-risk neuroblastoma: a target for PI-3 kinase inhibitor intervention
Plasmodium vivax Tryptophan-Rich Antigen PvTRAg33.5 Contains Alpha Helical Structure and Multidomain Architecture
Tryptophan-rich proteins from several malarial parasites have been identified where they play an important role in host-parasite interaction. Structural characterization of these proteins is needed to develop them as therapeutic targets. Here, we describe a novel Plasmodium vivax tryptophan-rich protein named PvTRAg33.5. It is expressed by blood stage(s) of the parasite and its gene contains two exons. The exon 1 encodes for a 23 amino acids long putative signal peptide which is likely to be cleaved off whereas the exon 2 encodes for the mature protein of 252 amino acids. The mature protein contains B-cell epitopes which were recognized by the human immune system during P.vivax infection. The PvTRAg33.5 contains 24 (9.5%) tryptophan residues and six motifs whose patterns were similar among tryptophan-rich proteins. The modeled structure of the PvTRAg33.5 consists of a multidomain architecture which is stabilized by the presence of large number of tryptophan residues. The recombinant PvTRAg33.5 showed predominantly α helical structure and alpha helix to beta sheet transition at pH below 4.5. Protein acquires an irreversible non-native state at temperature more than 50°C at neutral pH. Its secondary and tertiary structures remain stable in the presence of 35% alcohol but these structures are destabilized at higher alcohol concentrations due to the disturbance of hydrophobic interactions between tryptophanyl residues. These structural changes in the protein might occur during its translocation to interact with other proteins at its final destination for biological function such as erythrocyte invasion
Therapeutic targeting of autophagy in neurodegenerative and infectious diseases.
Autophagy is a conserved process that uses double-membrane vesicles to deliver cytoplasmic contents to lysosomes for degradation. Although autophagy may impact many facets of human biology and disease, in this review we focus on the ability of autophagy to protect against certain neurodegenerative and infectious diseases. Autophagy enhances the clearance of toxic, cytoplasmic, aggregate-prone proteins and infectious agents. The beneficial roles of autophagy can now be extended to supporting cell survival and regulating inflammation. Autophagic control of inflammation is one area where autophagy may have similar benefits for both infectious and neurodegenerative diseases beyond direct removal of the pathogenic agents. Preclinical data supporting the potential therapeutic utility of autophagy modulation in such conditions is accumulating.We are grateful to the Wellcome Trust (095317/Z/11/Z Principal Research Fellowship to D.C. Rubinsztein and strategic award 100140), the National Institute for Health Research Biomedical Research Unit in Dementia at Addenbrooke’s Hospital (D.C. Rubinsztein), and the National Institutes of Health (AI042999 and AI111935; V. Deretic) for funding our work. D.C. Rubinsztein has received grant funding from MedImmune and is a scientific advisor for E3Bio and Bioblast.This is the final version. It was first published by Rockefeller University Press at http://jem.rupress.org/content/early/2015/06/17/jem.20150956.full
Cigarette Smoking and p16INK4α Gene Promoter Hypermethylation in Non-Small Cell Lung Carcinoma Patients: A Meta-Analysis
BACKGROUND:Aberrant methylation of promoter DNA and transcriptional repression of specific tumor suppressor genes play an important role in carcinogenesis. Recently, many studies have investigated the association between cigarette smoking and p16(INK4α) gene hypermethylation in lung cancer, but could not reach a unanimous conclusion. METHODS AND FINDINGS:Nineteen cross-sectional studies on the association between cigarette smoking and p16(INK4α) methylation in surgically resected tumor tissues from non-small cell lung carcinoma (NSCLC) patients were identified in PubMed database until June 2011. For each study, a 2×2 cross-table was extracted. In total, 2,037 smoker and 765 nonsmoker patients were pooled with a fixed-effects model weighting for the inverse of the variance. Overall, the frequency of p16(INK4α) hypermethylation was higher in NSCLC patients with smoking habits than that in non-smoking patients (OR = 2.25, 95% CI = 1.81-2.80). The positive association between cigarette smoking and p16(INK4α) hypermethylation was similar in adenocarcinoma and squamous-cell carcinoma. In the stratified analyses, the association was stronger in Asian patients and in the studies with larger sample sizes. CONCLUSION:Cigarette smoking is positively correlated to p16(INK4α) gene hypermethylation in NSCLC patients
Tests of light-lepton universality in angular asymmetries of decays
We present the first comprehensive tests of light-lepton universality in the
angular distributions of semileptonic \Bz-meson decays to charged spin-1
charmed mesons. We measure five angular-asymmetry observables as functions of
the decay recoil that are sensitive to lepton-universality-violating
contributions. We use events where one neutral \B is fully reconstructed in
\PUpsilonFourS{} \to\B\overline{B} decays in data corresponding to \lumion
integrated luminosity from electron-positron collisions collected with the
\belletwo detector. We find no significant deviation from the standard model
expectations
Measurement of branching fractions and direct asymmetries for and decays at Belle II
We report measurements of the branching fractions and direct
asymmetries of the decays , , , and , and use these for testing the standard
model through an isospin-based sum rule. In addition, we measure the branching
fraction and direct asymmetry of the decay and
the branching fraction of the decay . The data are
collected with the Belle II detector from collisions at the
resonance produced by the SuperKEKB asymmetric-energy collider
and contain bottom-antibottom meson pairs. Signal yields are
determined in two-dimensional fits to background-discriminating variables, and
range from 500 to 3900 decays, depending on the channel. We obtain for the sum rule, in agreement with the standard model
expectation of zero and with a precision comparable to the best existing
determinations
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