Modulation of Ca2+-dependent anion secretion by protein kinase C in normal and cystic fibrosis pancreatic duct cells

AbstractThe study investigated the role of protein kinase C (PKC) in the modulation of agonist-induced Ca2+-dependent anion secretion by pancreatic duct cells. The short-circuit current (ISC) technique was used to examine the effect of PKC activation and inhibition on subsequent ATP, angiotensin II and ionomycin-activated anion secretion by normal (CAPAN-1) and cystic fibrosis (CFPAC-1) pancreatic duct cells. The ISC responses induced by the Ca2+-mobilizing agents, which had been previously shown to be attributed to anion secretion, were enhanced in both CAPAN-1 and CFPAC-1 cells by PKC inhibitors, staurosporine, calphostin C or chelerythrine. On the contrary, a PKC activator, phorbol 12-myristate 13-acetate (PMA), was found to suppress the agonist-induced ISC in CFPAC-1 cells and the ionomycin-induced ISC in CAPAN-1 cells. An inactive form of PMA, 4αd-phorbol 12,13-didecanote (4αD), was found to exert insignificant effect on the agonist-induced ISC, indicating a specific effect of PMA. Our data suggest a role of PKC in modulating agonist-induced Ca2+-dependent anion secretion by pancreatic duct cells. Therapeutic strategy to augment Ca2+-activated anion secretion by cystic fibrosis pancreatic duct cells may be achieved by inhibition or down-regulation of PKC

Brane Fluctuation and anomalous muon magnetic moment

We study the effects of extra dimensions on the muon anomalous magnetic moment with brane fluctuation. Since the coupling is naturally suppressed if brane fluctuation is considered by exponential softening factor for heavier states, the contribution from the whole Kaluza-Klein graviton tower is shown to be finite. The recent BNL E821 result is accomodated with $D=4+\delta$ dimensional gravitational scale, $M_D$, in the range of $M_D \simeq 1.0 - 5.1$ TeV ($\delta=2$), and $M_D \simeq 1.0 - 8.0$ TeV ($\delta=6$) with the brane tension parameter $f=(4\pi^2 \tau)^{1/4}$, in the range $f = 1 - 10$ TeV.Comment: 8 pages, LaTeX, 2 eps Figures, references added, version to appear in PL

Evolutionary Dynamics on Protein Bi-stability Landscapes Can Potentially Resolve Adaptive Conflicts

Experimental studies have shown that some proteins exist in two alternative native-state conformations. It has been proposed that such bi-stable proteins can potentially function as evolutionary bridges at the interface between two neutral networks of protein sequences that fold uniquely into the two different native conformations. Under adaptive conflict scenarios, bi-stable proteins may be of particular advantage if they simultaneously provide two beneficial biological functions. However, computational models that simulate protein structure evolution do not yet recognize the importance of bi-stability. Here we use a biophysical model to analyze sequence space to identify bi-stable or multi-stable proteins with two or more equally stable native-state structures. The inclusion of such proteins enhances phenotype connectivity between neutral networks in sequence space. Consideration of the sequence space neighborhood of bridge proteins revealed that bi-stability decreases gradually with each mutation that takes the sequence further away from an exactly bistable protein. With relaxed selection pressures, we found that bi-stable proteins in our model are highly successful under simulated adaptive conflict. Inspired by these model predictions, we developed a method to identify real proteins in the PDB with bridge-like properties, and have verified a clear bi-stability gradient for a series of mutants studied by Alexander et al. (Proc Nat Acad Sci USA 2009, 106:21149–21154) that connect two sequences that fold uniquely into two different native structures via a bridge-like intermediate mutant sequence. Based on these findings, new testable predictions for future studies on protein bi-stability and evolution are discussed

213-Bi-DOTATATE for Targeted Alpha Therapy in Neuroendocrine Tumours

Targeted alpha therapy (TAT) is promising for improvement of current peptide receptor radionuclide therapy for patient with metastatic neuroendocrine tumours. Due to the high LET of alpha particles, the possibility to cause double strand breaks in the DNA of a tumour cell is much higher than after therapy using beta particle emitters. At the same time, healthy tissues can be spared because of the short path length of alpha particles. _213_ Bismuth (_213_ Bi, an alpha emitter with a half-life of 46 min) was eluted from a _225_ Ac/_213_ Bi generator. _213_ Bi was attached to a peptide via a chelator, in our case a somatostatin analogue with the DOTA chelator, DOTA-Tyr3-octreotate (DOTATATE). In this thesis, _213_ Bi-DOTATATE was used for TAT to investigate whether it is superior compared to DOTATATE labelled with beta particle emitters, like _177_ Lu-DOTATATE for treatment of neuroendocrine tumours with somatostatin receptor expression. The stability of _213_ Bi-DOTATATE was investigated; the labelled peptide showed high stability up to 2 h after labelling. _213_ Bi-DOTATATE showed higher therapeutic efficacy in vitro compared to _177_ Lu-DOTATATE; a 5x more tumour cells killing potency was found. _213_ Bi-DOTATATE prolonged survival in xenografted mice with different tumour models with varying somatostatin receptor density and tumour size. Potential renal toxicity could be managed by renal protectant L-lysine application. Furthermore, biodistribution was imaged by a special SPECT camera dedicated to small animals imaging. Overall, _213_ Bi-DOTATATE showed to be promising for TAT for treatment of neuroendocrine tumours with somatostatin expression

Dynamic Dilatonic Domain Walls

Motivated by the ``universe as a brane'' idea, we investigate the motion of a $(D-2)$-brane (or domain wall) that couples to bulk matter. Usually one would expect the spacetime outside such a wall to be time dependent however we show that in certain cases it can be static, with consistency of the Israel equations yielding relationships between the bulk metric and matter that can be used as ans\"atze to solve the Einstein equations. As a concrete model we study a domain wall coupled to a bulk dilaton with Liouville potentials for the dilaton both in the bulk and on the wall. The bulk solutions we find are all singular but some have black hole or cosmological horizons, beyond which our solutions describe domain walls moving in time dependent bulks. A significant period of world volume inflation occurs if the potential on the wall is not too steep; in some cases the bulk also inflates (with the wall comoving) while in others the wall moves relative to a non-inflating bulk. We apply our method to obtain cosmological solutions of Ho\v{r}ava-Witten theory compactified on a Calabi-Yau space. tive to a non-inflating bulk. We apply our method to obtain cosmological solutions of Ho\v{r}ava-Witten theory compactified on a Calabi-Yau space.Comment: 32 pages LaTeX, 5 .eps figures, corrected some typo

Dengue in Madeira Island

This is a preprint of a paper whose final and definite form will be published in the volume Mathematics of Planet Earth that initiates the book series CIM Series in Mathematical Sciences (CIM-MS) published by Springer. Submitted Oct/2013; Revised 16/July/2014 and 20/Sept/2014; Accepted 28/Sept/2014.Dengue is a vector-borne disease and 40% of world population is at risk. Dengue transcends international borders and can be found in tropical and subtropical regions around the world, predominantly in urban and semi-urban areas. A model for dengue disease transmission, composed by mutually-exclusive compartments representing the human and vector dynamics, is presented in this study. The data is from Madeira, a Portuguese island, where an unprecedented outbreak was detected on October 2012. The aim of this work is to simulate the repercussions of the control measures in the fight of the disease

Flat histogram simulation of lattice polymer systems

We demonstrate the use of a new algorithm called the Flat Histogram sampling algorithm for the simulation of lattice polymer systems. Thermodynamics properties, such as average energy or entropy and other physical quantities such as end-to-end distance or radius of gyration can be easily calculated using this method. Ground-state energy can also be determined. We also explore the accuracy and limitations of this method. Key words: Monte Carlo algorithms, flat histogram sampling, HP model, lattice polymer systemsComment: 7 RevTeX two-column page

Simplified amino acid alphabets based on deviation of conditional probability from random background

The primitive data for deducing the Miyazawa-Jernigan contact energy or BLOSUM score matrix consists of pair frequency counts. Each amino acid corresponds to a conditional probability distribution. Based on the deviation of such conditional probability from random background, a scheme for reduction of amino acid alphabet is proposed. It is observed that evident discrepancy exists between reduced alphabets obtained from raw data of the Miyazawa-Jernigan's and BLOSUM's residue pair counts. Taking homologous sequence database SCOP40 as a test set, we detect homology with the obtained coarse-grained substitution matrices. It is verified that the reduced alphabets obtained well preserve information contained in the original 20-letter alphabet.Comment: 9 pages,3figure