Pharmacological Or Genetic Targeting Of Transient Receptor Potential (TRP) Channels Can Disrupt The Planarian Escape Response

In response to noxious stimuli, planarians cease their typical ciliary gliding and exhibit an oscillatory type of locomotion called scrunching. We have previously characterized the biomechanics of scrunching and shown that it is induced by specific stimuli, such as amputation, noxious heat, and extreme pH. Because these specific inducers are known to activate Transient Receptor Potential (TRP) channels in other systems, we hypothesized that TRP channels control scrunching. We found that chemicals known to activate TRPA1 (allyl isothiocyanate (AITC) and hydrogen peroxide) and TRPV (capsaicin and anandamide) in other systems induce scrunching in the planarian species Dugesia japonica and, except for anandamide, in Schmidtea mediterranea. To confirm that these responses were specific to either TRPA1 or TRPV, respectively, we tried to block scrunching using selective TRPA1 or TRPV antagonists and RNA interference (RNAi) mediated knockdown. Unexpectedly, co-treatment with a mammalian TRPA1 antagonist, HC-030031, enhanced AITC-induced scrunching by decreasing the latency time, suggesting an agonistic relationship in planarians. We further confirmed that TRPA1 in both planarian species is necessary for AITC-induced scrunching using RNAi. Conversely, while co-treatment of a mammalian TRPV antagonist, SB-366791, also enhanced capsaicin-induced reactions in D. japonica, combined knockdown of two previously identified D. japonica TRPV genes (DjTRPVa and DjTRPVb) did not inhibit capsaicin-induced scrunching. RNAi of DjTRPVa/DjTRPVb attenuated scrunching induced by the endocannabinoid and TRPV agonist, anandamide. Overall, our results show that although scrunching induction can involve different initial pathways for sensing stimuli, this behavior’s signature dynamical features are independent of the inducer, implying that scrunching is a stereotypical planarian escape behavior in response to various noxious stimuli that converge on a single downstream pathway. Understanding which aspects of nociception are conserved or not across different organisms can provide insight into the underlying regulatory mechanisms to better understand pain sensation

OPTIMIZATION AND EVALUATION OF CHLORPHENIRAMINE MALEATE ORAL STRIP FOR PEDIATRIC USE

Objective: The goal of performing this study is to prepare an oral strip, especially designed for pediatric use that provides fast onset of action with ease of swallowing particularly for young individuals who suffer from difficulty of swallowing, in addition provides maximum therapeutic effectiveness by reducing the first pass effect.Materials and Methods: The oral strip was prepared by solvent casting technique through using different sole polymers (hydroxypropyl methylcellulose [HPMC] 15cp, HPMC 50cp, polyvinyl alcohol, and sodium carboxymethyl cellulose). Maltodextrin (MD) was added as the secondary polymer in different ratios to optimize the release parameters, and disintegration time (DT), three different plasticizers were employed (propylene glycol, dibutyl phthalate, and glycerin) to boost the film forming polymer characteristics.Results: From this study, it is obvious that F10 which composed of HPMC as a main polymer and MD as a secondary polymer in ratio 2:1, respectively, provides adequate physicochemical characteristics, in vivo/in vitro DT (40/36 s), respectively, nevertheless a satisfactory release parameters as (59.9%) released at 2 min and 80% of drug released at 14.8 min.Conclusion: The optimized formula is pretty encouraging to originate an oral strip that provides ease of administration, fast onset of action with wide acceptance for the pediatric population

Vitamin D and IL28B genotyping as predictors for antiviral therapy: a retrospective study in Egyptian HCV genotype 4a

Purpose: To evaluate the role of pre-treatment vitamin D serum level and interleukin28B (IL28B) (rs 12979860) polymorphism in chronic hepatitis C (CHC) genotype 4a patients treated with pegylated interferon α2-A and ribavirin (peg IFN+RBV) as predictors of response.Methods: A retrospective study of clinical and pathological data and stored blood samples of 150 naïve chronic hepatitis C (CHC) genotype 4a patients, treated with pegylated interferon and ribavirin for 48 weeks. Follow-up to detect sustained virological response (SVR) was carried out. Based on SVR, two groups were studied; group 1 consisted of 75 responder patients to pegylated IFN + RBV therapy while group 2 comprised of 75 non-responder patients to standard hepatitis C virus (HCV) therapy. Vitamin D serum levels were assessed using Enzyme Linked Immunoassay (ELISA), quantitative reverse transcriptase- polymerase chain reaction (qRT-PCR for HCV RNA ), and IL28B gene polymorphism by Restriction Fragment Length Polymorphism Polymerase Cchain Reaction (RFLP-PCR).Results: Pretreatment vitamin D level was significantly higher in group 1 than in group 2 (p < 0.001). The sensitivity and specificity of vitamin D level for prediction of SVR at a cutoff value of 29.75 ng/ml were 100 and 96 %, respectively, with area under the curve (AUC) of 0.995 (p < 0.001). A significant difference was detected between baseline vitamin D level for early versus advanced fibrosis stage (p = 0.01) in group 1.Conclusion: Pretreatment vitamin D serum level (at a cutoff value of 29.75 ng/ml), IL28B gene polymorphism and quantitative HCV RNA are independent trait predictors of SVR.Keywords: Vitamin D, Interleukin 28B, Chronic hepatitis C, Sustained virological response (SVR), Antiviral, Genotypin

Mitochondrial DNA depletion syndrome presenting with ataxia and external ophthalmoplegia: Case report

The mitochondrial DNA depletion syndromes are autosomal recessive disorders characterized by decreased mitochondrial DNA copy number in affected tissues.Mutations in 2 genes involved in deoxyribonucleotide metabolism, the deoxyguanosine kinase gene and the thymidine kinase 2 gene, had been related to this syndrome. This study aims to describe the clinical, histochemical, biochemical and molecular diagnosis of one Egyptian pediatric patient with the myopathic form of mitochondrial depletion syndrome. The patient presented to Cairo University Pediatric Hospital with the clinical suspicion of mitochondrial encephalomyopathy. Histochemical and biochemical studies of the respiratory chain complexes were performed on the muscle biopsy specimen from the patient. Molecular diagnosis was done by quantitative radioactive Southern blot and sequencing analysis of the whole coding regions of the TK2 gene. Histochemical staining revealed cytochrome oxidase negative fibers and increased staining for succinate dehydrogenase. The activity of complex I was not detected and complex IV activity was about 46%of age matched controls. Southern blot analysis showed reduction of the mitochondrial/nuclear DNA ratio, the degree of depletion was around 30% of aged-matched controls. Sequencing analysis of the TK2 gene revealed no sequence variation. Targeted molecular diagnosis based on the biochemical analysis of the respiratory chain enzymes makes the molecular evaluation of mitochondrial disorders much easier. Involvement of other nuclear genes rather than TK2 gene in the pathogenesis of the myopathic form of mitochondrial depletion syndrome should be considered.Keywords: Mitochondrial; Nuclear; Sequencing; Depletion; Mutation

Planarian Fragments Behave As Whole Animals

Behavioral responses of freshwater planarians have been studied for over a century. In recent decades, behavior has been used as a readout to study planarian development and regeneration, wound healing, molecular evolution, neurotoxicology, and learning and memory. The planarian nervous system is among the simplest of the bilaterally symmetric animals, with an anterior brain attached to two ventral nerve cords interconnected by multiple commissures. We found that, in response to mechanical and near-UV stimulation, head stimulation produces turning, tail stimulation produces contraction, and trunk stimulation produces midbody elongation in the planarian Dugesia japonica. When cut into two or three pieces, the anterior end of each headless piece switched its behavior to turning instead of elongation; i.e., it responded as though it were the head. In addition, posterior ends of the head and midbody pieces sometimes produced contraction instead of elongation. Thus, each severed piece acts like an intact animal, with each midbody region having nearly complete behavioral capabilities. These observations show that each midbody region reads the global state of the organism and adapts its response to incoming signals from the remaining tissue. Selective lateral incisions showed that the changes in behavior are not due to nonselective pain responses and that the ventral nerve cords and cross-connectives are responsible for coordinating local behaviors. Our findings highlight a fast functional reorganization of the planarian nervous system that complements the slower repairs provided by regeneration. This reorganization provides needed behavioral responses for survival as regeneration proceeds

Genetic heterogeneity of CTX-M type extended-spectrum ß-lactamase producing Escherichia coli strains from diverse sources in Saudi Arabia

Background: The rise of CTX-M extended spectrum β-lactamase (ESBLs)-producing E. coli in non-human sources is a growing concern of public health. Understanding the extent of public health risk attributed to CTX-M type ESBLs-producing strains from different sources is critical for effective control.Objective: This study focuses on detection and molecular typing of CTX-M type ESBL-producing E. coli isolated from various sources in Taif, Western Saudi Arabia. Material and Methods: A total of 24 E. coli ESBLs-producing isolates from multiple sources were assessed for the presence of CTX-M groups gene by PCR, and subsequently their clonal relatedness by random amplifid of polymorphic DNA (RAPD) analysis. Isolates were selected according to a resistance phenotype consistent with production of ESBL-type beta-lactamase using double disk diffusion method.Results: A CTX-M gene was detected in all 24 isolates. RAPD typing of E. coli isolates bearing CTX-M gene showed 24 patterns verifid into two major clusters (A, B) and three sub-clusters (A1 – A3). Phylogenetic analysis indicating a degree of similarity among clustering isolates from human, sheep and raw milk origins. Identical profie was observed between three isolates obtained from pet bird and chicken

Completeness of algebraic CPS simulations

The algebraic lambda calculus and the linear algebraic lambda calculus are two extensions of the classical lambda calculus with linear combinations of terms. They arise independently in distinct contexts: the former is a fragment of the differential lambda calculus, the latter is a candidate lambda calculus for quantum computation. They differ in the handling of application arguments and algebraic rules. The two languages can simulate each other using an algebraic extension of the well-known call-by-value and call-by-name CPS translations. These simulations are sound, in that they preserve reductions. In this paper, we prove that the simulations are actually complete, strengthening the connection between the two languages.Comment: In Proceedings DCM 2011, arXiv:1207.682

Heme oxygenase effect on mesenchymal stem cells action on experimental Alzheimer's disease

The objective is to evaluate the effect of heme oxygenase-1 (HO-1) enzyme inducer and inhibitor on Mesenchymal Stem Cells (MSCs) in Alzheimer disease. Materials and Methods: 70 female albino rats were divided equally into 7 groups as follows: group 1: healthy control; group 2: Aluminium chloride induced Alzheimer disease; group 3: induced Alzheimer rats that received intravenous injection of MSCs; group 4: induced Alzheimer rats that received MSCs and HO inducer cobalt protoporphyrin; group 5: induced Alzheimer rats that received MSCs and HO inhibitor zinc protoporphyrin; group 6: induced Alzheimer rats that received HO inducer; group7: induced Alzheimer rats that received HO inhibitor. Brain tissue was collected for HO-1, seladin-1 gene expression by real time polymerase chain reaction, heme oxygenase activity, cholesterol estimation and histopathological examination. Results: MSCs decreased the plaque lesions, heme oxygenase induction with stem cells also decreased plaque lesions however there was hemorrhage in the brain. Both heme oxygenase inducer alone or with stem cells increased seladin-1 expression and decreased cholesterol level. Conclusion: MSCs alone or with HO-1 induction exert a therapeutic effect against the brain lesion in Alzheimer’s disease possibly through decreasing the brain cholesterol level and increasing seladin-1 gene expression

Spin and Rotations in Galois Field Quantum Mechanics

We discuss the properties of Galois Field Quantum Mechanics constructed on a vector space over the finite Galois field GF(q). In particular, we look at 2-level systems analogous to spin, and discuss how SO(3) rotations could be embodied in such a system. We also consider two-particle `spin' correlations and show that the Clauser-Horne-Shimony-Holt (CHSH) inequality is nonetheless not violated in this model.Comment: 21 pages, 11 pdf figures, LaTeX. Uses iopart.cls. Revised introduction. Additional reference

Towards a canonical classical natural deduction system

This paper studies a new classical natural deduction system, presented as a typed calculus named \lml. It is designed to be isomorphic to Curien-Herbelin's calculus, both at the level of proofs and reduction, and the isomorphism is based on the correct correspondence between cut (resp. left-introduction) in sequent calculus, and substitution (resp. elimination) in natural deduction. It is a combination of Parigot's $\lambda\mu$-calculus with the idea of ``coercion calculus'' due to Cervesato-Pfenning, accommodating let-expressions in a surprising way: they expand Parigot's syntactic class of named terms. This calculus aims to be the simultaneous answer to three problems. The first problem is the lack of a canonical natural deduction system for classical logic. \lml is not yet another classical calculus, but rather a canonical reflection in natural deduction of the impeccable treatment of classical logic by sequent calculus. The second problem is the lack of a formalization of the usual semantics of Curien-Herbelin's calculus, that explains co-terms and cuts as, respectively, contexts and hole-filling instructions. The mentioned isomorphism is the required formalization, based on the precise notions of context and hole-expression offered by \lml. The third problem is the lack of a robust process of ``read-back'' into natural deduction syntax of calculi in the sequent calculus format, that affects mainly the recent proof-theoretic efforts of derivation of $\lambda$-calculi for call-by-value. An isomorphic counterpart to the $Q$-subsystem of Curien-Herbelin's-calculus is derived, obtaining a new $\lambda$-calculus for call-by-value, combining control and let-expressions.Fundação para a Ciência e a Tecnologia (FCT