A calorimeter for the study of photoproduction at high transverse momentum

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Design, synthesis, and subtype selectivity of 3,6-disubstituted b-carbolines at Bz/GABA(A)ergic receptors. SAR and studies directed toward agents for treatment of alcohol abuse

A series of 3,6-disubstituted ß-carbolines was synthesized and evaluated for their in vitro affinities at axß3V2 GABAA/benzodiazepine receptor subtypes by radioligand binding assays in search of a1 subtype selective ligands to treat alcohol abuse. Analogues of ß-carboline-3-carboxylate-t-butyl ester (ßCCt, 1) were synthesized via a CDI-mediated process and the related 6-substituted ß-carboline-3-carboxylates 6 including WYS8 (7) were synthesized via a Sonogashira or Stille coupling processes from 6-iodo-ßCCt (5). The bivalent ligands of ßCCt (32 and 33) were also designed and prepared via a palladium-catalyzed homocoupling process to expand the structure-activity relationships (SAR) to larger ligands

Development of novel carriers for transdermal delivery of peptides

Recent developments in genetic engineering and biotechnology have resulted in anincrease in availability of therapeutic peptides and small anti-cytokines. Oraladministration is inappropriate as these molecules are unstable in the gastrointestinaltract and are subject to hepatic first-pass effect. Transdermal delivery is an attractivealternative as the skin exhibits less enzymatic activity and allows for a controlled,sustained local therapeutic drug concentration over a prolonged period of time.However, the skin’s lipophilic stratum corneum acts as a major barrier to thedelivery of hydrophilic molecules, including peptides, resulting in lack of efficacy ofthese compounds if applied topically. Considerable research effort has beenfocussed on the development of skin penetration enhancement techniques. However,many of these techniques have been limited by insufficient penetration enhancementand/or induced irritancy.We have investigated three approaches to enhance the delivery of peptides that havetherapeutic or cosmetic effect in the skin. These approaches include the use ofphysical energy to enhance the delivery of Alanine-Tryptophan (Ala-Trp), lipoaminoacid (LAA) conjugation to increase the permeability of a HNE inhibitor Ala-Ala-Pro-Val (AAPV) and a cosmetic peptide, acetyl hexapeptide-3 and cyclisation to enhancethe delivery of a core peptide (CP) which has anti-inflammatory activity.In vitro permeation studies across human epidermis were performed in Pyrex glassFranz-type diffusion cells. Ala-Trp was selected as a small molecular weight modeldipeptide to study the penetration enhancement effects of Dermaportation, which is anewly developed pulsed electro magnetic field (PEMF) technology. The dipeptidewas found to be unstable on exposure to skin at 37°C and Dermaportation (Pulsedelectromagnetic field technology) significantly increased the in vitro permeabilitycoefficient of Ala-Trp across human epidermis from 7.7 x 10-4 cm/h with passivediffusion to 1.94 x 10-2 cm/h with Dermaportation over an 8 h period.Dermaportation thus may provide an effective means of delivering molecules that arehighly susceptible to degradation like dipeptides, in higher amounts and in arelatively short duration.The effectiveness of coupling a short chain lipoamino acid to enhance transepidermaldelivery of a model human neutrophil elastase (HNE) inhibitor (Ala-Ala-Pro-Val) was assessed. The optimal conjugate structure for skin penetration andbiological activity of this therapeutic peptide with anti-inflammatory activity wasdetermined. In order to enhance the trans-epidermal delivery of the peptide,lipophilic derivatives with LAAs of chain length C6, C8, and C10 were prepared bysolid phase synthesis. Conjugation to a C6-LAA enhanced epidermal permeability ofthe tetrapeptide. Stereoselective permeation of the lipopeptide diastereomers acrossthe human epidermis was observed. The amount of C6(D)-LAA-AAPV (467.94μg/cm2) was significantly higher than C6(L)–LAA-AAPV (123.04 μg/cm2). Thesame was observed with C8(D)-LAA-AAPV. The effect of donor concentration andskin hydration on skin permeability of C8(D,L)-LAA-AAPV and C10(D,L)-LAAAAPVwas also assessed and it was observed that there was higher permeation ofC10(D,L)-LAA-AAPV at a higher donor concentration. The lipoamino acid conjugates were more stable than the native tetrapeptide and biological activity was retained after coupling of the tetrapeptide to C6, C8 and C10 LAA.A cosmetic peptide, acetyl hexapeptide-3 was coupled to individual diastereomers ofC12 (A)-LAA and C12 (B)-LAA. The preliminary study was designed to assess theeffect of coupling of a LAA of higher molecular weight on the transepidermalpermeation and accumulation of this hexapeptide. Accumulation of these peptides inthe skin was also quantified. Detectable amounts of C12(A)-LAA-hexapeptide-3 andC12(B)-LAA-hexapeptide-3 were not found in the receptor solution but higherquantities of these conjugates were found to be retained in the skin. The amount ofC12(B)-LAA-hexapeptide-3 (59.92 μg/cm2 ± 10.64) in the epidermis was highestfollowed by C12(A)-LAA-hexapeptide-3 (33.06 μg/cm2 ± 3.70) and acetylhexapeptide-3 (12.64 μg/cm2 ± 1.48).Lastly, skin permeability and in skin stability of an anti-inflammatory peptide (corepeptide: CP) and two analogues that have demonstrated improved biological efficacyand specificity: a cyclic peptide sequence (C1) and its linear sequence counterpart(C1-L) were assessed. The stability of C1 and C1-L was significantly higher ascompared to CP when placed in contact with skin at 37ºC. The epidermal penetrationof the core anti-inflammatory peptide improved after cyclisation. The order of Lastly, skin permeability and in skin stability of an anti-inflammatory peptide (corepeptide: CP) and two analogues that have demonstrated improved biological efficacyand specificity: a cyclic peptide sequence (C1) and its linear sequence counterpart(C1-L) were assessed. The stability of C1 and C1-L was significantly higher ascompared to CP when placed in contact with skin at 37ºC. The epidermal penetrationof the core anti-inflammatory peptide improved after cyclisation. The order of permeation of the analogues was C1>C1-L>CP after 48h and 6 days. The amount of peptide retained in the skin was higher after 48h as compared to 8h due to greater partitioning of these peptides in the skin.This work demonstrates the enhancement effects of these three techniques tooptimize the transdermal/topical permeation of therapeutic and cosmetic peptides

Association of Under-Approximation Techniques for Generating Tests from Models

International audienceIn this paper we present a Model-Based Testing approach with which we generate tests from an abstraction of a source behavioural model. We show a new algorithm that computes the abstraction as an under-approximation of the source model. Our first contribution is to combine two previous approaches proposed by Ball and Pasareanu et al. to compute May, Must+ and Must- abstract transition relations. Prooftechniques are used to compute these transition relations. The tests obtained by covering the abstract transitions have to be instantiated from the source model. So, following Pasareanu et al., our algorithm additionally computes a concrete transition relation: the tests obtained as sequences of concrete transitions need not be instantiated from the source model. Another contribution is to propose a choice of relevant paramaters and heuristics to pilot the tests computation. We experiment our approach and compare it with a previous approach of ours to compute tests from an abstraction that over-approximates the source model

A theory of normed simulations

In existing simulation proof techniques, a single step in a lower-level specification may be simulated by an extended execution fragment in a higher-level one. As a result, it is cumbersome to mechanize these techniques using general purpose theorem provers. Moreover, it is undecidable whether a given relation is a simulation, even if tautology checking is decidable for the underlying specification logic. This paper introduces various types of normed simulations. In a normed simulation, each step in a lower-level specification can be simulated by at most one step in the higher-level one, for any related pair of states. In earlier work we demonstrated that normed simulations are quite useful as a vehicle for the formalization of refinement proofs via theorem provers. Here we show that normed simulations also have pleasant theoretical properties: (1) under some reasonable assumptions, it is decidable whether a given relation is a normed forward simulation, provided tautology checking is decidable for the underlying logic; (2) at the semantic level, normed forward and backward simulations together form a complete proof method for establishing behavior inclusion, provided that the higher-level specification has finite invisible nondeterminism.Comment: 31 pages, 10figure

A Fully Verified Executable LTL Model Checker

International audienceWe present an LTL model checker whose code has been completely verified using the Isabelle theorem prover. The checker consists of over 4000 lines of ML code. The code is produced using recent Isabelle technology called the Refinement Framework, which allows us to split its correctness proof into (1) the proof of an abstract version of the checker, consisting of a few hundred lines of “formalized pseudocode”, and (2) a verified refinement step in which mathematical sets and other abstract structures are replaced by implementations of efficient structures like red-black trees and functional arrays. This leads to a checker that, while still slower than unverified checkers, can already be used as a trusted reference implementation against which advanced implementations can be tested. We report on the structure of the checker, the development process, and some experiments on standard benchmarks

Effect of blood storage on electrolyte levels

Background: Blood transfusion can be an immediate life saving measure in several acute conditions such as hemorrhage and anemia. However, various post transfusion complications are observed in patients which may be associated with the storage conditions of the collected blood. Electrolytes play a major role in maintaining homeostasis within the cells. Potassium is the most important extracellular cation responsible for maintenance of the cell integrity. Prolonged and improper storage of blood can lead to leakage of electrolytes, thus changing the cell morphology. This can adversely affect the patients who receive such blood. This study helps us analyze the effect of blood storage on electrolyte levels.Methods: For the study, 10ml of blood was collected from 30 blood bags containing CPDA-1 at the time of blood donation from 30 different volunteers. This blood containing the CPDA-1 was divided into 5 parts of 2ml and each 2ml sample was stored in plain bulbs. All the samples were stored at 4°C. Samples were tested to check for changes in the electrolyte (Na+, K+, Cl-) levels on day 0, 3, 7, 14 and 21. ANOVA was used to calculate the variance in the electrolyte levels.Results: Average sodium level on day 0 was 152.9±3.8 mEq/l. There was a significant decrease and it was measured at 139.5±4.8 mEq/l on day 21. Average potassium level on day 0 was 4.2±0.4 mEq/l. A significant spike was observed in potassium levels. The final reading of potassium level on day 21 was 15.2±0.7 mEq/l. Average chloride level on day 0 was 71.9±6.6 mEq/l which significantly declined to 67±5.9 mEq/l.Conclusions: Though blood is stored in proper conditions, a biochemical change occurs within the cells due to prolonged storage and thus affects its viability

Design and analysis of solid state transformer

This paper tries to make appoint that Solid State Transformer is an effective replacement for the conventional L F (Low frequency) transformer. The common topologies of SST are discussed. The present drawbacks of LF transformer and the advantages and future applications of Solid State Transformer are also mentioned. A Solid State Transformer is a bit complex system to barrier of universal acceptance is discussed and projected. In this paper discusses the features of power electronic based solid state transformer and its application in different electrical field, where conventional transformer can be replaced by the solid state transformer

Safety and efficacy of an oral insulin (Capsulin) in patients with early‐stage type 2 diabetes: a dose‐ranging phase IIb study

Aim This randomised, twelve-week open-label study compared the pharmacodynamic properties of different dose of regular human insulin administered in capsule form twice daily. Methods 100 persons (48 male, 52 female) with type 2 diabetes on metformin completed the study according to protocol. Mean (SD) age 48.5 (6.7) years, BMI 25.7 (2.8) kg/m2, HbA1c 8.10 (0.65) %. Subjects randomised on admission were assigned to one of three groups receiving 75iu BD of formulated regular insulin or 150iu insulin BD, or 300iu BD in enteric-coated capsules. Primary and secondary endpoints were change from baseline in HbA1c and FPG respectively. A total of 100 subjects from 15 different centres completed the study within protocol. Results The study met its primary clinical endpoint of a decrease in HbA1c ≥ 0.5% (least square mean decrease 0.52%; p = 0.004, median decrease 0.6) in the dose group receiving 150iu BD. In a subset of this population, with starting HbA1c values between 9 and 9.5%, an average decrease of 1.575% was seen. In the total population, least square mean decreases in HbA1c for groups 75iu BD and 300iu BD were -0.11% and -0.42% respectively. Mean change in FPG in the 150iu BD dose group was -18.8mg/dL (p = 0.017) and -14.8 and -2.7mg/dL for groups 75iu BD and 300iu BD respectively. A decrease of 20% for triglycerides (-40 mg/dL) was seen in the 150iu BD dose group . No significant increases in body weight were observed, and significant decreases in systolic blood pressure were seen in all groups. No serious treatment-related adverse events were recorded, and no incidence of hypoglycaemia was reported throughout the whole twelve-week study period. Conclusions Capsulin oral insulin administered twice per day at a dose of 150iu per capsule is safe, with no confirmed treatment-linked hypoglycaemic events, and results in significant decreases from baseline in HbA1c, Fasting Plasma Glucose and triglycerides