Development of Immobilised Biopolymer Stationary Phases based on the Efflux Transporters

The body is continuously exposed to a variety of toxins and metabolic waste products but is able to rid itself of these by using various detoxification mechanisms such as enzymes and transmembrane transporters. A large number of the transporters which play an essential role in the detoxification mechanisms are found in the liver, kidney and intestines. The largest family of transporters is the Solute Carrier (SLC) Superfamily with 255 members in humans. While most SLC transporters are highly specialized, a number of these transporters are polyspecific, generalized transporters that play a major role in the elimination process. Accordingly, the aim of this research programme was to develop novel methodology to enable the study of the interaction of drugs and related compounds with these transporters, in a rapid and facile manner. In the initial studies the application of affinity chromatography was carried out with the use of α1-acid glycoprotein (AGP) column to achieve enantioselective separation of the drug ketamine and its metabolites. The enantioselective separation of ketamine and norketamine from plasma samples was achieved and the assay conducted was sensitive and reproducible. Building upon the experience gained in this work on affinity chromatography and LC-MS, these useful tools for the determination of chiral drugs in biological fluids were also used in the study of drug-protein interactions. With the nicotinic acetylcholine receptors it was possible to explore the use of immobilized liquid chromatographic stationary phases containing drug transporters in on-line high throughput screening (HTS). I Thus having demonstrated that a stationary phase containing immobilized membranes can be used to identify substrate/inhibitors of an expressed receptor/transporter the next and principal phase of the programme was to adapt the methodology to other target biopolymers such as P-glycoprotein which over the last decade has been focused upon for its role in drug resistance in cancer treatments. In particular liquid chromatographic columns containing the drug transporters, P-glycoprotein (Pgp) and human organic cation transporter 1 (hOCT1) were prepared, evaluated and exploited. Initial studies were conducted to confirm the functionality of a stably transfected cell line expressing Pgp (Pgp-(+), LCC6/MDR1 cell line) through a comparison with the non-transfected cell line (Pgp-(-), LCC6 cell line). Initially membranes from the Pgp(+) and Pgp(-) cell lines were then immobilized on immobilized artificial membranes. However, although the resulting column could actively bind the Pgp substrates, strong non-specific interactions with the IAM backbone led to large retention times and peak tailing. A more successful approach was to immobilize on the surface of open tubular capillaries. Such columns were used to sort compounds with or without affinity for Pgp, by comparing the differential retention time on the Pgp (+) and Pgp (-) columns. In this way the non-specific interactions with the constituents of the cellular membrane were compensated for. The results from the sorting by differential chromatography were compared with the behavior of the same compounds in Caco-2 monolayers cultured in 96-well transwell plates, the standard method for the determination of substrates for Pgp. A group of 14 compounds II previously characterized as substrates or non-substrates of Pgp were studied using the chromatographic and Caco-2 methods. In the parallel chromatographic screen, the value o

Interpreting 750 GeV diphoton excess in SU(5) grand unified theory

The ATLAS and CMS experiments at the LHC have found significant excess in the diphoton invariant mass distribution near 750 GeV. We interpret this excess in a predictive nonsupersymmetric SU(5) grand unified framework with a singlet scalar and light adjoint fermions. The 750 GeV resonance is identified as a gauge singlet scalar. Both its production and decays are induced by 24 dimensional adjoint fermions predicted within SU(5). The adjoint fermions are assumed to be odd under $Z_2$ symmetry which forbids their direct coupling to the standard model fermions. We show that the observed diphoton excess can be explained with sub-TeV adjoint fermions and with perturbative Yukawa coupling. A narrow width scenario is more preferred while a simultaneous explanation of observed cross section and large total decay width requires some of the adjoint fermions lighter than 375 GeV. The model also provides a singlet fermion as a candidate of cold dark matter. The gauge coupling unification is achieved in the framework by introducing color sextet scalars while being consistent with the proton decay constraint.Comment: Discussion added, conclusion unchanged; Matches published version in Physics Letters

Encountered Problems and Outcome Status in Nascent Entrepreneurship

Post-printThe relationship between outcome status and encountered problems in the business start-up process is investigated. Contrary to expectations, we find that starters do not substantially differ from quitters in number and type of problems encountered, and that problems encountered generally do not affect outcome status. This research is based on a sample of 414 Dutch nascent entrepreneurs followed over a three year period. Its design is comparable to the U.S. PSED (Panel Study of Entrepreneurial Dynamics)

Labour productivity in state-owned enterprises

In the aftermath of the Global and Financial Crisis (GFC), between 2013 and 2015, the Portuguese government revoked four holidays for both public sector and private employees. We test whether the revocation had an effect on labour productivity in State-Owned Enterprises (SOEs) in Portugal. Moreover, we also study whether such effects are different taking into account the SOEs managed by the Central Government or the Local and Regional Governments. Our results show that revocation of holidays did not impact labour productivity for either central or local and regional government managed SOEs. Though revocation of holidays espoused to improve productivity, the policy seems to have served a ceremonial purpose, but not an economic oneinfo:eu-repo/semantics/publishedVersio

2020 ATL Pavement Design: A Case Study

Four projects on I-65 were selected, designed, and constructed as 2020 ATL (added travel lanes) projects. During the pavement design stages, six alternatives with MEPDG (Mechanistic Pavement Design Guide) analysis, cost (per lane miles), and LCCA (life cycle cost analysis) were considered. Ultimately all projects were selected to be total reconstruction with an alternate bid (HMA vs. concrete) in anticipation of a lower bidding cost. In the end, INDOT saved 14% on these projects ($200M total cost). In this session we will describe various alternate pavement design analyses with cost analysis

Aneurysmal Bone Cyst of Clavicle in a Six-Year-Old Male Child

Aneurysmal Bone Cyst (ABCs) is a cystic expansile lesion which is usually found in solitary locations in the metaphysis of long bones. The most common locations of ABC are long bones of lower limbs. There is little knowledge about the presence of this tumor in Clavicle. Here we present a case of a six year old male child who presented with complaint of swelling in left shoulder for four months. There was a dilemma in the diagnosis of the swelling due to its unusual presentation and appearance. The Fine Needle Aspiration Cytology was also inconclusive. The diagnosis of ABC was made only by excision biopsy. The Clavicle regenerated to nearly normal anatomy at 15 weeks follow up period. The patient is asymptomatic now and is able to perform all daily activities without any restrictions. The uniqueness of this case lies in the fact that this is the first case where ABC has been reported in Clavicular region in young Asian male of less than 10 years age

Warfarin induced hematuria

Warfarin is an oral vitamin K antagonist prescribed to those patients for the treatment and prevention of thromboembolism. The major challenges to be faced during the therapy were a greater risk for both major as well as minor bleeding, which makes the regular monitoring of INR (international normalized ratio) mandatory. Herein, we reported a case of Warfarin induced hematuria which is serious and we concluded this causality as possible category according WHO-UMC causality category

How Do Young Firms Manage Product Portfolio Complexity? The Role of Absorptive Capacity and Ambidexterity

Building a complex portfolio of products can be beneficial for young firms due to increased sales growth and competitiveness. Yet, the benefits from product portfolio complexity (PPC) are often outweighed by rising costs, leading to an inverted U-shaped relationship between PPC and performance. Recent research has called for an increased understanding of how firms are able to better manage higher levels of PPC. We suggest that absorptive capacity and ambidexterity are vital to enhancing the benefits and mitigating the costs of increasing PPC. Using a sample of 215 young high technology firms, we find support for positive moderating effects of absorptive capacity and ambidexterity on the inverted U-shaped relationship between PPC and firm performance