Sialic acid derivatives and mimetics: tools for the investigation of sialic acid processing enzymes

I. Synthesis and inhibitory activity of sialic acid derivatives targeting viral sialate-O-acetylesterases and sialate-O-acetyltransferases Sialate-O-acetylation is a common structural modification of sialic acid, which has been associated with many human disease states (including cancer and autoimmune disease). This highly regulated and tissue-specific modification is carried out by sialate- O-acetylesterase (SOAE) and sialate-O-acetyltransferase (SOAT) enzymes. The availability of these enzymes make inhibition studies a viable endeavour, considering that SOAT/SOAE inhibitors may provide interesting tools/drug leads for the development of antiviral compounds or treatments for various disease states. A synthesis of suitable 4-O- and 9-O-functionalised sialic acid derivatives has been established which enabled the investigation of 4- and 9-sialate-O-acetylesterase enzymes. Sialic acid derivatives were screened for the inhibition of a set of viral SOAEs and while no inhibition of 4-SOAE could be detected, a 9-O-methyl derivative showed inhibition of the recombinant influenza C virus SOAE. The functionalised sialic acid motif thus serves as an initial template for the design and synthesis of future sialic acid derivatives towards SOAT/SOAT inhibition. II. New tools for the characterization and investigation of influenza virus neuraminidases: towards novel influenza virus sensors Tamiflu™ (Oseltamivir), has been employed as a mimetic of the sialic acid “oxocarbenium” intermediate formed during enzymatic hydrolysis, leading to inhibition of virus-bound neuraminidase (NA) enzyme. Phospha-isosteres of oseltamivir provide access to monoesters which retain the efficacy of the pharmacophore and allow the synthesis of novel influenza neuraminidase-specific materials. Phospha-oseltamivir-stabilised gold nanoparticles (“TamiGold”) have been synthesised and NA inhibition studies with “small TamiGold” show activity against influenza virus strains investigated compared to control gold nanoparticles. The binding interactions displayed by “large TamiGold” may provide the basis for a colorimetric method of influenza detection and as such a novel prototype influenza sensor. To the best of our knowledge this is the first example of a multivalent approach to influenza virus binding utilising sialylmimetic scaffolds immobilised on a nanoparticle platform which specifically target the NA (instead of the hemagglutinin, HA). The synthesis of phospha-oseltamivir conjugates and their ligation to biological reporter groups afford small molecule tools with high affinity and selectivity towards influenza NA. These derivatives can be applied towards novel multivalent phospha-oseltamivir materials and used as novel diagnostics, independent of existing methods

Establishing Factors Influencing Building Maintenance Practices: Ghanaian Perspective

The study was to establish factors influencing the decision to carry out building maintenance practices. The paper reviews the existing literature on building maintenance, types of maintenance, causes of maintenance, stages of maintenance and specific factors influencing the decision to carry out maintenance. The study utilized a structured questionnaire, which was administered on the residents of the private house owners called Landlords and Landladies in the study area.  Data analysis indicated that, common factors and agent which are fundamental to deterioration of building components included ageing stock of building, obsolescence of building, environmental or climate issues, moisture, selection of materials, and design maintainability. Misuse of building after completion, faulty designs, and unavailability of skilled labour to undertake maintenance operations and poor financial support for maintenance work were also identified as the major factors inducing the decision to carry out maintenance work. Replacement and conditioned-based types of maintenance were also established as often undertaken. The paper  in  conclusion  makes recommendations  for  consideration of maintenance during the early phase of construction and must be  done with the highest quality in term of professionals and materials and components, hence, the need  for  engaging professionals from design to construction stage at least and create public  awareness  on  the  danger  of  lack  of maintenance and the advantages of good maintenance practices. Keywords: Maintenance Practices, Agent of Deterioration, Private, Landlords and Landladie

Multicurrency extension of a multiple stochastic volatility libor market model

Das libor Markt Modell (LMM) ist seit seiner Entwicklung in den Veröffentlichungen von Brace, Gatarek, Musiela (1997), einerseits, und unabhängig von diesen von Miltersen, Sandmann, Sondermann (1997), andererseits, zu dem anerkanntesten Instrument zur Modellierung der Zinsstruktur und der damit verbundenen Preisfindung für relevante Finanzderivate geworden. libor steht dabei für London Inter-Bank Offered Rate, ein täglich in London fixierter Referenz-Zins für kurzfristige Anlagen. Drei- oder sechsmonatige Laufzeiten sind in Verbindung mit dem LMM üblich. Die Forschung zur Verbesserung dieses Modells hat in den letzten Jahren an Zuwachs gewonnen. Beim Versuch den Fehler der Anpassung an die täglich beobachteten Preise von Zinsoptionen wie Caps und Swaptions zu verringern, erhält man in der Folge auch genauere Bewertungen für andere, exotischere, Derivate. Die zugrunde liegende und zentrale Idee des LMM besteht darin, die Forward (Termin) Zinsen direkt als primären (Vektor) Prozess mehrerer libor Sätze zu betrachten und diese simultan zu modellieren, anstatt sie nur herzuleiten aus einem übergeordneten, unendlich dimensionalen Forward Zinsprozess, wie im zeitlich früher entwickelten Heath-Jarrow-Morton Modell. Das überzeugendste Argument für diese Diskretisierung ist, dass die libor Sätze direkt im Markt beobachtbar sind und ihre Volatilitäten auf eine natürliche Weise in Beziehung gebracht werden können zu bereits liquide gehandelten Produkten, eben jenen Caps und Swaptions. Dennoch beinhaltet das Modell eine gravierende Insuffizienz, indem es keine Krümmung der Volatilitätsoberfläche, im Hinblick auf Optionen mit verschiedenen Basiszinsen, abbildet. Wie im einfachen eindimensionalen Black-Scholes Modell prägen sich auch hier die Ungenauigkeiten der Verteilung in fehlenden heavy tails deutlich aus. Smile und Skew Effekte sind erkennbar. Im klassischen liborMarkt Modell wird in Richtung der Basiszinsdimension nur eine affine Struktur erzeugt, welche bestenfalls als Approximation für die erwünschte Oberfläche dienen kann. Die beobachteten Verzerrungen führen naturgemäss zu einer ungenauen Abbildung der Realität und fehlerhaften Reproduktion der Preise in Regionen, die ein wenig entfernt vom Bereich am Geld liegen. Derartig ungewollte Dissonanzen in Gewinn und Verlustzahlen führten z.B. in 1998 zu gravierenden Verlusten im Zinsderivateportfolio der heutigen Royal Bank of Scotland. ..

Smoking and Thromboangitis Obliterans– Are they related

Introduction: In 1908 Leo Buerger first gave the world the clinical picture of this dreadful disease which he called Thromboangitis Obliterans. Virtually all investigators believe that smoking or tobacco use in some form is a requirement for the diagnosis of Thromboangitis Obliterans. We studied the demographic profile and smoking pattern of patients with Thromboangiitis Obliterans. Methods: Retrospective study carried out in a tertiary level hospital of South India from 1st January 1997 to 31st December 2003. Patients fulfilling Shionoya’s criteria form the study group. Incidence of Thromboangitis Obliterans, relation to smoking habits, type and nature of manifestation were analyzed. Results: A total of 105 cases were studied and found to have declining pattern of incidence from 0.9%-0.3%. All patients were males, smokers at the time admission and 76% out of them were from low socioeconomic background. Patients smoking 5-15 cigarettes per day, for 5-10 years duration constituted 45% of the study group. The most frequent reasons for being referred to hospital were ischemic ulcers (83.80%), claudication (78.0%) and rest pain (26.66%).   Conclusions: In those who present early with the disease the number of cigarettes and duration of smoking shows no direct correlation to the severity. Most patients continue to smoke inspite of counseling and awareness that the disease progresses due to smoking. Ulcer, intermittent claudication and rest pain are the three common presenting symptoms of Thromboangitis Obliterans.  Keywords: smoking; thromboangitis obliterans

Multiple stochastic volatility extension of the Libor market model and its implementation

In this paper we propose an extension of the Libor market model with a highdimensional specially structured system of square root volatility processes, and give a road map for its calibration. As such the model is well suited for Monte Carlo simulation of derivative interest rate instruments. As a key issue, we require that the local covariance structure of the market model is preserved in the stochastic volatility extension. In a case study we demonstrate that the extended Libor model allows for stable calibration to the cap-strike matrix. The calibration algorithm is FFT based, so fast and easy to implement

Genetic validation of Aspergillus fumigatus phosphoglucomutase as a viable therapeutic target in invasive aspergillosis

Aspergillus fumigatus is the causative agent of invasive aspergillosis, an infection with mortality rates of up to 50%. The glucan-rich cell wall of A. fumigatus is a protective structure that is absent from human cells and is a potential target for antifungal treatments. Glucan is synthesized from the donor uridine diphosphate glucose, with the conversion of glucose-6-phosphate to glucose-1-phosphate by the enzyme phosphoglucomutase (PGM) representing a key step in its biosynthesis. Here, we explore the possibility of selectively targeting A. fumigatus PGM (AfPGM) as an antifungal treatment strategy. Using a promoter replacement strategy, we constructed a conditional pgm mutant and revealed that pgm is required for A. fumigatus growth and cell wall integrity. In addition, using a fragment screen, we identified the thiol-reactive compound isothiazolone fragment of PGM as targeting a cysteine residue not conserved in the human ortholog. Furthermore, through scaffold exploration, we synthesized a para-aryl derivative (ISFP10) and demonstrated that it inhibits AfPGM with an IC(50) of 2 μM and exhibits 50-fold selectivity over the human enzyme. Taken together, our data provide genetic validation of PGM as a therapeutic target and suggest new avenues for inhibiting AfPGM using covalent inhibitors that could serve as tools for chemical validation

Influence of Soil and Rain on the Levels of Inorganic Anions in Amaranth Leaves from Selected Parts of Kenya

The aim of this work was to determine the level of inorganic anions (NO3-, Cl-, SO42-, PO43-, F- and I-) in the leaves of two species of amaranth (Amaranthus hypochondriacus and Amaranthus cruentus) planted in Kenya. The mean levels of inorganic anions, nitrate (NO3-), chloride (Cl-), sulphate (SO42-), phosphate (PO43-), fluoride (F-) and iodide (I-), in the soil from four study regions (Kenyatta University (KU), Bureti, Kisii and Elgon) of Kenya were quantitatively determined. The levels were determined using spectrophotometric, potentiometric and titrimetric methods. The mean levels of  Cl-, SO42-, PO43-, NO3-, F- and I- in soils ranged from 1146.54 to 2733.31 mg/100 g, 1821.60 to 2185.33 mg/100 g, 828.54 to 1111.36 mg/100 g, 1015.55 to 1910.66 mg/100 g, 66.95 to 79.77 mg/100 g and  8.00 to 12.57 mg/kg respectively. The levels of most anions in leaves of A. hypochondriacus and A. cruentus were not significantly different. The means levels of the anions in leaves of the two species indicated that Cl- ion had range of 503.74 to 673.81 mg/100 g, SO42- 701.61 to 955.17 mg/100 g, PO43 532.36 to 629.46 mg/100 g, NO3- 495.79 to 880.99 mg/100 g, F- 7.22 to 9.67 mg/100 g while I- ranged from 2.54 mg/kg to 5.26 mg/kg dry weight. The levels of all inorganic anions determined were found to be within the allowed daily intake (ADI) values. Based on the results of this study, it is recommended that leaves and grains from both species of amaranthus grown in most regions in Kenya may be consumed for nutritional requirements. The consumption of between 250 g and 300 g of fresh amaranthus leaves is sufficient to provide the required daily intake of all the anions considered in this study for all healthy individuals. Keywords: Amaranth, Anions, Amaranthus, Tonui

Targeting a critical step in fungal hexosamine biosynthesis

Acknowledgements We wish to thank the Dundee Drug Discovery Unit for access to the Fragment library and the European Synchrotron Radiation Facility, Grenoble and Diamond Light Source, Oxford for time at the beamline. The assistance from Mr Martin Kierans, School of Life Sciences, University of Dundee with the Electron Microscopy is gratefully acknowledged. Funding and additional information This work was supported by a Wellcome Trust Postdoctoral Research Training Fellowship for Clinicians (WT105772/A/14/Z) to DL and an MRC Programme Grant (MR/M004139/1) to DMFvA. DB was funded by a University of Aberdeen Summer Research Scholarship.Peer reviewedPostprintPublisher PD