In Palm Beach, Old Money Isn't Having a Ball Essay - 1

In Palm Beach, Old Money Isn't Having a Ball - Essay Example The Red Cross Ball in Palm Beach has, for nearly half a century, brought together the island’s upper-crust families to drink, dance, donate money and is easily the most prestigious party for old Palm Beach society. Top socialites, foreign ambassadors, entertainment superstars and occasional royalty from Europe mingle with Palm Beach’s newcomers and hundreds of out-of-town friends that can shell out money to give out and donate as well as pay for their designer tuxedos’ and gowns, flashy jewelries and cars. This has led to a somewhat tolerable â€Å"battle† between old and new money and is holding true to all traditional blue-blood communities in the country. Arguably, new money has surged in the Unite States and has overtaken the older elite in terms of statistics. This is evidenced by the journal documenting that â€Å"the number of the super wealthy in the U.S. has surged with 430,000 households now worth more than $10 million. That’s up from 65,000, adjusted for inflation in 1989. In 2001, the top 1% of Americans ranked by net worth controlled 33% of all personal assets.† (Frank 2005) Increasingly, these clashes between the desire of the nouveaux rich being accepted into high society by buying their way into exclusive clubs and into the stream of the old wealthy and the actual acceptance they receive hasn’t significantly changed. The old rich safely guard and selectively choose which clubs can be joined in. For the nation’s richest, this rapid shift in the composition of the wealthiest Americans is striking. Inherited money is being taken over by entrepreneurial endeavors of businessmen. Case in point is Bill Gates’ $48 billion net worth is more than twice the Rockefeller family’s current fortune. (Frank 2005) This striking difference is never been more evidently felt than in the Palm Beach area where the influx of new money has ignited off disputes over realty values as the status symbols. As

Financial Analysis of Burberry Group Plc Coursework

Financial Analysis of Burberry Group Plc - Coursework Example In relation to the study the company which has been selected is Burberry Group Plc is a British luxury fashion house established in 1856 and listed on the London Stock Exchange since 2002. Its business’s mainline involves the sourcing, designing, manufacturing, and marketing of high-end clothing as well as non-apparel accessories for customer segments including women, men, and children. Customers can reach Burberry products through its diversified distribution network of retail, wholesale, digital and licensing channels operated in the United Kingdom and across the world. In the year 2012, Burberry was ranked the 82nd best global brand in the world with regards to its high operating value and such ranking has been improved for the past few years. Therefore, it is worth studying its financial information to see how its operation has developed causing increasing company’s value. For the purpose of carrying out a financial performance analysis of Burberry, the financial st atements of the company pertaining to the last three financial years have been reformulated (See Appendix). The reformulation of balance sheet reveals the net operating assets (NOA) of the company, net debt, and net equity. On the other hand, the reformulation of income statement has revealed the recurring items and non-recurring or exceptional items in the income statement of Burberry. The income statement has been reformulated in two ways, i.e. full reformulation and basic reformulation. The basic reformulation does not include exceptional or non-recurring items in the income statement, whereas in full reformulation, each and every time has been included in the reformulated income statement. The overall analysis of the income statement for Burberry pertaining to the last four financial years shows that the sales growth declined in 2010 in comparison with 2009, whereas the growth rate showed improvement on consistent basis in 2011 and 2012. The main reason behind this consistency in sales growth is considerable increase in the retail sales of the company in the last two years. In addition to this, as the company is also engaged in the wholesales, there is a insignificant increase in wholesales also noted, which has contributed to the growth in sales revenue to some extent. Reformulated Income Statement (Full) 2012 2011 2010 2009 (Sales growth based on previous financial year) 1.24 1.17 1.07 1.21 As per the reformulated income statement, common size income statements for full and basic income statements have been prepared. Common Sized Income Statement Based on Full Reformulation (Excludes Unusual Items

Global Forces of Change Essay Example for Free

Global Forces of Change Essay 1. From the case facts, describe how globalization and technology have influenced the business directions of GE Medical Systems. Technology Since new requirements in healthcare business had been emerged, in the market it is required to implement personalized medicine to support specific client – not mass population. Moreover, trend on find the way to prevent sickness is more concerned than to heal. This is massive challenge to medical equipment manufacturers whether which company can find the best technology to support these requirements. GE believed that the best technology would always win in the marketplace so they responded to these requirements by investing more on RD and also product design. As the result, corporate RD invented some new products which replace need of existing product, for example, digital detectors for X-ray machines that would replace the need for X-ray film. Globalization Globalization increases connectivity and interdependence of the world’s markets and businesses. Emerging middle-classes of Asia, Eastern Europe and Latin America is also an opportunity for healthcare company like GE to expand their markets, increase sales and profits. Beside of sales side, GE can also reduce their manufacturing cost by shifting manufacturing from high-cost countries to low-cost countries. This would increase their competitive advantage. 2. Identify possible projects by which a company dealing in Healthcare and Medical Diagnosis like GEMS can profitably ride the waves of globalization, liberalization and technology. * Shifting manufacturing base from high-cost countries to low-cost countries in order to reduce production cost. * To develop healthcare IT system, this is to manage necessary data systematically such as patient data, treatment record etc. This is also helpful for diagnosis. * To apply Free Trade Agreement with emerging countries in order to facilitate access of healthcare products. * Even general needs of customers in healthcare in each country is same but there are some specific requirements which are required individually so GEMS should not neglect RD in each local market. Hiring local staffs is an effective alternative since local people might understand needs in their society well. * RD is vital since technology changes every day. GEMS should keep investing on find out the way to increase effectivene ss of their equipment and also invent new products which can replace existing one. 3. Describe the world do you envision in 2050, especially with China and India likely to take center-stage? Touch on the economic, political, social and cultural adaptation that you think can take place. According to many reports show that over the next 50 years China and then India’s economies will overtake US. Large and growing market opportunities in China and India are widely seen and understood as evidenced by the large flows of foreign direct investment to China, both for the domestic market, but also to use China as a low cost platform for exports to the rest of the World. China is communist. Due to their political characteristics, control in a repressive way substantial part of the economy, especially the financial sector that brought about massive imbalance. A centralized decision-making process, although discretionary would presumably ease political action by by-passing all types of necessary approvals from a parliament or congress in a democratic system. So changing of Chinese government would possibly change the world. About social and culture, as foreign companies would base their manufacturing in China, learning local culture would be very important in order to have smooth operation and avoid any conflict. China language will become as vital as English. On the other hands, due to growing of China economic dominance, Chinese people will also spread over the world. Their culture will unavoidably absorb to everywhere. We have no choice but adapt with it.

High Throughput Screening (HTS) Assays: Uses and Formats

High Throughput Screening (HTS) Assays: Uses and Formats The increasing demands placed upon the pharmaceutical industry to produce a rapid turnaround of new drugs is a driving factor in the automation of the processes at the initial screening stage of drug discovery. This has lead to the development of numerous high throughput screening (HTS) assays, with the increasing miniaturization of the whole process (1). An explosion in genomic and proteomic studies in recent decades has lead to the generation of large numbers of functional protein molecules. The physiological function of these proteins has yet to be elucidated, but many could be important future drug targets, such as receptors or enzymes involved in disease pathogenesis (2). These ‘orphan receptors’ can be studied by high throughput screens of small molecules, which may be potential ligands. These chemicals can be sourced from existing drugs, pharmaceutical company chemical compound libraries or from natural products, such as plants or animals (figure 1; 3). Chemical l ibraries are now vast, since the advent of combinatorial chemistry, which produces novel compounds by high throughput methods. These mixtures can then be assessed for biological activity against a specific target molecule (most commonly a protein), either as a mixed chemical pool, or in parallel. A positive/active interaction, or ‘hit’, can then be further explored. Numerous assay detection formats that are suitable for automation have been developed to detect such receptor – ligand and enzyme – substrate interactions, to allow the potential drug molecule to be further explored. Each assay has advantages and problems and the most commonly applied techniques are discussed in this review. As research progresses these processes become modified to overcome problems created by the progressive automation and miniaturization of the assays. Use of computation to analyse the interactions and extract more information from them is also increasing (4). Recent advances in the literature suggest that future development of HTS is likely to result in ultra-HTS assay formats, which may be within closed systems such as glass capillaries, or on silicon wafer chips. References Fonseca MH List B (2004) Curr Opin Chem Biol, 8, 319-326. Gilchrist A (2004) Expert Opin Ther Targets, 8, 495-8. Bleicher KH, Bohm HJ, Muller K, Alanine AI (2003) Nat Rev Drug Disc 2, 369-378. Kato R, Nakano H, Konishi H, Kato K, Koga Y et al. (2005) J Mol Biol, 351, 683-92. Techniques in molecular biology, chemistry and their associated branches are advancing at a rapid rate. This has enabled the mechanisms underlying many diseases to be explored at the molecular level. The ever-increasing sophistication of proteomic and genomic research procedures are producing an explosion in the number of possible drug targets. Until the development of high throughput screening (HTS) assays, the time taken to evaluate the potential bioactivity and usefulness of compounds to act on target molecules and become drugs to act to ameliorate symptoms or even cure or prevent a disease from occurring, was a rate-limiting factor. Since the automation of a number of suitable assays for HTS the trend has led to the number of compounds available for testing against targets becoming the limiting factor. This has spurned the growth of combinatorial chemistry, to such an extent that many consider it to be a branch of chemistry in itself. HTS can be defined as an automated method of conducting a large number of in vitro assays on a small scale (Patrick 2005). Most commonly, 96-well plates of 0.1ml are used for a number of bioassays to detect the biological activity of compounds which have the potential to be developed as drugs. These may interact with the target, as a ligand-receptor interaction, or may involve inhibition of an enzyme or interaction with a nucleic acid macromolecule. The reaction produces a detectable output change, which can be detected and/or measured. Thousands of chemicals can easily and quickly be screened this way, and only active compounds taken to the next stage of testing to find out if it has the potential to become marketed as a drug. There is increasing pressure on drug companies to produce new drugs to keep pace with developments in medical research, as well as an increasingly demanding public and share holders. HTS technology is a crucial to meeting these demands, and continues to be dev eloped to produce faster, cheaper and more efficient ways of screening compounds during the initial stages of the drug discovery process. ROLE OF HIGH THROUGHPUT SCREENING IN DRUG SCREENING Molecular biology techniques are allowing us to understand more about the mechanisms of disease, thus providing biomacromolecular targets for potential drugs to interact with. Such targets include receptors, enzymes and nucleic acids and may require inhibition (enzymes) or agonistic/antagonist receptor ligand binding to produce the desired pharmaceutical effect. In addition, studies using proteomic and genomic techniques are revealing more and more ‘orphan receptors’; these are proteins (predominately), lipids and nucleic acids (and to some extent carbohydrates) that are now known to be produced by the body, but their messenger and function is unknown. Using these as targets against which to screen compounds will help to elucidate their function, and more importantly, may turn out to be drug target interaction sites which will be beneficial in disease. As the function of these targets is unknown, there are no lead compounds that could be used as a starting point for exploration, so HTS is particularly beneficial for screening vast numbers of compounds in the hope that at least one will interact with the mystery target. The number of potential drugs to be screened is vast; pharmaceutical companies have libraries of 0.5-2 million synthetic compounds (King 2002) that have not made it through screening to become marketed drugs. There are also commercially available libraries of compounds, such as the Chemical Abstract Service (CAS) registry file, which contains 39 million compound (Abraham 2003). Intermediates in synthetic processes to make another drug should also be screened, as they may have the desired pharmaceutical properties. Isoniazid is an intermediate and has now been developed into an effective anti-tuberculosis drug. Existing drugs are also worth screening, as their biological activity may stretch beyond that for which they are intended. For example, cyclosporin A was isolated from soil and had been intended for use as an antibiotic, until its immune-suppressive properties were observed and for which it is now sold. The body’s own endogenous chemical messengers, such as morphine, whi ch has similar activity to released endorphins, could also be screened as they may provide a lead compound that can be modified to enhance activity. Combinatorial synthetic processes can also be used to generate vast numbers of novel compounds, which is crucial to prevent the availability of new compounds being a limiting factor in drug development, as HTS is able to screen them so quickly (Carell et al. 1995). It is common for combinatorial synthesis to produce mixtures of compounds, which can be tested as a chemical pool or batch by HTS for biological activity against a specific target macromolecule. This means that thousands of compounds can be screened in a very short time and only pools containing biologically active constituents screened further. This usually involves deconvolution processes (such as micromanipulation, recursive deconvolution or sequential release from resin beads used for the synthetic process) to identify exactly which component(s) of the pool is/are active, so that they can be isolated and screened further for drug potential (Wilson-Lingardo et al. 1996). It is now being superseded by production of new c ompounds in parallel, with a single component in each well. Potential drug molecules can also be derived from natural sources, such as plant extracts, but these are less abundant as isolation and purification take time. They are often novel, complex molecules and can produce unexpected interactions. An example is artemisinin, an effective antimalarial drug developed from extracts from a Chinese plant; it has a highly unstable trioxane ring (Ploypradith 2004). There are so many compounds to be tested against a large range of potential drug targets that high throughput methods are essential to test the numerable combinations of drug and target interaction to find those that are biologically compatible. HIGH THROUGHPUT SCREENING ASSAYS In theory any assay that can be performed on the laboratory bench could be automated and scaled up to be used for HTS. In practice, however, some assays are intrinsically more suitable than others. High throughput screens require the automation of the entire process. This is best achieved if there are as few steps as possible in the assay; ideally the test should be able to be performed in a single well, with addition of the test sample the last key step. Obviously, it is important that the reaction between a target and biologically active compound must be readily detectable. It should ideally be detectable with high sensitivity while the products are still mixed together in the well, rather than needing further steps to separate or purify components of the reaction mixture. This can be difficult to achieve with automation and will increase the time taken per test, so becoming less efficient and cost effective. Assays used for chemical screening can be cell-free or cell-based (Silverman et al. 1998). Cell-free assays use solutions of relatively pure protein targets, such as receptors or enzyme substrates, which minimizes the number of steps required. It also allows for easy detection of biological activity in the wells of reaction mixture. Cell-based assays have the advantage that they are a closer representation of the normal physiology of the chemical environment inside a cell. Receptor-ligand interactions and enzyme inhibition reactions are more likely to be indicative of what will happen in vivo (Silverman et al. 1998), especially if ligand-gated ion channels are involved. Cell assays also allow specific processes to be studied and the output can be measured. Indirect effects of small molecule/protein binding which trigger secondary messenger systems, such as calcium ions or cAMP, can also be observed in their biological context. Cells can be manipulated to express target molecules on t he surface, so that they are available to bind to novel ligands, which may be tagged for detection. Cell assays can also provide additional information about cytotoxicity and bioavailability of a potential drug. Mammalian cells are expensive and can be difficult to culture in automated HT systems, but yeasts can provide a suitable alternative. Microorganisms such as yeasts are easy to propagate and have been demonstrated to have some homologous chemical processes, or can be easily genetically modified to express human processes accurately (Klein Geary 1997). HTS ASSAYS AND DETECTION FORMATS Fluorescence Fluorescence occurs when a fluorophore molecule absorbs a high-energy photon (often in the ultraviolet range) and emits a lower energy photon, which is typically in the visible range of the spectrum. There are many naturally occurring substances which have this intrinsic property, such as luciferin in fire-flies. There are a number of fluorescence – based assays available for use in HTS, to detect whether an interaction has occurred between target and potential drug molecule during random screening. Fluorescence assays are generally sensitive, versatile, stable, safe and easy to perform, which gives them a great advantage in automated systems for HTS. They have the disadvantage that quenchers can be present in the sample which dampen the light emission. There may also be background autofluorescence from free reagents in the reaction mixture (Grepin Pernelle 2000). Many of the assays have developed protocols that take these problems into account. Energy transfer formats: Homogeneous time resolved fluorescence (HTRF) uses the ion of the rare earth metal lanthamide (Eu3+ ), bound to crypate as a donor molecule. Following laser excitation (at a wavelength of 337nm), energy is transferred from this complex to an allophyocyanin (APC) acceptor molecule. This results in emission of light of 665nm, over a long period (milliseconds), which is recorded in a time resolved fashion so that any background fluorescence from free APC or media is not recorded. Peak emission of light occurs at 620nm for unbound Eu-cryptate, so the ratio of 620:665nm emissions can be used to quantify biological complexes in solution (see Figure 1). This technique can be widely applied to screening programs and has already been developed into a 1,536 well plate HTS, with plans to expand this to become ultra HTS (uHTS) and for use in cell-based assays. Figure 1: HRTF schematic explanation (from: Grepin Pernelle 2000) Fluorescence resonance energy transfer (FRET) is a slightly different form of detection, using the principle that excitation energy can be transferred between two fluorophore molecules. These can be different types of green fluorescent protein (GFP) or other bioluminescent molecules, such as luciferase (Hu et al. 2005). from: Becker et al. 2004 Fluorescence polarization (FP) FP can be used as the basis for homogeneous HTS assays for enzymatic and ligand-receptor binding interactions. The principle behind this detection assay is that when polarized light hits a small molecule that is binding to a larger (target) molecule, there will be rotational diffusion of the light beam. This change induced by binding can be detected by measuring the light emitted in orthogonal and normal planes of the polarized light. There is no interference from absorptive compounds in complex mixtures, as can occur with other fluorescence based techniques, and FP is quick and easy. Because of this it is used widely in high-throughput screening systems. Kim and colleagues (2004) developed a FP assay for the molecular chaperone Hsp90 (heat-shock protein), which is believed to have a role in cancer. They validated the assay for a high throughput format using molecules known to bind Hsp90, such as geldanamycin. The assay can now be used to screen for novel inhibitors of Hsp90, which m ay lead to a cancer drug being developed. Stricher and others (2005) have developed a high throughput FP assay for the CD4 binding site of HIV-1 glcoproteins, such as gp120, which are crucial targets to protect against HIV infection. Their assay used a 384-well plate and CD4M33, a mimic of host cell receptor antigen CD4, found on T helper lymphocytes. Some studies indicate that FP assay technology can also be developed as part of a HT structure-activity (SAR) study. Newman Josiah (2004) showed that FP is sufficiently sensitive to differentiate between high-affinity small molecule inhibitors interacting with the target and low-affinity ones, with Src kinase activity as a model. FP can also be used in cell-based assays, in conjunction with confocal microscopy (Heilker et al. 2005), as it shows high sensitivity even at minute volumes of reaction mixture, down to femtolitres. This type of assay can be described as fluorescence intensity distribution anaylsis (FIDA) and measures the absolute concentration of both bound and unbound ligand, thus providing the data with its own internal control. FIDA has been used to explore ligands which bind to G-protein coupled receptors (GPCR), which are widespread throughout the body and involved in signal transduction for numerous cell processes. They are therefore important therapeutic pharmaceutical targets, and can be studied in association with membrane fragments from cells over-expressing GPCR or associated with virus-like particles. Fluorescence correlation spectroscopy (FCS) FCS uses a two-photon excitation to measure the relative fluorescence of different molecules within a homogeneous mixture, from which the amount of each can be calculated. The technique can be applied to measure the relative amounts of ligand bound versus unbound receptor molecules, or cleaved versus intact enzyme substrates. FCS can be conducted using minute reaction volumes, less than 1 femtolitre (fl) is adequate for this sensitive, fast assay, which can study interactions of single molecules (Sterrer Henco 1997). FCS can also be used to study ligand-receptor interactions in live cells (Pramanik 2004), which allows reactions to be assessed, and to some extent the properties of the interaction quantified, in their biological context. The use of such live cell assays in a high throughput format will provide a wealth of information not observable in chemical solutions alone. Many applications of FCS are conducted in conjunction with confocal microscopy, which allows interaction kinetics to be examined on a molecular level, by the changes in diffusion patterns of the excitation. Confocal microscopy uses a high numerical aperture lens to focus the laser, to provide excitation and produces minimal background excitation, which allows such minute quantities to be studied. It can be used to detect spatial and temporal interactions in live cells, increasing the amount of information that can be obtained and used for drug development (such as interactions with other cell components or pH effects within the cell; Zemanova et al. 2003) The dual-colour cross- correlation spectroscopy method of FCS uses two different, spectrally separated, fluorophore molecules, which are attached to each of, for example, a receptor and possible ligand, or potential substrate to be cleaved. The two colours will be observed to fluoresce together if an interaction occurs, or separately if a substrate has been cleaved and the kinetics of this can then be assessed (Kettling et al. 1998). This can be demonstrated using, a DNA strand that has a red fluorophore molecule attached to one and and a green one to the opposing end. The strand is cleaved by restriction endonuclease enzyme ecoRI, which is detected by spectroscopy as a decrease in the quantity of DNA molecules with fluorescence at both ends. The method was shown to be suitable for this type of enzyme kinetics study, by accurate detection of catalytic activity down to an enzyme concentration of 1 pM (pico molar) and proper description of the reaction by the Michaelis-Menten equation. This method, dual-colour FCCS, therefore has great potential for HTS of enzyme and ligand binding reactions. Biomolecular fluorescence/reporters There are numerous molecules produced by plants and animals naturally that produce fluorescence, or what is sometimes called bioluminescence. Some of these have been adopted as research tools, such as green fluorescent protein (GFP), which produces green light at 509nm following excitation by blue light (Arun et al. 2005). The gene that encodes for this fluorescent protein has been elucidated and is now commonly inserted into the genomes of genetically modified microrganisms and cell lines. It is then expressed under the control of desired promoters, often as a fusion protein. In this way patterns of gene expression can be observed and changes in transcription detected. HTS for new drugs use this technology to detect changes in transcription that occur via secondary messenger systems following receptor-ligand binding in a live cell. For example, Changsen and others have validated a GPF microplate assay, using an acetamidase promoter associated with the gfp gene, to screen for antitub erculosis drugs (2003), and found it to be suitable for HTS for novel drugs. GFP reporter technology requires a detection system and most of those described for detecting fluorescence from synthetic fluorophores can also be applied, such as FRET (Zhang 2004), FCS and confocal microscopy. FITC (fluorescein – 5- isothiocyanate) FITC can be bound to other molecules as a marker and the fluorescence measured robotically in HTS systems. For example, FITC bound to heparin sulphate (HS) has been used to screen for heparanase inhibitors in a HT assay: 384-well microtitre plates are used, which are coated with fibroblast growth factor (FGF). This captures the FITC-HS, and labelled fragments are only released into the media when cleavage by heparanase has occurred. This is quantitatively measured by robotic detection of the amount of fluorescence in solution. Heparanase is believed to have roles in inflammation, tumour angiogenesis and metastasis, so is an important drug target in the treatment of cancer (Huang et al. 2004). Chemiluminescence Some assays using chemiluminescence have been adapted to use HT formats. These rely on chemical reactions to produce light emission as a side-product, which can be detected. One such HTS uses coupled reactions involving the enzymes acetylcholinesterase, choline oxidase and horse-radish peroxidase, in 96 and 384-well plate formats, to screen for novel acetylcholinesterase inhibitors to become new drugs to treat Alzheimer’s Disease (Andreani et al. 2005). Scintillation proximity assay (SPA) Scintillation proximity assays are used for quantitatively studying binding reactions. The receptor/target is bound to a surface such as a plastic bead. The ligand is labelled with radioactive isotype (typically H3 or I125 ) and emit electrons with a short range of about 10um. A scintillation counter under the surface to which the target is bound detects the ligand only when it is bound. When it is free in solution the media absorbs the electrons and they are not counted. This allows binding interactions to be quantified whilst at equilibrium. Zheng and others (2004) have used SPA as part of a HTS and have identified several novel inositol monophosphatase inhibitors, which may be developed as drugs fro bipolar disorder. Mass spectrometry Mass spectrometry is currently a popular option for HTS, as it is sensitive, selective and easily automated. It allows the activity, molecular weight (most drug-like molecules are 150-400 Da), elemental composition and structural features of a test compound to be analysed. This wealth of information is of great use for exploring the molecular interactions between target and potential drug compounds. A very high throughput can be achieved using flow injection analysis, which does not require any sample preparation. Solutions of the samples are sprayed, using electrospray or APCI (atmospheric pressure chemical ionization), which ionises the molecules in the sample, prior to analysis by the mass spectrometer. Sometimes tandem mass spectrometers are employed, to glean more structural information and elemental composition. The advantage of these techniques are that as well as being very high precision they can be conducted on the original sample, without the need the separate the compound out from a mixture. For LC-MS (liquid chromatography mass spectrometry), semipreparative HPLC (High Peformance Liquid Chromatography) is often used before the HTS to verify the structure and purity of each compound to be tested, especially those from a combinatorial library. Improving purity in this way facilitates more accurate observation of any biological interactions that occur between the target and the test compound, as well as easing interpretation of structural information about the test molecule or changes induced by the interaction (Abraham 2003). HPLC is easily automated and involves detection of a UV signal above a threshold level, which triggers collection of the fraction. Several fractions may be obtained from one sample, or the computers controlling sample collection can be programmed to detect only at peaks of desired molecular ions, following ionisation by a suitable technique, such as electrospray or MALDI (matrix-associated laser desorption/ionisation), which can be used as a gentle way of ionising more fragile molecules (Hillenkamp et al. 1991). LC-MS can be slower than other approaches but is sometimes necessary. Further developments to speed up the automated process include parallel LC-MS, in which multiple HPLC columns are interfaced to a single mass spectrometer (Kenseth Coldiron 2004), and fast HPLC. NMR NMR is a useful technique for exploring the 3-dimensional structure of biomacromolecules, in a concentrated solution. It is limited by the small size of molecule amenable to this technique; typically below 30kDa, so is more useful for small drug-like molecules than the molecular target they interact with. Structure-activity relationships (SAR) can be studied by observing alterations in a protein’s NMR spectrum. This not only indicates that ligand binding has occurred, but can give an indication of the location of the binding site (Shuker et al. 1996). X-ray crystallography X-ray crystallography enables the 3-dimensional structure of protein molecules to be studied, with resolution to the atomic level. The technique requires the molecule to be studied in its crystalline form, which is not a problem for the majority of biomacromolecules that are drug targets. Protein crystallization technology has also had to adapt to high throughput methods, so as not to become a bottleneck. Some fully automated systems can now produce as many as 2,500 to 140,000 crystallization experiments a day (Kuhn et al. 2002). Studying the 3-D structure of the target often produces clues to the type of ligand that will bind, which speeds up the time taken to find lead compounds in drug discovery. An example of this is the development of antiretroviral drugs used to treat AIDS (acquired immunodeficiency syndrome), such as amprenavir (‘Agenerase’), which followed from the study of the structure of the drug target, HIV (human immunodeficiency virus) viral protease. Another drug developed from such structure based studies is zanamivir (‘Relenza’); a flu treatment based on the crystal structure of the surface glycoprotein, neuraminidase, which is crucial for viral infectivity (Varghese 1998). This is likely to be an important weapon in the fight against an influenza pandemic. In X-ray crystallography, the macromolecular 3-D crystal is bombarded with X-rays, by a rotating-anode X-ray generator or a synchrotron, and the diffraction pattern produced is detected. Multiple measurements of diffracted waves generate much data, which can be analysed using calculations, such as Fourier synthesis and a structure revealed (Blundell et al. 2002). Advances in the structure determination process have aided the resolution of structures, for example, multiple-wavelength anomalous dispersion (MAD), in which selenomethionine is incorporated into proteins that are overexpressed by genetically modified micro-organisms, which simulates isomorphous replacement and allows the phases to be calculated (Hendrickson et al. 1990). Low-affinity binding reactions between ligand and target may have important properties and provide leads that would be missed by other HTS methods. Development of high throughput X-ray crystallography, by increased automation at all stages of the procedure, has lead to its growing use in lead discovery as well as its more traditional role in lead optimisation (Abola et al. 2000). This enables the technique to screen compound libraries, including those from combinatorial synthesis. Crystallographic screening for novel ligands in this way has already had some success; for example, a new class of urokinase inhibitors have been discovered, for treating cancer (Nienaber et al. 2000). Co-crystallization of receptor-ligand complexes allows the interaction between the molecules to be studied and conformational changes in the target, upon binding, to be discovered. This approach is known to be used by several industrial laboratories and has the capacity to compare the interactions of ‘hit’ ligands in the generation of a lead series. It also decreases the time taken to explore hits, which is a crucial factor for the pharmaceutical industry (Abraham 2003). Another way of achieving crystallized receptor-ligand interactions is to soak the ligand, often as molecular fragments dissolved in DMSO (dimethyl sulphoxide), into the receptor protein crystal (Nienaber et al. 2000), and observe changes in electron densities indicative of interaction. Structure based drug design in silico Three-dimensional structures can also be used in computer modelling programs to predict which ligands might bond/interact with targets or receptors, as an initial stage of drug design. This is truly a high throughput method as computing power allows the rate at which ligand-receptor interactions can be virtually screened to be incomparable to even the fastest high throughput methods involving physical experimentation. This is often termed virtual ligand screening (VLS), or in silico screening (Klebe 2000). Perrakis and his colleagues (1999) combined automated protein model building with iterative structure refinement, using ARP (automatic pattern recognition), which has been crucial for structure based drug design (SBDD). Diffraction data is fed directly into the computer program and a protein crystallization model produced automatically. Various programs have been developed to assess docking of virtual ligands into known target receptor sites and scoring of their suitability and fit, determined by energy. Some algorithms seem to have some bias towards certain chemical families; this can be reduced by using multiple docking algorithms simultaneously (Charifson et al. 1999). Software programmers and chemical modellers must remember to take into account the natural properties of protein molecules, as they are more flexible and accommodating of small changes than the rigidity suggested by traditional computer programs, although some programs now attempt to recreate this (Schapira et al 2000). Optimal results for structure based drug design are likely to be achieved by combining virtual and experimental methods, such as ‘SAR-NMR’ technology advocated by Shuker, Fesik and colleagues (1996). Microarrays DNA microarrays have been constructed following the sequencing of the human genome, using cDNA to study thousands of genes. From this has stemmed the growth of proteomics and protein biochips, as these are the functional molecules encoded by the genome. Protein arrays/biochips consist of immobilized proteins, which can be used, in the drug development context, to study ligand-receptor interactions (Lueking et al. 2005). Interactions of known pharmaceutical chemicals with proteins can also be explored. For example, Leflunomide (an isoxazole derivative) has been shown to have anti-inflammatory properties in vivo. Analysis of protein interactions using an array revealed that it was not only interacting with the suspected mitochondrial enzyme, but a number of other proteins in the cell, such as pyruvate kinase (Mangold et al. 1999). As the majority of drug targets are proteins, and many of the drugs themselves proteins too, protein arrays are likely to become more popular, as well as hig her throughput. CONCLUSION CHOOSING THE BEST HTS ASSAY: The literature reveals numerous modifications and validated systems of all the possible assays that are suitable for adaptation to high throughput screening in drug discovery. Many of the traditional weak points of each assay have therefore been addressed in this way, making critici

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Credit Rating Check: How to Find Your Credit Score Finding out your credit score is one of the most important steps you can take towards a stronger financial future. It is extremely important for everyone to be well-informed of your credit score so that you can make smart decisions about credit and how to use it to your advantage. Luckily, finding your credit score is incredibly easy and something that everyone should do! The Fair Credit Reporting Act It’s easier than ever to check your credit rating because of the Fair Credit Reporting Act (FCRA). This requires the three main credit bureaus -Equifax, Experian, and TransUnion- to each offer you a credit report once every 12 months. You may choose to order these reports at different times throughout the year, or all at once. How to Order Your Free Reports Although you are entitled to yearly credit checks at no cost, there is still action required on your part. There are three different ways to request a report from each company. Online, you can visit www.annualcreditreport.com or you can call toll-free at 1-877-322-8228. Th...

Where Have You Gone, Joshua Chamberlain? :: Free Essays Online

Where Have You Gone, Joshua Chamberlain? To some, it may be considered a minor inconvenience. To others, a drawn-out ordeal with annoying aspects, but one they realize will be completed shortly. Yet to some, to a select, elite group of young, paranoid, and, let’s face it, broke, lot of people known as college students, it’s a travesty. An impossibility. An object traveling deep into the Void, never to be seen again. This trip into the parallel universe to which some objects traverse without return is known as: The Loss of a Package Sent by your Parents. It wasn’t a package of cookies -- oh no, it couldn’t be something sweet, simple, and purely meant as a tasty surprise. Nor was it a warm, knit blanket, something to keep me toasty warm during long, cold nights of studying in my fairly-heated dorm room. Mail accidentally sent to my home address instead of my brand-new, thoroughly unfamiliar college address it was not. It was a package of books, hand-picked by my dad, for my first college presentation, discussing the life of a Civil War general, Joshua Lawrence Chamberlain. My father is somewhat of a self-taught expert on the subject. A man who has been that annoying voice in the back of a group tour, constantly asking questions and making comments (this â€Å"he-usually-makes-fun-of-this-person† day took place at the Joshua Chamberlain Museum in Brunswick, Maine). A man who has scoured every remote bookstore location in Maine, searching, praying, for another addition to his collection of scores of books concerning the late, great Joshua Chamberlain and the 20th Maine. This past summer, he hit the jackpot. While walking in Freeport, Maine, land of the wondrous L.L. Bean store, my father stumbled upon a small shanty of a store with a meager painted sign which read: â€Å"BOOKS: 20TH MAINE.† With bated breath, my dad entered the store. And there, among rows of Civil War memorabilia, regiment flags and extremely overpriced bronze replicas of battles such as Little Round Top, Dan Beaulieu found heaven. To this day, I wonder if he breathed once in that store, for fear that a puff of air might blow away his Holy Grail of bookstores. After a very exciting hour of buying T-shirts with inspiring quotes

Human Resources JDT2 Essay

Summary: Based on recent quality testing on the toys manufactured for elementary school aged children, it has been noted that the metal whistles contain an amount of lead that is over the United States legally acceptable limit for children age 7 and under. A large shipment is packaged and scheduled to depart at the end of the week. The whistles were manufactured under our company name and at our own warehouse facility. Decision Alternatives: Alternate Process In creating the following possible decision scenarios, the well-being of this company is a massive concern to everyone when a situation such as this arises. The outcome from any decisions made not only effect the consumer of the product, but also the Toy Company, it’s employees, stakeholders, and future customers based on the reputation of the company. In order to determine the best decision, without favoritism, a decision model (7 step decision making process) has been used to guide each deciding deliberation. Therefore, understand that all possible alternatives have been researched and only the best three possible solutions have been included for review. Decision Alternatives: Alternate Advantages and Disadvantages Explain Decision Model or Process Used for Each Advantages Disadvantages Financial considerations Legal considerations Ethical considerations Contact the South American Ministry of Education 7 step decision model, shown above. Allow product receiver to make decision Contamination of company reputation. 50/50 chance of increased reproduction cost. Release of legal obligations once South American Ministry accepts product. The possible subjection of harm to innocent children is simply unethical. Reproduce Contaminated Toy 7 step decision model, shown above. Maintain higher level of satisfaction. Increased costs of reproduction, product delivery late. Approximate cost of $100,000 will be incurred. Maintained federal requirements even outside of geographical requirements. Providing safe products to all children. Ship Product As Is 7 step decision model, shown above. Lowered costs. Potential harm to innocent children Possible litigation cost if families choose to enact a class action. Possible litigation and class action suit The subjection of harm to innocent children is simply unethical. Decision Alternatives: Alternate Considerations 1. Contact the South American Ministry of Education This decision will allow for the receiver of the product to determine for themselves if in fact the shipment is not acceptable and needs replaced. Each government has developed their own criteria of quality control aspects, and should be respected in their own research and limitations of product quality. Within this decision the possibility of the cost of reproduction has a weighing chance of a 50/50 percentage based on the request of the South American Ministry of Education. Also, the informing of and accepting of the product as is will place no further legal obligations on the toy company. 2. Reproduce Contaminated Toy Within the borders of the United States of America, this is the only  acceptable decision to be made. The lead amounts found are above the legal limits and should by all considerations be destroyed and reproduced under the proper legal lead limit guidelines produced by the United States Consumer Product Safety Commission. The cost of this reproduction will fall solely on the shoulders of the company. The approximate cost to be incurred is $100,000. Also, in the making of this decision the Toy Company will be required to contact and inform the consumer of the production issue and the steps being taken to remedy the issue. The consumer may in turn be upset at the delay and remove their business from our company or may find our honesty in the situation to be respectable and assist in promoting our company due to highly ethical character display. 3. Ship Product As Is The guidelines for lead contamination are much more detailed within the United States than that of most regions. The product could easily be shipped and arrive on time for the opening of school in the South American region expected to receive the whistles. The product information would be included in the packaging, leaving the decision for a return of the product to be determined on the chance someone will notice the lead limits information. This choice could possibly rid the company of any further expenses. However, this leaves to chance the harming of many children, the legal allegations that can be brought up by the South American Ministry of Education, and the extreme tarnish of the company’s reputation within the United States and as a worldwide supplier of children’s products. During the narrowing of possible decisions to be established, a system of steps was utilized to enable a criterion for selecting the best possible outcomes. Each of the previous actions stated posse a decision between respect, ethical behavior, or financial consideration. As a whole each of these three actions must be carefully considered as a possible benefit to the company, as well as a possible strike against the reputation that has been so carefully created through producing top quality products for children all over the world. Alternative Recommendation: Recommendation Justification Of the three best available choices the superior choice would be the Reproduction of the Product. The reasoning in this decision is: Legal Aspect: Although as a company legal retaliation could be avoided if the  consumer accepted the product as is after being fully informed, the families of the children involved will still have the legal right to produce a class action claiming Product Liability on the part of the company for allowing the acceptance of the product by the South American Ministry of Education. Under Product Liability when individuals are harmed by an unsafe product, they may have a Cause of Action against the persons who designed, manufactured, sold, or furnished that product. West’s Encyclopedia of American Law, edition 2. (2008) Financial Aspect: The reproducing of the product will initially cost the company approximately $100,000. This by all considerations is a financial blow to any company; however, if you consider the alternative cost of ongoing litigation and a class action pay-out, $100,000 seems rather insufficient. Also consider the possible benefit from this loss of monies; not only will the children involved not be affected negatively by a product produce in the land of the free, but the word will quickly spread about the companies quick action plan to resolve an issue for the safety of their consumer, before being forced to do so by the courts. In addition to the consideration of time, effort, and the expense of recovery, an effective plan to recover from the loss incurred on the reproduction of the product there are a few majors concerns that will be on the front line of significance; Brand Protection: The importance of brand protection is only outweighed by the health and safety concerns of the consumer. Cost recovery is a secondary concern. (Belcastro & Alfonso, 2011) Supplier relationships. Supplier issues that may make cost recovery difficult include difficulties in tracking supplier contracts or supplier insurance documentation and preservation of supplier business relationships. (Belcastro & Alfonso, 2011) Ethical Aspect: For a moment let us look at this situation from the consumer’s side. Would we as parents want the toy company we trust to first consider our children before their personal gain? I would assume anyone would agree that a child should never be subjected to the cruelty of mass production oversight in the products that will be utilized to teach them, care for them, feed them, or protect them. As a company the media would portray any action less than replacement of the product as a grotesque  display of unethical and malice behavior. All businesses, small and large, have an ethical obligation to their consumers, first of all to provide the product purchased and then to not harm anyone-including the consumer. (Gray, 2011) Product safety is an ethical obligation to the extent that companies have a duty to provide consumers with whatever it is they pay for and products are assumed to be safe for ordinary use. (Gray, 2011) Alternative Recommendation: Recommendation Ana lysis Overall, the purpose behind any decision that focuses on an issue that requires action on the part of the company is the ethical obligation the company has, not only to the consumer of the product but also to the employee that we depend on to produce the product, the children for which the product is purchased, and the Board of decision makers for the company and the general public that will recommend our product or company to others based on previous experiences. By providing a less than optimal product, we as a company, say that it is acceptable to lessen our value when the product is for children outside of the United States; this is not an acceptable way of thinking, nor an acceptable reputation of the company and its stakeholders. Moving forward on the remanufacturing of the whistle-even though it is a costly choice-will show for the value the company holds in their customers and the general population of consumers. Displaying a behavior of ethical decision practices will develop a stronger relationship between consumer and producer. This behavior can also produce a chain reaction of ethical revisions in other company actions. In current business the dollar comes before the consumer-making a move to be above the competition will place the company above others in their guarantee to produce only the best. Alternative Recommendation: Social Responsibility The remanufacturing of the product will display this company as being of the utmost ethical level in protecting its consumers even though the consumer is not on the American soil. Placing consideration in the safety and well-being of children of all aspects of geographical location, financial status, and nationality shows American and foreign manufacturing companies that the dollars involved do not come before that of the safety of the people that depend on our moral stature as a producer of children’s toys.  By maintaining the same standards internationally as we would within the American borders, with our products we can inevitably lessen the boundaries between product and consumer all over the world. The ground floor for a decision has been laid for all involved in the determination of an appropriate action in this case. Based on the information provided here, it is desired that a decision based on the good of all mankind-both producer and consumer will be in consideratio n in the deciding of the steps to follow. The American people base much of their perception of a company on its viewpoint to the greater good to humanity; this should what is seen in the products we supply. References: Belcastro, Denny and Alfonso, Bert, October 2011, Capturing Recall Costs Measuring and Recovering the Losses Retrieved on December 27, 2013, http://www.ey.com/Publication/vwLUAssets/Capturing_Recall_Costs/$FILE/Capturing_recall_costs.pdf. Gray, JW, May 16, 2011, Moral Issues Related to Consumers, retrieved from: http://ethicalrealism.wordpress.com/2011/05/16/moral-issues-related-to-consumers/ Product Liability. (n.d.) West’s Encyclopedia of American Law, edition 2. (2008). Retrieved December 27 2013 from http://legal- dictionary.thefreedictionary.com/Product+Liability