Sequencing Technology for Epilepsy Diagnosis

Sequencing Technology for Epilepsy Diagnosis Epilepsy: It is estimated that at many as 10% of the general populace will experience a seizure in their lifetime. (Persad et al., 2003) Epilepsy is a chronic neurological disease defined by its characteristic symptom, recurrent and spontaneous seizures. (Berg et al., 2011) (Asher Y et al., 2012) Epilepsy is a common condition with an occurrence of up to 3% in the population (Deng H et al., 2013). According to Pal D.k et al., (2010) over half of epilepsies have a genetic cause. A large body of research has gone into identifying the genetic causes and corresponding molecular mechanisms of epileptic disorders. Epilepsies have a wide variety of causes including dysfunctional ion channels (channelopathies), abnormal brain development and errors of metabolism etc. (Garofalo S et al., 2012) Research in the genetic mutations behind epilepsies is vital in further understanding the pathology of the many different conditions and developing superior treatments for the afflicted patients. Early Onset Epileptic Encephalopathy: Epileptic Encephalopathies are a large number of rare (prevalence of 1et al., 2010). The symptoms of an EE generally include severe and recurring seizures along with cognitive and developmental delay and/or deterioration. This cognitive and behavioural decline may be influenced by the seizure activity as well as the underlying mechanisms of disease (Kaiman B.A. et al., 2012). The term Epileptic Encephalopathy encompasses a wide variety of syndromes with a diverse range of genetic causes and considerable overlap with other syndromic disorders such as Autism and Mental Retardation. (Berg et al., 2011). The overlap in these syndromes and continuing progression in our understanding of EE’s has resulted in A.T. et al (2010) emphasising that the term epileptic encephalopathy should be viewed as a â€Å"concept and a description† of the wide spectrum of epileptic conditions with an encephalopathic course that are being observed in the clinic. A key diagnostic feature is that Epileptic Encephalopathies tend to occur in infancy to early childhood. While adults can suffer from epilepsy with encephalopathic features this does not tend to be as severe as the Early Onest Epileptic Encephalopathies (EOEE). Children suffering from EOEE’s rarely make it to adulthood due to their poor prognosis. Berg A.T. et al (2010). While more research is coming to light on the potential lasting damaging effects of seizures (Berg et al., 2011) what is certain is that the early onset and repetition of the severe seizures present in EOEE’s is devastating to the early development of patients and their continued growth. As the patients progress from a neonate towards childhood their symptoms will also progress. For example seizures in neonates may not be observable to a clinician as the axonal pathways are not fully myelinated yet and prevent the â€Å"surge† from reaching the motor cortex. Once the brain is fully myelinated the seizures would become observable clinically even though the onset was much earlier in the neonatal stage. This progression of the clinical presentation of epileptic seizures is mirrored in the likelihood of infants suffering from Early Infantile Epileptic Encephalopathy (Otohara syndrome) to develop into Infantile Spasms (IS) at 3-6 months in life. Patients’ suffering from IS tend to develop into Lennox-Gastaut syndrome in childhood. (Asher Y et al., 2012) Diagnosis and treatment: As seen in table 1 and table 2 there are a number of epileptic encephalopathies with a clear enough presentation to make an accurate diagnosis based on the clinical symptoms alone. However due to the rarity of these conditions and the occurrence of EOEE’s with unclear presentations (I need a %?) confirmation of a candidate mutation (gene?) is considered the gold standard when it comes to EOEE diagnosis. (Lemke J.R. et al., 2012) In Lemke J.R. (2012) it was shown that when comparing the diagnostic results of a target gene panel against a clinician’s suggested diagnosis that the gene panel results matched the suggest diagnosis in the EOEE’s with clear presentations. This accounted for 50% of the cohort. However for the remainder of the cohort with unclear EE symptoms there very few suggested diagnoses and not all of these were accurate. It has been suggested by Kay C, (2012) that the significant failure to confirm a genetic diagnosis for unclear EE’s is due to the role of de novo variants as candidates. While we may have the above lists of confirmed disease and causative gene mutations in tables 1 and 2 there are still many other EOEE’s without validated genetic causes that could be the result of de novo mutations in the patients. Considering the ever increasing list of epilepsy linked (but not validated) genes, 265 of which identified in (Lemke J.R. et al., 2012)) it is clear that the current gold standard of diagnosing EOEE’s isn’t high enough. A case study shown by Zupanc M.L., (2009) recorded the diagnostic process of a patient â€Å"Kay† that originally presented with slight head drops at 7 months old. Correlating the head drops to an epileptiform EEG (in this case a â€Å"generalised high-amplitude burst of polyspike, spike and slow wave discharges†) allowed certain conditions to be ruled out however it was highlighted that while a confident diagnosis was reached there were alternatives that cou ldn’t be ruled out. Difficulty in EOEE diagnosis can stem from the multitude of potential genetic causes available for some presentations which can lead to a clinician wandering blindly picking candidates for Sanger sequencing to identify a candidate mutation. (Lemke J.R. et al., 2012) Next generation sequencing technology: If the issue in diagnosing EOEE’s is the lack of validated genetic causes for the different presentations then the most comprehensive way to investigate the matter is to examine the EOEE genomes in comparison to controls and identify the candidate genes. Next generation sequencing technology has provided the means to do this and recent years have seen a surge of NGS based studies in EOEEs and their genetic causes. (Lemke et al., 2012) (Veeramah K.R. et al., 2012) (Veeramah K.R. et al,. 2013) The original human genome project was officially announced as completed in April 2003 (Wheeler D.A., et al. 2013). This project made use of the hierarchal shotgun sequencing method (Chial H et al., 2008). This entailed the use of bacterial artificial chromosome clones (BAC) which each housed a 100Kb fragment of DNA. Over 20,000 over these BAC clones were mapped to the human genome and the order in which these BAC clones would be aligned was the tiling path that would be followed to sequence each human chromosome. The BAC clones are further sub divided into 2 Kb fragments (appropriately sized for sequencing) and these are sub-cloned into plasmid vectors and the fragments that will undergo sequencing. The sequencing was undergone by capillary electrophoresis methods. As long as there is sufficient overlap between these sequences they can be aligned to recreate the BAC clone structure. Then using the BAC clone mapped tiling path the sequences of the BAC clones can be aligned to create a contiguous stretch of sequence that represents the human chromosome. (Mardis E.R., 2008) The advances made in this area to create the next generation sequencing technologies involve a movement away from capillary electrophoresis methods and changes in the methods of how the DNA fragments are assembled to produces the genome sequence. Whole Genome Sequencing removes the use of BAC clones and instead the genome is fragmented into different distinct size classes and placed into plasmid and fosmid subclones. By generating paired end reads and using the number of bases between these reads based on the size classes the genomes can be sequenced quicker than using BAC clones. Next generation sequencing platforms allow for massively parallel DNA sequencing and come in a variety of different set ups. As the need for BAC clones has been removed the sample preparation process is much quicker and cheaper than the method used in the original human genome project. Also while the actual run time of the next generation sequencers is longer than that of the capillary based platform the fi nal yield of reads is much higher (from 96 reads on the capillary platform to up to tens of millions on a massively parallel system). This explosion in genomic sequencing technology less than two years after the completion of the first human genome project has provided an astonishing change in the pace of genomic research. (Mardis E.R., 2008) NGS read diagrams? Next generation sequencing and epilepsy: The study of genetic diseases including the EOEE has benefitted greatly from the genome sequencing revolution. Whole genome sequencing techniques have been used to identify a de novo variant in the SCN8A gene which encodes voltage gated sodium channel pore-forming alpha-subunits. Following discovery of the variant the effects of the variant on channel function was observed and shown to implicate the gene’s involvement in EOEE and Sudden Unexpected Death in Epilepsy (SUDEP). (Veeramah K.R., et al., 2012). Targeted gene panels (next generation sequencing of a list of target genes coding regions only) has proven effective in diagnosing clear presenting EOEE and even providing a potential causative variant when no clinical diagnosis is possible. Most impressive of all was the use of whole exome sequencing (WES) to identify de novo candidate variants of relevance in 7 out of 10 children and potentially identifying 3 new genes that could be linked to EOEE (Veeramah K.R. et al., 2013 ) WES is the process of sequencing only the human exome rather than the whole genome. The exome consists of all the coding regions (exons) of the genome. Even though the exome only accounts for 1% of the whole genome it is estimated to contain 85% of disease causing mutations (Choi M et al., 2009). As of April 2013 U.S. National Human Genome Research Institute claims to sequence a whole genome at the price of $5826. The Howard Hughes Medical Institute claims to sequence the whole exome at the all-inclusive cost of $500. The Broad Institute of Massachusetts Institute of Technology estimates that whole exomes can be sequenced at four times the rate of the genome in their facility (Perkel J.M 2013). This rapid and ongoing reduction in cost is mirrored at the rate WES projects are being undertaken. With a date filter for the end of 2010 on Pubmed I performed the search â€Å"exome sequencing† and found a total of 44 articles. By the end of 2012 this 805 and by the end of 2013 the nu mber had more than doubled to 1,751. Whole exome sequencing projects have the advantage of not only being cheaper and faster than whole genome projects but also are a more comprehensive option than targeted gene panels for identifying EOEE candidate variants. While not as complete in whole genome sequencing in scope 85% covers a significant amount of data to be analysed and only leaves a 15% chance of not finding a candidate variant. It should also be noted that the exome is much easier to process and analyse while the whole genome includes non-coding areas which we are currently not really able to analyse in such a way to validate the relevant link between disease and non-coding variants (Perkel J.M 2013). Hypothesis: The question we are trying to answer with these projects is â€Å"Can whole exome sequencing detect candidate disease causing variations in early onset epileptic encephalopathy patients†? As this project involves isolated probands and one family trio it also raises the question of whether the inclusion of parent WES data allows for more rapid and accurate variant analysis. As such the end research goals are to identify likely and relevant disease candidate variations in the proband WES data and confirm their presence with Sanger sequencing The benefits of WES studies in EOEE candidate variants are numerous and important. Identifying a confirmed candidate mutation can allow an affect family to receive genetic counselling. If a clear mechanism of disease can be ascertained from the disease candidate then potentially alternative anti-epileptic therapy can be implemented based on the specific condition to improve patient prognosis even slightly. Along with this as EOEE have such a wide variety in causes and mechanisms some can respond poorly to some standard anti-epileptic drugs and lead to rapid deterioration of the patient. Identifying a genetic cause can prevent this from happening. (FIND REFERENCE) On a larger scale understanding the complex mechanisms of these devastating disorders is the only way to improve and develop treatments for these conditions and improve patient prognosis. Understanding how these rare forms of epilepsy manifest may in turn provide clues into the mechanisms of the more common forms of epilepsy . (FIND REFERENCE) As more research is beginning to highlight the role of earlier onset of seizures on the developing brain and the encephalopathic effects WES could become an effective screening tool in the future that would allow early intervention to control or prevent these devastating seizures and greatly improve patient standard of life and change EOEE to a more manageable condition. (Berg et al., 2011) References: (Persad V, Epilepsy and developmental disability) Berg AT ET al, epilepsy cognition and behaviour Asher Y Molecular bases and clinical spectrum of EIEE Scheffer I., Genetic testing in epilepsy what you should be doing Deng H Molecular biology of genetic based epilepsies D.K. Pal, A.W. Pong, W.K. Chung, Genetic evaluation and counseling for  epilepsy. Nature reviews, Neurology 6 (8) (2010) 445e453. Garofal S from genetics to genomics of epilepsy Hennekam, care for patients with ultra rare disorders Kaiman B.A. et al., A genetic diagnostic approach to infantile epileptic encephalopathies Berg AT et al Epilepsy, cognition and behaviour. Lemke J.R. Targeted next generation sequencing in epileptic disorders. Kay C whole genomes in the clinic (Veeramah K.R. et al de novo pathogenic SCN8A mutation identified (Veeramah K.R. et al, Exome sequencing reveals new causal mutations in children epilepsia (Chial H et al., 2008) DNA Sequencing Technologies Key to the Human Genome Project .(Mardis E.R., 2008) Next generation DNA sequencing methods. (Veeramah K.R., et al., 2012) de novo pathogenic SCN8A (Veeramah K.R., et al., 2013) WES 9/10 de novos (Choi M et al., 2009) Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. (Perkel J.M 2013) ScienceMag exome sequencings towards

Taiwan: Major Industires

Taiwan: Major Industires TAIWAN: MAJOR INDUSTRIES The major industries in Taiwan are electronics, petroleum refining, armaments, chemicals, textiles, iron and steel, machinery, cement, food processing, vehicles, consumer products, pharmaceuticals. We can have a look at the major industries one by one and then do an analysis on the investment opportunities on one of them. SEMICONDUCTOR INDUSTRY Taiwan has truly emerged as a global leader in the semiconductor and microelectronics industry and serves as the home of the worlds top IC foundries, Taiwan Semiconductor Manufacturing Corporation (TSMC) and United Microelectronics (UMC), which hold a majority of the market share. Taiwan is also an important player in Mask ROM production, IC packaging and IC testing, accounting for 57.1%, 32% and 36% of global market shares respectively. Taiwan-based Advanced Semiconductor Engineering Inc (ASE) and Siliconware Precision Industries (SPIL) lead the IC packaging industry, while ASE Test and ChipMOS Technologies lead the IC testing industry. Taiwans IC design industry has ranked second only to the US, accounting for 28.4% of the market worldwide. Media Tek, VIA, Realtek and Sunplus are among the top 20 IC design houses. Taiwan ranks as the worlds 3rd largest maker of DRAM components, supplying 17.1% of the market. Taiwan also serves as a key IC market, with a value of US$11 billion in 2002, representing 25.7% of the market in Asia and 8.1% of the global market. Competitive Advantage and Market Strengths Taiwan plays a major role in the global semiconductor industry, as the unique structure of its IC industry fosters close cooperation among diverse yet essential elements in the value chain, ranging from IC design and manufacturing to packaging and testing. Investment Opportunities and Market Potential The National Si-Soft Project was launched in 2003 in an effort to upgrade Taiwans IC industry from mainly contract manufacturing to RD and innovation oriented production. The project aims to make Taiwan the one-stop shop for IC designs, mix-and-match intellectual properties, manufacturing, and testing. The National Si-Soft Project is devoted to developing System-on-Chip (SoC) infrastructure in Taiwan. Specific contents of the Si-Soft Project include automation software, silicon intellectual property (IP), embedded software, and system single chip, which are all essential in IC design. New IC designs will in turn drive the development of information household appliances, photoelectricity, internet technologies, energy, communication, biological chips, and nanotechnology. The project offers various benefits such as: Providing available IP sources and a more simplified transaction flow for the IC design industry (including design services), in order to decrease the time required for IC design. Improving the competitiveness of practitioners in the system industry as they realize the system knowhow in their own SoC Effectively cultivating star IP vendors in the IP industry Attracting more customers with value-added products (more complete IP features) for chip manufacturers Allowing practitioners in the packaging and testing industries to interchange freely and learn about the most advanced technologies relevant to their field in order to further enhance their technological expertise DISPLAY AND OPTOELECTRONICS Taiwan has seen significant growth in its color imaging (CI) industry in recent years. The overall production value of the flat panel display (FPD) industry alone has increased more than twofold since 2001, totaling US$7.39 billion, of which 83.4% came from the production of large size TFT-LCD units. In Q1 2004, the islands Flat Panel Display (FPD) sales reached NT$171.3 billion (US$5.1 billion), a 115% increase on the previous year, and 2004 sales are projected to reach NT$727.1 billion (US$21.7 billion). As Taiwan manufacturers are positioned to start mass production on next generation panels (6th, 7th, and 7.5), the total production value of Taiwans FPD industry will surpass NT$1 trillion. Taiwan is currently expected to account for 41% of large-sized TFT-LCD panel supply in 2004, becoming the worlds largest production base. Major TFT-LCD makers in Taiwan, such as AU, Chi-Mei, CPT, QDI, Hannstar, Toppoly, and PVI, have contributed greatly to the progress of the CI industry. AU, which receives the majority of its funding from Taiwan, is the third largest panel supplier in the world, and is the largest producer in Taiwan. Chi Mei, the second largest producer in Taiwan, is fast approaching AU in terms of production value. Competitive Advantages and Market Strengths Over 30% of the key components for FPD, such as polarizers, backlight modules, color filters and driver ICs, are manufactured in Taiwan, and local component makers such as Optimax (polarizers), Forhouse and Radiant (backlights), Allied Material Technology, Cando and Sintek (color filters), Novatek and Winbond (driver ICs), work very closely with panel makers. These component and finished product manufacturers are clustered around the Taoyuan, Hsinchu, and Tainan areas, creating an integrated supply chain that further strengthens Taiwans position in the global IT industry. Investment Opportunities and Market Potential As Taiwan is the worlds second largest producer of panels and the market for components is quite large, the government is inviting foreign suppliers of materials and equipment to build factories in Taiwan, to enable faster and more effective product and service deliveries. Panel makers in Taiwan plan to establish G5 and G6 production lines, with the goal of becoming the leading panel supplier in the world. The government aims to generate US$40 billion in FPD production value by the year 2006. In the next three to four years, enterprises specializing in advanced components will have ample space for high growth potential. The government offers investors in the color imaging industry special tax reduction and investment incentives. Combined with a highly skilled workforce and abundant experience in the IT industry, Taiwan is the ideal destination for investment in the color imaging industry. Foreign Direct Investments in Taiwan The color imaging industry in Taiwan has grown very rapidly in the past few years. In light of an increasing demand for flat panels in the global market and strong competition, Taiwans vendors realize the importance of improving their technology and producing the right key components. The cost ratio for TFT-LCD components is quite high, with color filters at around 26% and glass substrate near 4%. Taiwans government has been active in soliciting foreign investors to manufacture these key components in Taiwan. BIOTECHNOLOGY AND PHARMACEUTICALS Taiwans concerted policy efforts to develop research, development and production capabilities in the biotech sector have paid off in creating a wealth of investment opportunities. Biotech research at Taiwans top academic institutions is gaining international attention, while development capabilities, fostered through joint industry and government support, are turning these research achievements into commercially viable products. Taiwans mature production and logistics capabilities, evidenced by its over 100 cGMP-awarded pharmaceutical manufacturers, have been widely recognized as powerhouses in this area. Goals for the Coming Decade Having established a solid foundation, the Taiwan government has designated the biotechnology industry for further development into a key industry in its Two Trillion, Twin Stars Plan and Challenge 2008 National Development Plan. Through the combined efforts of government, academia, research and industrial sectors, Taiwan is poised to become a major hub and logistics operations center for RD, manufacturing, and operations in the biotechnology and pharmaceutical industries within the Asia-Pacific region. The governments plans to promote the industry include achieving targets of NT$150 billion (US$4.34 billion) in investments and 25% annual revenue growth by 2008 and five hundred biotech-related companies within ten years. Competitive Advantages and Market Strengths Superior pharmaceutical production and manufacturing capabilities Geographically positioned close to potential markets in Asia allows for enhanced product development for Asian markets Excellent springboard for entering other Asian markets Ease of communication and reduced cultural barriers Strong venture capital and financial resources Abundance of technical specialists in organic chemistry, optoelectronics, integrated circuitry, automated systems, and other relevant fields Excellent research facilities and well-staffed healthcare organizations TELECOMMUNICATION Taiwan offers much potential in the telecommunications market, with one of the most advanced telecommunications networks in the region. High penetration rates in both the fixed-line and mobile phone sectors have encouraged growth in telecom products and services. Looking to 2004, the Ministry of Economic Affairs has announced plans to make the telecommunications industry one of Taiwans trillion dollar industries, which will nurture the development of wireless applications, 3G, and broadband services. Competitive Advantages and Market Strengths Taiwan is currently the fourth largest producer of PCs. As PC-related IC design and manufacturing technology in Taiwan have reached world standards, wireless communication and broadband communication products, related components/assemblies and systems products manufacturing technology have all been the beneficiaries of a multiplier effect. A growing number of Taiwan manufacturers boast manufacturing and marketing capabilities for research and development of xDSL, DLC, SDHH, DWDM, and cell-phone related products. If these are combined with telecommunications service capabilities of foreign companies, particularly in the area of content services, their ability to enter newly developing markets will surely stimulate a new wave of product demand. Taiwans world-class technological advantages enable it to benefit from US and Japanese RD resources. Taiwans central location in the Asian Pacific region provides ideal access to the emerging Mainland China and Southeast Asian markets and to manufacture highly-competitive communications technology products. For manufacturers advancing into newly developing markets, Taiwan remains the most advantageous base for business operations in the region. Investment Opportunities and Market Potential In order to establish Taiwan as a broadband communications technology island, the government has classified telecommunications as a strategic industry, allowing it to benefit from a host of investment and tax incentives. The Related Industries Promotion Plan is expected to facilitate the establishment of communication-oriented SoC IC design, fiber-optic components/assemblies, production facilities, software and telecommunications service industries innovation. IT product manufacturing is expected to reach its goal of surpassing US$ 30 billion by 2007. At the same time, in order to comply with telecommunications industry liberalization and national infrastructure requirements, Taiwan has in recent years gradually liberalized the 3G and wired network markets. Estimates for 2005 anticipate US$50 billion in equipment purchase orders and US$20 billion in telecommunication service industry revenues. Market opportunities are tremendous, making Taiwan the ideal investment destination for the equipment manufacturing industry and content service providers. MATERIALS AND FINE CHEMICALS The production value of the material and fine chemical industry in Taiwan has averaged approximately US$44.38 billion annually, with petrochemical materials, polymer, electrical materials and fine chemical products as major output. Taiwan is the largest producer of ABS, the second largest supplier of PTAs, and the fourth largest in PVCs, supplying the Taiwan domestic market and the worlds major markets, especially Mainland China. With a well-developed supplier chain and marketing channels all over the world, Taiwan plays a key role in many markets today. In fact, a growing number of leading companies, such as Chi-Mei, Nan Ya Plastics and Formosa Plastics in the material industry, and UPC, Dahin, Lee Chang Yung Chemical in the fine chemical industry, are emerging more visibly in the international markets. In addition, Eternal Chemical and Chang Chun Plastics in the electrical material industry, and Taiwan Shiseido, Grand Glory Biotechnology, Taiwan Sugar, and Taiwan Salt in the cosmetics industry are already well-established in their respective markets. As the IT industry becomes more competitive, Taiwans material and fine chemical industry has been focusing on semiconductors, plane display materials, print circuit boards, nanotechnology materials and other high value-added products. Investment Opportunities and Market Potentials Taiwan is home to a great number of talented RD and design people who are well-educated and possess experience with international companies, making the island more advantageous location for multinational companies to localize as part of a globalization strategy. In recent years, Taiwans IT industry has shown impressive progress the semiconductor, TFT-LCDs, and print circuit board industries are seeing dramatic growth and have reached large-scale production levels, thereby gaining strength in the international markets. The materials and fine chemical industry in Taiwan will be highly essential in supporting the IT industry and meeting its rigorous demands. The Challenge 2008 National Development Plan, a government-support project that shows a list of plans and incentives on land lease, funding, taxes, and other benefits, demonstrates the value that the materials and fine chemical industry brings to Taiwan. Taiwan has created vast opportunities for both international and domestic firms, with Mainland China as the biggest and most prominent market. With its strategic geographical location and experience in world trade, Taiwan makes the ideal center for manufacturing and market development in the Asia-Pacific region. FINANCE, SECURITIES AND INSURANCE With foreign exchanges reserves of over US$200 billion at the end of 2003, and a forecasted 4.5% economic growth rate for 2004, Taiwan continues to maintain a robust economy, due in part to government action on internationalization and liberalization policies. Competitive Advantages Market Strengths As a growing number of global industries are migrating to the Far East, Taiwan is an ideal location to establish a financial base. Multinational companies in Taiwan have access to more precise information on the Asia-Pacific region as they expand their business. In recent years, East Asia has become an important investment location for European and American countries. Taiwans stock market index is covered in both Dow Jones and Morgan Stanleys stock indices, to the benefit of foreign investors. In addition, the government has loosened restrictions on foreign capital in the Taiwan stock market, bringing more attention to Taiwans market. Investment Opportunities and Market Potential In pursuing its goal of becoming the financial center of East Asia, Taiwan is revising its financial policies to bring them to international standards. Examples of such policies include: Lifting constraints on offshore banking units (OBUs) Policies include expanding the depth and breadth of foreign currency market, and broadening the offshore banking units market and foreign currency overnight rate market to attract foreign financial institutions and enhance Taiwans position as a regional funding center. Taiwan will therefore expand its stock and bond markets, improve market regulation and efficiency, and promote the internationalization of the securities market. Foreign investors can buy and sell securities, bonds and public warrants freely without restrictions of time or location, have more versatility in managing investments, and vitalize the market. Ongoing liberalization of capital markets for foreign investors the ROC government has opened up its stock market to foreign investors with minimal restrictions. With the introduction of more financial commodities in the market and more diversified channels for funds, Taiwans capital markets are opening to increasing foreign investors, who are now allowed to manage derivative financial products instead of spot commodities. In addition, foreign capital is now permitted in the private placement market, and these newly available commodities are attracting more foreign investment. Opening the insurance market to foreign investors Fifty-five insurance companies are currently in operation in Taiwan, of which 21 are foreign-owned. Other measures to liberalize the Taiwan insurance market include: relaxing restrictions on the approval of commodities; liberalized rates; investment policies and procedures; the opening of cross-strait insurance exchanges; the promotion of risk-based capital (RBC) systems; information disclosure systems; and a certified actuary system. With monitoring of all foreign insurance companies in Taiwan to ensure compliance with policies on remuneration for Taiwan citizens, the foreign insurance industry in Taiwan can operate in a fair and reasonable business environment. In addition, with the islands excellent location and workforce, Taiwan has the potential to become the Asian insurance market hub for foreign investors. Increasing the liquidity of financial capital in the stock market The Securitization of Financial Assets Law was implemented on July 24, 2002, with the aim of improving and increasing the liquidity of financial assets, including fully liberalized foreign investments in the public and private placement of securitization of financial assets. Several domestic banks are in the process of cooperating with foreign financial institutions in this regard. According to the rules for MFN and National Treatment, foreign invested banks in Taiwan can compete on an equal footing with domestic banks. They are all granted licenses and can operate as fully-functional branches in Taiwan. In addition, as stated in the Banking Law and Financial Holding Company Law, a foreign financial institution may invest up to a 100% stake in a domestic bank. Moreover, foreign banks and financial holding companies that have sufficient experience and a good reputation can hold shares of up to 100% under their original name. Foreign financial groups may merge with Taiwans local financial institutions under the Merger Law for Financial Institutions, which has been established for the purpose of regulating the merger of financial institutions, expanding economies of scale, enhancing the efficiency of financial institutions and protecting proper competition environments. The law provides a friendly legal environment and mechanism for the operation of Asset Management Companies. Flexible government restrictions allow foreign investors to set up their operations headquarters in Taiwan to conduct multilateral trade a growing trend for foreign companies to gain a more competitive edge. ANALYSIS OF THE TAIWANESE BIOTECHNOLOGY SECTOR Taiwans biotechnology industry includes biotechnology, pharmaceuticals and medical devices. In 2003, the total annual revenue for these industries in Taiwan was approximately NT$131.6 billion, of which NT$29.6 billion came from biotechnology0.9 percent of the total global revenue-represented by 223 companies, each with an average revenue of NT$133 million. Business scope covered included genomics, drugs, diagnostics, agricultural biotechnology, environmental biotechnology, protein drugs, contract research organizations, biochips and bioinformatics. The islands pharmaceutical industry returned NT$61.4 billion,0.4 percent of the global total with 429 companies active in this sector, averaging NT$143 million per company. The medical devices industry returned NT$40.6 billion,0.6 percent of the global total, coming from 397 companies, with an average revenue of NT$102 million each. The biotechnology workforce size is 35,610, of which 7,200 are in the biotechnology industry, 14,224 in the pharmaceutical industry and 14,186 working in the medical devices industry. Status of Biotechnology Development in Taiwan (2003) Units: NT$100 million Industry Biotechnology Pharmaceutical Medial devices Total Revenue 296 614 406 1,316 Number of Companies 223 429 397 1,049 Size of work force (number) 7,200 14,224 14,186 35,610 Export value* 113 45 288 446 Import value* 120 339 425 884 Domestic sales vs. export 62:38 93:7 29:71 66:34 Domestic market demand* 303 908 543 1,754 BIOTECH INDUSTRY ANALYSIS: MICHAEL PORTERS FIVE FORCES MODEL Advantages and opportunities in Taiwans biotech industry Advantages: 1. Active and continuous efforts to build up an attractive investment environment by the government 2. Large input to investment of up- and mid-stream RD and infrastructure 3. Close bond with fast growing Asian markets 4. Sufficient domestic capital for investing from intensive partners 5. Solid foundation and experience from the past development of the electronics industry 6. Proper environment for the development of small- and medium-sized enterprises; and the diligent and aggressive entrepreneurial spirit of the Taiwanese 7. Ample biotechnology and pharmaceutical professionals based both locally and overseas 8. Relatively homogenous ethnic Chinese population, ideal for the development of an Asian-prevalent-disease-related biotech industry 9. Qualified RD personnel who are capable of establishing a knowledge economy to reflect Taiwans uniqueness 10. Advanced traditional agricultural technology to support development of agricultural biotechnology Opportunities: 1. The key industry in the governments Challenge 2008 six-year national development plan 2. The listed incentive industry among newly encouraged emerging strategic industries 3. Rising demand in better living standards in the Asia-Pacific; and growing economy and market for potential development 4. Increasing number of strategic alliances and technology transfer cases 5. RD and precision processing sectors are ready to take advantage of the growing global trend towards outsourcing in the biotechnology industry. 6. Right timing for endless business opportunities in post human gene decoding 7. High value-added, long life cycle and value chain of biotechnology; many points of entry available, from RD to marketing 8. Flourishing biotechnology RD service industries (technical evaluation, RD design, intellectual property services, and start-up incubation services) 9. Many large-sized high-quality medical centers, providing optimal conditions for undertaking clinical trials 10. Clear market segmentation from temperate zone products of advanced countries with Taiwans sub-tropical climate to develop Asian sub-tropical agricultural biotechnology 11. Plentiful related information aggregated from National Health Insurance program 12. Diseases associated with a modern sedentary lifestyle, with potential for drug and disease screening technology platforms Objective. RECOMMENDATIONS 1. Although there are a few biotech companies but all of them are small scale operators. Hence a consolidation programme can be started. 2. Since biotech is going to help pharmaceutical companies in a big way hence pharma companies can make a conscious effort to start RD centers with emphasis on biotechnology. 3. Although the government is supportive of the sector but not many FDIs have been invited. The government can specifically invite FDIs in this sector. 4. Large companies like Biocon and Brighton Research labs should be asked to set up facilities. They can be promised access to markets in mainland China through Taiwan. 5. Most of the raw materials required is being imported, so the government can devise strategies to develop auxiliary industries and make the sector self sufficient. 6. Newer and more challenging topics can be taken up to study. Like human genome sequencing which would help in determining the genetic causes for diseases like cancer and AIDS.

Language :: essays research papers

Language is an abstract concept which is acquired early in life by the vast majority of children through an intricate process. There are many different theories concerning the acquisition of language that have been considered, and these are constantly being refined, along with the technology which enables researchers to further investigate the process. Bilingualism has also been a complex area of interest which has elicited various theoretical viewpoints. There are various aspects which are true to every language. These include: phonology, semantics, syntax, and pragmatics. The phonology of a language includes a set of phonemes: the different sounds, and the rules governing the combination of these sounds which can be found within the language. The semantics involved in a language deals with the meanings of the sentences, words, and grammatical markers (morphemes) in the language. The syntax concerns the rules about organizing the morphemes into sentences, and pragmatics are the communication skills involved in the use of the language (Shaffer, 1999, p.352-353). These are merely the basics required for language acquisition. Knowledge of the nature of communication, in addition to the fashion in which the language is acquired are also integral. The acquisition of a language has instigated a controversy regarding the process through which it is acquired. The empiricist perspective, inspired by B. F. Skinner in 1957, states that children learn language by imitating caregivers who model and reinforce their speech (Shaffer, 1999, p.355). Also during the 1950's, Noam Chomsky hypothesized that languages are too complex to be learned by imitation (Shaffer, 1999, p.356 & Brownlee, 1998, p.48). Therefore, humans are born with a "language acquisition device" (Shaffer, 1999, p.356 & Brownlee, 1998, p.53) and a "universal grammar" (Brownlee, 1998, p.48) which predisposes them to the ability to learn languages and apply the grammatical rules to the languages which they hear. The large interest in the area of language has been elicited as a result of the intricacy of the acquisition process of a language, and the fact that all children appear to have the ability to acquire and understand such an abstract concept. The study of language, as the study of any subject, is an ongoing process, as illustrated by various researchers over the years. These studies have evolved form mere theoretical statements about language to involved studies which have caused the previous hypotheses to be rejected. This is largely due to the evolution of related technology which has facilitated research in the area.

Alcohol and the Causes of Student Binge Drinking Essay -- Expository C

Causes of Student Binge Drinking We've all heard it before: "Too much of anything is bad for us." The amount of binge drinking occurring on American college campuses today proves that college students do not heed this warning. Binge drinking, or drinking for the purpose of getting drunk, harms both drinkers and non-drinkers alike. As today's college students come dangerously close to being swept away in the sea of papers, exams, jobs, and interviews, they use bingeing as the lifeboat that allows them to escape the stress. It allows them to forget their worries, fit in with the crowd, and live on the edge in a fast-paced world that normally does not leave time for such activities. Teetering on the brink of adulthood, yet still trapped in childhood makes drinking decisions difficult for many college students. A desire to get away from our usual lives because of societal regulations and conformity, psychological and emotional problems, and the stress of everyday life causes college binge drinking. The need to conform to societal norms set by peers leads to college binge drinking. Over the years, drinking has become a popular pastime for college students. A study conducted by Dr. Katherine C. Lyall of the University of Wisconsin defined binge drinking as "five or more drinks in a row one or more times during a two week period for men, and four or more drinks in a row one or more times during the same period for women." Lyall's study, in which 145 colleges from 40 states participated, found that 84% of all students drank during the school year. It also found that 44% of all students were binge drinkers, and 19% binged three or more times within a two week period (Lyall). Students feel the need to drink in order to fit in wit... ... well as those surrounding him or her. Societal norms, psychological and emotional problems, and stress all contribute to binge drinking. These factors should not be excuses, however. Today's college students are capable of finding a legal and safe lifeboat that keeps them from being sucked under the waves of daunting college pressures. Works Cited Addeo, Edmond G. and Jovita Reichling. Why Our Children Drink. Englewood Cliffs: Prentice Hall, 1975. Hamilton, Cheryl. Communicating for Results. Belmont: Wadsworth Publishing Company, 1997. Lyall, Katherine C., PhD. "Binge Drinking on American College Campuses." August 1995. October 14, 1998. (available online). http://www.hsph.harvard.edu/cas/RWJ_S.htm North, Robert and Richard Orange, Jr. Teenage Drinking. New York: Collier Books, 1980. Rouse, Ewing. Drinking. Chicago: Nelson-Hall, 1978.

COP 3530, Discrete Data Structures and Algorithms, Summer 1999, Homework 1 :: UFL Florida Computer Programming Homework

Class Notes: Data Structures and Algorithms Summer-C Semester 1999 - M WRF 2nd Period CSE/E119, Section 7344 Homework #1 -- Solutions (in blue type) Note: There have been many questions about this homework assignment. Thus, clarifications are posted below in red type. When you answer these questions, bear in mind that each one only counts four points out of 1000 total points for the course. Thus, each one should have a concise answer. No need to write a dissertation. * Question 1. Suppose you want to find the maximum of a sequence or vector a of n distinct integers. Write an algorithm to do this in O(n) time, for any sequence of n distinct integers. max = very large negative number input(a) for i = 1 to n do if a[i] > max then max = a[i] endfor output(max) * Question 2. You could assume that you know the maximum value of a before you search for it. That is, if a has values in the interval [0,101], then the maximum would be 101. The best case (least work) in the preceding algorithm would occur when the maximum of the n-element sequence is the first element of the sequence. Where is the maximum located for the (a) worst case, and (b) average case? Support each answer with a proof, not just an example. Alternatively, you could assume that the maximum was not known beforehand, and a)-b), above might be easier...Either assumption is o.k. o Case 1: Maximum unknown a priori -- You have to search through the entire array to find the maximum. Thus, there is no worst case or best case if you consider the work as comparisons (dominant cost) only. o Case 2: Maximum known a priori -- This becomes a linear search problem (find the maximum).

The gender income gap

Abstract The Gender Wage Gap is something invented by prehistoric man back in the sass's. Designed to keep women from making the same money and receiving the same benefits as their male counter-parts. This was a devise born in gender discrimination , intended to keep women in her place. When it was found to be unconstitutional they tried to fix it , but the monster had grown out of proportion. It had gotten so out of hand that no one not even the original creator could recognize it.There are so many factors that make up the gap but the largest factor still remains as discrimination. The Gender Gap For as long as there have been Jobs and Women in the workplace. There still exists a terrible unaddressed form of gender prejudice. Statistics indicate that it doses*Г? matter if they have the same Skills, more time on the Job or the same Education. Women do not make the same money and receive the same benefits as men doing the same Job. How many female Coo's have you seen in fortune 50 0 companies?According to Francine Blab & Lawrence Kahn from the National Bureau of Economic Research @ http://www. Never. Org/papers/we Both gender-specific factors,including gender differences in qualifications and discrimination, and overall age structure contributed to this ever increasing gap. As far back as 1957 women chose occupations for which on -the -Job training is less important, gender differences in occupations would also be expected. Women would especially avoid jobs requiring large investments in skills which are unique to a particular enterprise.Because the returns to such investments are reaped only as long as one remains with that employer. At the same time, employers may be reluctant to hire women for such Jobs because the firm bears some of the cost of such firm-specific training, and ears not getting a full return on that investment. Many employers thought of women as temporary workers due to the probability of them leaving to start a family or already having a family or a successful husband who had the means to support them. Here lies the fallacy off man has to support his family.The ever present threat of pregnancy loomed in the heads of most employers. The playing field was evened out a little with the emergence of the birth control pill. The Power of the Pill. According to Claudia Golden & Lawrence Katz from the National Bureau of Economic Research @ http://www. Never. Org/papers/7527 When the pill was introduced to the female population after FDA approval in the sass's. Its had a direct positive effect on women's career investment by almost eliminating the chance of getting pregnant and thus the cost of having sex.The Pill also created a social multiplier effect by encouraging the delay of marriage generally and thus increasing a career woman's likelihood of finding an appropriate mate after professional school. Even though women are outpacing men in getting college degrees thief not enough to close the gender pay gap. The American As sociation of University Women tackled he pay gap question by looking at workers of the same educational attainment*name kind of college, same grades;loading the same kinds of Jobs, and having made the same choices about marriage and number of kids.They found that college-educated women earn 5 percent less the first year out of school than their male peers. Ten years later, even if they keep working on par with those men, the women earn 12% less. .. Jane Farrell and Sarah Jane Glenn explore the question of whether there is more gender equality among minority men and women than among whites†¦. Playing the Numbers. The Gender *rising High Education. According to Doyle, William R. Change. (May/June 2010) volume 42 Issue corporate Resources. There are two factors that contribute to the higher education gender gap in the US.First, the gap begins, and in mostly accounted for, by gaps in high school completion. Second the labor market continues to provide differential earnings for men and women, even those who are similar in terms of the education, experience, and choice of careers. Even if women and men had similar educational credentials, scores on standardized tests, field of study, and degree from college of similar selectivity the gap in earnings would be about $4,400. The Gender Gap for Young Professionals in the Corporate and Financial sector.According to a report written by M. Bertrand, C. Golden and L. Katz from the National Bureau of Economic Research @ http://www. Never. Org/papers/w14681 The career's of Mamba's, who graduated between 1990 and 2006 from a top US Business school, are studied to understand how career dynamics differ by gender. Although male and female Mamba's have nearly identical (labor) incomes at the outset of their career's , their earnings soon diverge , with a male annual earnings advantage reaching almost 60 log points and ten to 16 years after MBA completion.There were three identifiable reasons for the large and rising gender ga p in earnings: is differences in training prior to MBA graduation; differences in career interruptions; differences in weekly hours. Gender differences in earnings across the years following MBA completion. The presence of children is the main contributor to the lesser Job experience, greater career discontinuity and shorter work hours for female Mamba's. Gender differences in the annual Income of psychiatrists. According to Weeks, W. B. , & Wallace. ,A. E. (2007)Psychiatric Services,58(4),51 5-20.American Psychiatric Publishing,Len. In this article published on a study of the annual Income of female psychiatrists vs. that of male counterparts was 13% lower on an average from the 1980 thru to the 1990 and persisted on thru to 2001. It also stated that the female Doctor would more likely be employees of the practice, as opposed to having an ownership interest in the practice. This tells me that it din*Г? even matter how much education a woman had . Even in the halls of higher lea rning , there still existed this gender gap.It din*Г? matter if she had the same Education as a male doctor, There was still no equality in pay. And you know there was no physical inhibitors. Why wives earn less than husbands. According to Kraft,Susan. American Demographics.. Jan 94, Volvo. 16 Issue 1, Corporate Resources. Some married women are closing the earnings gap with married men, but most work fewer hours and at lower paying Jobs. A woman has a hard time matching a mans income, even if the man doses*Г? work. Because men who don*Г? work still have income from unemployment, disability, pensions, and investments.Working wives whose husbands don*Г? work make the largest contribution to family income, but even their contributions accounts for less than half(42%) of that segment's aggregate income. Then we have the two income households, where many wives find it too expensive to work. Many dual income families must subtract the cost of child care, and a second car. They only add an addition 14% to the families income. So more than likely they are working for Job benefits. And last but not least according to Thatcher, J. (2013). Art Monthly 50:50, (367), 5-8.Women are still woefully under-represented in the art world argues Jennifer Thatcher. :Last year an artist fired one of their studio assistants for being pregnant. She recalled that as soon as she made the announcement she was treated fervently , and spoken to as though she had made a huge mistake. Despite working as hard as she could in an attempt to prove she could manage the work. She was eventually asked to leave and forgo her rights to statutory maternity pay. There lies the Physical inhibitors, Gender Specific discrimination.This type of discrimination still exists in the work place, and they are not trying to hide it. To be spoken to and treat like you had a disorder of some sort is Just not exceptionable and against the law. For over 50 years women have suffered the consequences of this wage gap, between them and their male counter-parts. Since 1963 there has been a bill sitting in the halls of Justice and not in-forced due to its lack of Importance to our nations leaders (UN-popular). Women have suffered UN-imaginable hardships caused from this gap . Women are doomed from the beginning starting with their very first paycheck.The gap Just gets wider and wider not stopping until they receive their very last Social Security check. This gap has had serious ramifications for women and their families. What happened to our human rights? I thought I lived in America, we have gone to war in foreign countries defending their human rights. But when this issue comes up , they Just explain it away by saying men have to support their families Based on the evidence that I have submitted, you be the Judge is it fair that men and women doing the same Job don*Г? get paid the same money? This is discrimination in its worst form.

Indian Economy: Adopting New Approach Essay

After independence, India chartered a path of economic development based on mixed economy, building a new industrial structure around the public sector and a closely monitored, regulated and controlled system where government played the role of licenser in the process of building industry. There were few hiccups in between. In the late 70s Mrs. Indira Gandhi brought in small doses of liberalization. In the mid 80? s Rajiv Gandhi did likewise but the real change came in 1991 when economic crises were looming large on the horizon. India’s economy could be termed as a developing economy which is characterized by the coexistence, in greater or lesser degree, of utilized or unutilized manpower on the one hand and of unexploited and exploited natural resources on the other. A developing economy bears the common features of technological backwardness at low per capita income coupled by widespread poverty, heavy population pressure, low grade productivity, high unemployment, low level utilization of country’s natural resources, rigid social structure, predominance of old beliefs, lack of opportunity for capital formation, pre-dominance of agriculture and scanty participation in international trade etc. But all this is amidst a possibility of economic development, small pockets of high rates of economic growth and affluence. It is gain saying truth what the world economy has experienced that colonization directly lead to the exploitation of the colonized country by the colonial rulers. Colonization is also a factor for the underdevelopment of a country’s economy. India was a victim of the colonial feature of economic exploitation for more than hundred years. The British colonial exploitation in India can be broadly divided in three periods. They are (i) the period of merchandised capital, (ii) the period of industrial capital which leads to the drain of Indian wealth for the interest of British industry and (iii) the period of financial capital. During British period foreign capital flowed into India. However in real terms those capitals were not according to the proper needs of Indians and directly helped the capital growth of Britishers. The overall impact of British rule in Indian economy can be summed up as stagnation of per capita income ever a long period of time, high priority to the traditional method of agricultural activities, repeated famines and acute poverty of handicrafts and traditional village industries defective land holding and erroneous implemen tation of zamindari practices etc. The basic aim of British administration in India was to transform Indian subcontinent as a consumer market for British furnished goods, Technological up gradation and development of infrastructure as well as social infrastructure were negligible. During the independence Indian economy had almost all the features of an underdeveloped economy. In the last fifty years of self-rule, a lot of policy initiative has been taken up by the government of India to upgrade the economic base of the country. Still Indian economy is gripped by poverty, population explosion, backwardness both in agriculture and industry, low grade technological development, high unemployment and wide difference between the high and low income levels. Now in India incidence of poverty is coexisting with sophisticated nuclear technology. The policy measures taken within the last five decades metamorphosed Indian economy to break the stagnant per capita income to achieve self sufficiency in food grain production. Indian economy is a unique blend of public and private sector otherwise known as a mixed economy. It is also a dualistic economy both modern industry and traditional agricultural activities exist side by side. The mandatory economic rights which the Constitution promises are (i) equality of opportunity unemployment or appointment to any office irrespective of race, caste and sex, (ii) all the citizens of India shall have property or carry on any occupation, trade or business, (iii) right to acquire private property by the state with compensation paid under the procedure established by law, iv) ban on begging, child labour and trafficking of human beings. The federal economic structure of India includes the central government and the state government within a unitary system. Demarcations of responsibilities are divided between the central and state governments. However, the residuary power is vested with the central government. Besides finance commission, other economic commissions are set up by the central government time to time to look after the parity of resources distribution among the states. Annual budgets (both general and railway) and five year plans aye the backbone of India’s economic policy initiatives. Indian Economy since Independence-After India’s independence long spell of stagnation was broken with the introduction of economic planning. Since 1950s net national product at factor cost had arisen from Rs. 40,454 crore to 11,224 crores in 1999-2000. The growth of national income was 3. 8 percent. India’s per capita income has been running since 1950-51. India’s per capita income at current price was Rs. 160, 47. Apart from the growth in quantitative terms, there have been significant changes in India’s economic structure since independence. During the second plan priority was acceded to capital intensive manufacturing units. These industries now account for more than fifty percent of the industrialproduction. The transport system in India over the past four decades has grown both in terms of capacity and modernization. Then road network is one of the largest in the world as a result of spectacular development of roads under various lanes. The total road length comprising national high ways state high ways and other road accounted for 24. 66 lakhs km in 1996-97 progress of shipping, railways and civil aviation has equally been impressive. Though the country is presently facing an energy crisis but this sector has also gained much in termsof production. Similarly irrigation facilities in the country have increased raising irrigated area. Since independence significant reformation has taken place in the banking and financial sector ofIndia. The process of nationalization was initiated after independence. First the Reserve Bank was nationalized in 1949, thereafter in 1995 the Imperial Bank of India, a leading commercial bank of that time, was nationalized and renamed the State Bank of India. In 1969 fourteen big commercial banks were nationalized. This act of government undermined thecontrol of big capitalists on the finance capital. From the above argument we can conclude that the Indian economy is no longer caught in low levelequilibrium trap.