Cystic Fibrosis: Molecular Mechanisms and Diagnosis

Cystic Fibrosis: Molecular Mechanisms and Diagnosis Cystic fibrosis is a membrane transport disorder which is commonly affected in the autosomal recessive disease of white populations. It is also identified at birth by a certain condition called meconium ileus which means intestinal obstruction. In the advance stages, clinically it has been diagnosed by sticky viscous secretion of the pancreas and lungs (Gelehrter, 1998). Many years of direct research has failed to recognise the specific gene which is involved in cystic fibrosis (CF), although there are some various indirect research done which has indicated that there appeared an abnormality in the transport of ions during the process of cell membrane development. A very common diagnosis has been used to recognise this disease which is high increase of chloride content in sweat. Children suffering from this disorder develop pancreatic insufficiency which is usually treated with enzyme supplementation, antibiotics and physical treatments which are used to reduce the chest infection. Earlier the survival average is about 25 years. (Gelehrter, 1990). But in a recent study, it has been said that the life expectancy for cystic fibrosis patients has increased over the last 40 years. It has been necessary to identify the respiratory viruses in Cf to make the clinical decision to proceed with the necessary treatment. (cited in Wat, 2008). It is said that one can calculate approximately the frequency of heterozygous carriers would be about 1 in 25 individuals. There are various research works done on cultured cells and animal models to further study on the basic defects of the disease and find a successive treatment. (Hodson, M.E., 1995). HISTORY: From centuries the study and research of Cystic fibrosis has been done. Earlier people started diagnosing this condition in the newborns due to the salty taste in their skin. The survival rate was so low as six months. But as years followed, during the 1930s, a scientist named Guido fanconi had described the symstoms as gastrointestinal symdrone but latter named it as cystic fibrosis. The research had advanced when the cystic fibrosis gene was discovered following the study of mendels law researched by Gregor Mendel. The genetic knowledge on this particular disease was made more improving which indirectly improved the survival ascepts of CF patients. By 1980s, a deeper understanding of human genetics were developed. In 1989, two researchers had isolated the damaged gene in causing CF which was the main cause in affecting the chloride channel function. These were the channels which were helping in the movement of water and salt in the cell walls. Further study on this is making it pos sible to understand and find a treatment for this genetic disease. In recent years, various study via Gene theraphy has been helping various researches to fix the damaged gene. If this particular gene is fixed, the possible prevention, treatment and cure of CF would become a (Giddings,2009) Basic molecular genetics of Cf: In the year 1985, several groups were experimenting on gene therapy by linkage analysis, a linkage was observed on the chromosome 7, which in turn proceeded with testing some of the markers on chromosome 7 where they found CF gene near to these markers (met and J3.11). Techniques like physical mapping showed that the distance between these markers was approximately 1.6 million bp, which is as large for approximately 50 genes. Various interesting research were made in which it was found that a vast majority of chromosomes carrying the Cystic fibrosis mutation were also carrying a particular alleles for XV-2c and KM-19 which was further named as allele for XV-2c and + allele for KM-19. This type of hapotype (-/+) showed approximately in 25% of normal chromosomes, whereas rest showed other different patterns. A term was defined for this type of disease gene associated with a allele with the nearby markers, which was named as Linkage Disequilibrim. This term was made used to understand that these CF mutated genes were being descended from a common ancester. (Gelehrter, 1998) In a recent research, a genetic analysis was conducted by carefully cloning of a 500,000 bp candidate which resulted in three possible genes from the specific region which was studied. In testing under northern blotting technique it was found that this specific gene was coding for a 1480- amino acid protein including 26 exons with a length of 250,000 bp of DNA and the mRNA transcript was found to be 6129 bp long. In further studying a cloned and sequenced cDNA was prepared using the sweat glands of a Cf patient, it was found that there was a difference in exon 10 from a normal sequenced gene. There was a deletion in the 3 -bp found which might have caused the deletion of a single amino acid (phenylalanine) at the specificresidue 508. (Gelehrter, 1990). This type of mutation is known as Delta F508 or F508. Patients with homologous delta F508 mutation will tend to suffer with severe symptons of this disease, causing a very heavy loss of chloride ion transport.This causes an improper balance in the sodium and chloride ion ratio, eventually secreting a thin, mucus secretion in the lung area which traps bacteria, this causes severe lung infection, resulting a high mortality rate in CF patients. CFTR gene: This gene was initially cloned in 1989 in which it was mapped to human chromosome 7q21, with more interest in this particular region, researches were able to indentify 2 more closely linked markers other than (labelled MET and D758) which were D75122 and D75340, those were 10 kb part. Using lambda genomic DNA libraries, 280 kb of DNA were sequenced which were used to make long range restriction maps. These were also probed with cDNA clones to isolate a total of 500 kb. This can be seen in the figure By using various approaches like screening zoo blots, northern blots and cDNA libraries the genomic DNA clone was isolated. Four different regions were isolated, out of that, only one proved to be CF gene which was 6.5 kb sequence in length. Eventually, it was concluded that the CF gene controls the CFTR (cystic fibrosis transmembrane regulator) which encodes chloride channels which were responsible for the water transport on the plasma membrane of the epithelial cells which were connected to the lung airways. This mutation was causing the problem. Structure of the CFTR gene: After sequencing the CFTR gene, further study was done on it. The sequenced coding region of this gene showed a polypeptide molecular mass of 168138 daltons. The best site seen in this predicted protein was that it showed two repeated motifs, which showed some similarities to the nucleotide-binding domains (NBD) which is present in the membrane bounded protein. These membrane consisted in them six hydrophobic regions which composed 234 amino acids. Hydrophilic domains: These 2 hydrophilic domains contains approximately 150 amino acids in which some phenylalanine residue has been deleted at the region of the first NBD which shares similar homologies with the proteins which binds with the nucleotide. These two motifs are connected by a highly charged cytoplasmic domains referred as R- domain or regulatory domains. This domains encodes 13 exons that help in the phosphorylationby protein kinase K and rest helps in binding sites by protein kinase C. These domains and nucleotide binding folds in the binding sites suggest that hydrolysis is involved in the transportation of CFTR gene. CFTR Promoter: It was found out that CFTR gene had a addition promoter region with a size of 3.5 kb, later on, it led that these promoters showed the characteristics of housekeeping gene along with tissue specific functions. There were five reasons that were focused to show that the CFTR gene had these charactertics which were as follows: There were no TATA box element within the first 500 basepairs of the transcription sites. The GC content in the promoter region was high. There were addition multiple minor transcription sites identified along with the major transcription sites. Couple of SP1 sites were also identified. There was a very low expression of the CFTR gene found in the epithelium layer. Another conclusion was made that the CFTR gene might control transcription regulation. (prin mg, tho) Phenotypic function of the diseased gene: To understand the phenotype of the disease, it has been confirmed that an individual suffering must have two copies of a mutated Cystic fibrosis transmembrane conductance regulator (CFTR) gene to be expressed. It has also been understood that the development of this disease in different individuals varies due to differential influence by environmental and genetic factors. This various different forms of other genes can affect the phenotypes of the mutated gene of this disease.   MUTATED GENE: As it been understood that the most common mutated gene found in most cystic fibrosis defective gene is the delta F508. A detailed study about this gene was done in which it was found that CFTR protein helps in encoding single amino acid at position 508 on the chromosome 7. As this mutation affects the CFTR to perform its work in the cell and prevents it from locating itself in the cell membrane. Usually it is seen that, a newly synthesized CFTR protein adds itself to the missing chemical group by folding itself into appropriate shape which are escorted by their specific molecular chaperons to the surface of the cell. Because of the presence of this mutated CFTR gene, the imperfect CFTR binds onto the cell membrane which has a defect while opening and closing during regulating the chloride ion flow within the cell membrane. There are different mutated genes, in which some do not this synthesis or any modification or integratation into the membrane of the cell. Sometimes, these mutated genes fail to even respond to the signals within the cell that are responsible for the opening and closing of chloride flow. In some cases, the CFTR protein enters the cell membrane and also responds to the cell membrane but there would show a problem when the channel opens and there is improper flow of chloride ion out of the cell. Different mutations vary with different patients, patients with absent or very low CFTR protein in its cell membrane would cause severe disease causing depleting pancreatic functions. There are patients which have delta F508 mutation on both CFTR gene copies, this causes very poor pancreatic function which would secret high amount of mucus causing varying degrees of infection in the lungs. Another CFTR mutation namely R117H also develops a partial functioning CFTR protein, this mutation pairs w ith the severe mutated gene delta F508 causing the CF disease severe but varying in lung disease. It has been seen that some men who have been detected with this particular mutated gene R117H shows only one symptom of CF that is being Infertile which is due to lack of vas deferens. Inheritence of the CF gene: Diagnosing cystic fibrosis In most cases, cystic fibrosis is diagnosed by screening tests, which are carried out very early in life. However, some babies, children and even young adults have some unexplained illness in future so they are diagnosed later. There are four main ways of diagnosing cystic fibrosis: newborn testing antenatal testing carrier testing sweat testing Newborn Screening: In newborn screening there are two tests the first one is blood test in which small amount of blood is taken from the babys heel and transferred onto the card and it is examined in the laboratory for CF and it is also test inherited conditions, such as sickle cell anaemia and phenylketonuria.. Another test is genetic test in which saliva sample taken from the cheek and check whether a newborn has faulty CFTR genes. Antenatal testing: This test is done during the womens pregnancy to know that fatus has CF or not. There are following Amniocentesis: in it inserts a needle through abdominal wall into the uterus and take amniotic fluid surrounds the baby and tested in the laboratory Chorionic villus sampling: In it needle passed through the stomach into the womb sometimes a fine tube passed through the vagina into the neck of the uterus as an alternative. And take chorionic tissue which is a tiny piece of the developing placenta and these chromosomes which are in the cells of the tissue are examined in the laboratory for CFTR genes are normal or not. Both tests have risk of complication and also chance for miscarriage so it is offered only those mothers who have high risk of having child with the CF. Carrier testing: People who have two CFTR genes one is normal and another is faulty are CF carriers. So carriers pass faulty CFTR genes on to their children. This is simple test which is uses mouthwash to make sure that person is a carrier of cystic fibrosis. Swishing the mouthwash to collect the cells. And these containing cells are checked for the faulty gene. Sweat test: If blood and genetic tests have positive sign for CF so for confirmation sweat test diagnosis using This test measure the amount of salt in sweat. For that in one treatment room small area of skin on an arm or leg tested. Rub this skin with sweat producing chemical and then produce gentle electrical current with help of electrode it gives warm feeling .collect sweat on a pad or paper for analze. High levels of salt confirm diagnosis of CF. (180,205) Immunoreactive Trypsinogn: This analysis is used after sweat test if little sweat measured in newborns. Blood samples are taken after 2-3 days of birth and examined for immunoreactive trypsinogen (IRT) which is the increased levels of pancreatic enzyme. If IRT level is high then also it is not strong indicator of CF. Because infants with intestinal malformations and condition as bowel obstruction also have high level of enzyme which is for function of impair pancreatic. Lung X-rays and function tests: In the tests measure the amount of air the lungs can hold and how fast a person can breathe out to show how lungs add oxygen and remove carbon dioxide from the blood with the help of chest X-ray which show lung scarring from recurrent inflammation.This test do not confirm a diagnosis of CF but help in evaluating the severity of an individuals lung damage. Sinus X-ray: This test give signs of sinusitis, which indicates an infection and inflammation of nasal cavities. The X-ray shows the underlying cause becomes important for sinusitis. By cause of sinusitis is showing allergies and poorly functioning immune system. DNA mutation analysis: For highly specific result we used this technique for CF to look for the presence of many mutations in the CFTR gene. In it DNA isolated and purified from the blood sample or from a smear inside the cheek and for detect disease genes and indentify mutation within a specific DNA sequenced used micro array technology Sputum cultures: For this test, take a sample of your sputum (spit) to see what bacteria are growing in it. If there are bacteria called mucoid Pseudomonas, then it is advanced CF that needs aggressive treatment. (Giddings, 2009) TREATMENT In early years, there were no proper complete cure for cystic fibrosis . This has changed in recent years due to various researches done to treat CF which have been improved drastically. The aim for the treatment of cystic fibrosis are to Prevent infection in lungs,Remove the thick and sticky mucus from lungs, Prevent blockages in intestines and to Provide adequate nutrition.(http://www.nhlbi.nihHYPERLINK http://www.nhlbi.nih.gov/.gov/) Treatment for lung problems: It is essential to begin the treatment by reducing the infection and removing the thick and sticky mucus from the lungs. This can be done by performing the following lung treatment methods. CHEST PHYSICAL THERAPHY (CPT): This theraphy is also called percussion. CPT include pounding the chest and back over and over with the hands and a device that reduce the mucus layer from the lungs. Breathing techniques are also helpful to remove mucus from lungs. This techniques involve forcing out of some short or deeper breaths and following with a relaxed breath. The major purpose of this therapy for CF is to increase clearance of mucus and control infection in the lung and also to provide adequate nutrition and prevent intestinal blockage. MEDICINES: This is the primary treatment for the cystic fibrosis. Using medicines it helps in treating lung infection, decreases the swelling ,reduces the mucus and also opens the airways. The following types are the antibiotics used for cystic fibrosis treatment: Oral antibiotics are use to treat the lung infection. Inhaled antibiotics are used to control the infection caused by the pseudomonas bacteria. Intravenous medicines are used for control the severe infection. Anti-inflammatory medicines used to reduce swelling in airways. Drugs or steroids such as azithromycin, ibuprofen, prednisone and pentoxifylline are used to reduce inflammation. For the treatment of bacterial infection various lung antibiotics such as nebcin, tobrex, ciprofloxin, myambutol, biaxin, azactam are used Exercise: Aerobic exercise can help to reduce and clear the mucus from the airways. Regular exercise also enables to cut back on the CPT. Intracytoplasmic sperm injection is used to provide fertility for men with cystic fibrosis LUNG TRANSPLANTATION: Lung transplantion is a effective therapeutic option for the cystic-fibrosis patient. The successfully lung transplanted patients are able to control diabetic problems easily as the patients exercise capacity improves and the respiratory infection reduces.(Madden, 1992). In lung transplant ,the infected lung is replaced with a healthy lung by surgery. If CF is very advanced then lung transplantion is a good option. It is a major operation and sometimes also leads to some serious complications Oxygen Therapy: If oxygen level is very low in the blood then oxygen therapy is very effective(http://cystic-fibrosis.emedtv.com). NUTRITIONAL TREATMENT: C.F causes many digestive problems such as slow growth, pain, intestinal gas and severe. Nutritional treatment can improve the growth, development and strength of patient. It involves a balanced diet with low fat and high protein which make strong the patient to resist aganist some infection (http://www.healthscout.com). It contain pancreatic enzymes to digest protein and fat and absorbance of various vitamins. Nutriational therapy also contain supplements of different vitamins. The other treatment for digestive problems is medications for the treatment of intestinal blockages (http://www.nhlbi.nih.gov/). GENE THERAPY: Gene therapy involve transfer of DNA for therapeutic purpose. For the treatment of cystic fibrosis two approaches have been used. In the first approach, adenovirus was used as a vector, it has the epithelial cell lining. In this approach, adenovirus type-2 late promoter drives the CFTR gene. In the second approach, positively charged liposomes was used which can bind negatively charged DNA on its surface. These initial experiments have been used to change the electrical conductance of the nasal membrane. By these approaches a little correction of conductance abnormalities is possible. In the recent studies aerosol inhalers is used to saturate the upper part of the respiratory system. The reversal of the path physiology is possible if the correct form of CFTR gene is expressed. At present, retroviral-mediated gene transfer system is used for gene transfer for gene therapy of CF. Adenovirus is a suitable vector for gene transfer to the airway because it uses humans as a permissive host and it has a natural tropism for the lung .Liposome-mediated DNA transfer system is also used for gene transfer in gene therapy. Liposome is positively charged interact with DNA which is negatively charged and form lipid-coated DNA complex Different positively charged liposomes used to transfer the CFTR including DOTAP, DMRIE and DOTMA-DOPE. Several new treatments are developed to treat the CF. In one case, the sodium-channel inhibitor amiloride is insert to the airways of the patients which inhibit sodium absorption. The other possible approach is to allow to bypass the CFTR chloride channel and regulate other chloride channel present in the membrane of airways. The most effective way to treat the CF is to insert a new and normal copy of CFTR gene into the airway of respiratory tract of CF patients. RECENT ADVANCES: In recent years, various research works have improved the way to diagnose and treat cystic fibrosis. In the year 2006, it was published in the Science daily that certain scientists from Stanford University, USA were able to find out the basic defect causing CF. In which they had concluded that the airway blockage caused in CF was not caused due excessive fluid being reabsorbed within the glands but due to lack of fluid secretion from cystic fibrosis glands. (http://www.sciencedaily.com/releases/2006/03/060318232035.htm) In another research work done in the year 2008, certain scientist from USA were able to discover that a particular protein called CFTR were either missing or not present in the lungs of the CF patients which helps in fighting various bacteria like Pseudomonas aeruginosa when inhaled. Further studies are conducted to find the treatment through these proteins. (http://www.sciencedaily.com/releases/2008/09/080910210525.htm). In 2010, A team led by Professor Justin Hanes from John Hopkins university had researched on a mucus penetrating biodegradable nanoparticles which would help in delivery wide range of therapeutic molecules from small to various size of macromolecules to reduce the infection of lungs of the CF patients. In another research study done this year 2010, a team of researches were able to find out that a certain calcium- activated chloride channel were able to enable CF mucous cells to secrete normally which is required in the CFTR channel. So, it was concluded that drugs should be produces to enchance the ability of the calcium response which helps in activating the calcium activated chloride channels which are secreted in the CF cells. (http://www.sciencedaily.com/releases/2010/09/100917151848.htm)

The Yellow Wallpaper by Charlotte Perkins Gilman :: The Yellow Wallpaper Essays

The Yellow Wall Paper: Profound I believe that American Literature is very profound to understand it. It has a lot of meaning that can help us see our American society in a different way or help us understand it better. Everything in American literature is express through words, not images. However, Literature most of the time open our mind to visualized what is being said. In "the Yellow Wall Paper" story, I believe the author is expressing herself through words as if she is describing an abstract painting. I believe this story is not literal. I believe this story is composed as an abstract painting that is full of meaning. Ralph Waldo Emerson was a strong influential on the lives of many writers during the time this story was written. "Emerson's emphasis on individuality, nonconformity, and resistance to traditional authority defines a national identity for Americans still seeking independence from English influence;"(NIck Evans). Now, I believe that Gilman was very much influence by what Emer son said in his lectures during this time. The purpose of this paper is to show how Gilman had a respond to what emerson said through my interpretation of Charlotte Perkins Gilman story. Now, the overall body of this paper is first,I will give many paragraphs with a particular point on each one of them together with my interpretation of each one. My Point is that each paragraph will be adding up to the final Paragraph which will give my final interpretation of the story. In the conclusion, I will restate my interpretation together with some historical facts and emersons ideas that will correspond to my interpretation of Gilman. My goal of this paper is to show how Gilman is using the story like an abstract painting to open the eyes of women to be nonconformists in society and at home. First of all, John and his wife arrived to live in a big house for a short time together with John sister. In this house there is a room with a yellow wall paper. Before they arrive this room was use as a nursery, playroom and gymnasium. I believe this three different functions gives us a summary of the experiences of John's wife in this room. She arrive here to have a "total rest cure" for her depression. What is the significance of the room being a nursery? The Yellow Wallpaper by Charlotte Perkins Gilman :: The Yellow Wallpaper Essays The Yellow Wall Paper: Profound I believe that American Literature is very profound to understand it. It has a lot of meaning that can help us see our American society in a different way or help us understand it better. Everything in American literature is express through words, not images. However, Literature most of the time open our mind to visualized what is being said. In "the Yellow Wall Paper" story, I believe the author is expressing herself through words as if she is describing an abstract painting. I believe this story is not literal. I believe this story is composed as an abstract painting that is full of meaning. Ralph Waldo Emerson was a strong influential on the lives of many writers during the time this story was written. "Emerson's emphasis on individuality, nonconformity, and resistance to traditional authority defines a national identity for Americans still seeking independence from English influence;"(NIck Evans). Now, I believe that Gilman was very much influence by what Emer son said in his lectures during this time. The purpose of this paper is to show how Gilman had a respond to what emerson said through my interpretation of Charlotte Perkins Gilman story. Now, the overall body of this paper is first,I will give many paragraphs with a particular point on each one of them together with my interpretation of each one. My Point is that each paragraph will be adding up to the final Paragraph which will give my final interpretation of the story. In the conclusion, I will restate my interpretation together with some historical facts and emersons ideas that will correspond to my interpretation of Gilman. My goal of this paper is to show how Gilman is using the story like an abstract painting to open the eyes of women to be nonconformists in society and at home. First of all, John and his wife arrived to live in a big house for a short time together with John sister. In this house there is a room with a yellow wall paper. Before they arrive this room was use as a nursery, playroom and gymnasium. I believe this three different functions gives us a summary of the experiences of John's wife in this room. She arrive here to have a "total rest cure" for her depression. What is the significance of the room being a nursery?

What advantage does Zara gain against the competition by having a very responsive supply chain?

Q. What advantage does Zara gain against the competition by having a very responsive supply chain? A. In an industry where the customer demand is unpredictable, Zara having a responsive supply chain has enabled it to enjoy greater customer turnover due to its 5 to 6 weeks cycle time leading to more profits as mostly the products are then sold at full price. Moreover being responsive has also enabled Zara to reduce its inventories and also the forecast error. Q. Why has Inditex chosen to have both in-house manufacturing and outsourced manufacturing? Why has Inditex maintained manufacturing capacity in Europe even though manufacturing in Asia is much cheaper? A. To be responsive in the rapid changing world, Inditex opted for both outsourced manufacturing, for the production of products with predictable demand, and in-house manufacturing, for the production of products with highly uncertain demand. Inditex has maintained large fraction of manufacturing capacity in Portugal and Spain (Europe) despite the higher cost there because this allows Zara to respond quickly to changing fashion trends in Europe. Q. Why does Zara source products with uncertain demand from local manufacturers and products with predictable demand from Asian manufacturers? A. Zara’s main competitive advantage is responsiveness and to retain it Zara source products with uncertain demand from local manufacturers because local manufacturers offer fast and flexible sourcing and such products are to be delivered quick instead of at low-cost (with greater lead time as it is manufactured in Asia). Whereas products with predictable demand are sourced from Asian manufacturers because outsourcing is cheaper that is products are manufactured at a low-cost. Q. Why is Zara building a new distribution centre as its sales grow? Is it better to have the new distribution centre near the existing one or at a completely different location? A. New distribution centre (DC) is being built by Zara in response to the increase in sales because the stock turnover is increasing and in order to cater the growth of sales and avoid any declination in it due to mismanagement of stock availability and customers’ demand. Q. What advantage does Zara gain from replenishing its stores twice a week compared to a less frequent schedule? How does the frequency of replenishment affect the design of its distribution system? A. Frequent replenishment allows Zara to match supply and demand more effectively than the competitors. The frequency of replenishment affect the design of its distribution system in a way that the more frequent the replenishment will take place, the more responsive and up to date the distribution system will be while on the other hand delayed replenishment will also make the distribution system delayed and slow with respect to customer’s demand. Q. What information infrastructure does Zara need in order to operate its production, distribution, and retail network effectively? A. In order to operate the production, distribution and retail network effectively, Zara should have an information infrastructure which is highly responsive and provides timely and accurate information that helps in better decision making as well as planning and forecasting. TOYOTA: A GLOBAL AUTO MANUFACTURER Q. Where s hould the plants be located and what degree of flexibility should be built into each? What capacity should each plant have? A. The location of the plants should be such that it complements the assembly plants and maximum profitability of Toyota. Plants operating locally can be cost prohibitive, while plants that operate globally can only reduce the interest in local markets. Logically, Toyota should apply the â€Å"global complementation† strategy to turn plants, and locate plants in areas that minimize costs (currency exchange, transportation, inventory holding, etc). This will allow them to achieve local/regional agility and remain flexible enough to supply non-local factories/assembly plants however necessary. The capacity of the plant should not exceed the projected demand for local / regional manufacturing sites / assembly plants that each plant will be part of supply. The ability to adequately supply factories is essential, and each plant must be designed with the ability to supply factories in the region. Q. Should plants be able to produce for all markets or only specific contingency markets? A. It depends upon the location and production capacity of each plant. Furthermore, since Toyota follows the strategy of global complementation, plants must be able to supply at least one more market/region than it’s normally responsible for supplying. Depending on the requirements of global parts, it may be appropriate for plants to be able to supply to all markets. But in the case that markets are so differentiated that the ability for a plant to provide global supply is cost prohibitive, then a specific contingency market should be designated for each regional plant. A plant in a certain region should only serve markets in that specific region; otherwise costs will inevitably go up. Q. How should markets be allocated to plants and how frequently should this allocation be revised? A. The allocation of markets to plants should be as efficient as possible. The standard allocation should be optimized during the planning phase. However, as markets mature, currency rates fluctuate, and demand changes, it is possible that an adjusted allocation will provide more efficiency and higher returns for Toyota. For this reason allocation should be adjusted when necessary, reviewed either annually or bi-annually, and optimized to increase efficiency and take advantage of the part plants flexibility. Q. What kind of flexibility should be built into the distribution system? A. The distribution system should closely monitor the flexibility of the global complementation strategy. The regional distribution should be optimized between the factories and supply of parts. However, when adjustments are made to the allocation, it will be necessary for cost-effective distribution to occur between plants and factories to non-local markets. Q. How should this flexible investment be valued? A. The flexible investment should be highly valued as this will lead Toyota to capture the demand and the income of non-local markets where the local cost, demand, etc declines. The flexible production and distribution will prevent idle facilities and reduced profits during economic downturns. And moreover, through the integration of flexible production and distribution, supply chain of Toyota will have greater access to markets and has the potential to capture greater value. Q. What actions may be taken during product design to facilitate this flexibility? A. There should be uniformity between global products which will provide the most cost effective means to facilitate flexibility between local plants and factories. During the product design, engineers must prepare the elements that maximize both the uniformity and meet local needs. This flexibility will help the plants and factories looking for the pieces to produce for non local markets and reducing dependencies and vulnerabilities of operating in specific local markets.

Math Glossary Mathematics Terms and Definitions

This is a glossary of common math terms used in arithmetic, geometry, algebra, and statistics. Abacus:  An early counting tool used for basic arithmetic. Absolute Value:  Always a positive number, refers to the distance of a number from 0, the distances are positive. Acute Angle:  The measure of an angle with a measure between 0 ° and 90 ° or with less than 90 ° radians. Addend:  A number which is involved in addition. Numbers being added are considered to be the addends. Algebra Algorithm Angle Angle Bisector Area Array Attribute Average Base Base 10 Bar Graph BEDMAS or PEDMAS Definition Bell Curve or Normal Distribution Binomial Box and Whisker Plot/Chart:  A graphical representation of data that spots differences in distributions, and plots the ranges of data sets. Calculus:  The branch of mathematics involving derivatives and integrals. The study of motion in which changing values are studied. Capacity:  The amount a container will hold. Centimeter:  A metric unit of measurement concerning length, abbreviated as cm. 2.5 cm is approximately an inch. Circumference:  The complete distance around a circle or a square. Chord:  The segment which joins two points on a circle. Coefficient:  A factor of the term. x is the coefficient in the term x(a b) or 3 is the coefficient in the term 3y. Common Factors:  A factor of two or more numbers. A number that will divide exactly into different numbers. Complementary Angles - The two angles involved when the sum is 90 °. Composite Number:  A composite number has at least one other factor aside from its own. A composite number cannot be a prime number. Cone:  A three dimensional shape with only one vertex, having a circular base. Conic Section:  The section formed by the intersection of a plane and a cone. Constant:  A value that doesnt change. Coordinate:  The ordered pair that states the location on a coordinate plane. Used to describe location and or position. Congruent:  Objects and figures that have the same size and shape. The shapes can be turned into one another with a flip, rotation or turn. Cosine:  The ratio of the length (in a right triangle) of the side adjacent to an acute angle to the length of the hypotenuse Cylinder:  A three -dimensional shape with a parallel circle at each end and connected by a curved surface. Decagon:  A polygon/shape that has ten angles and ten straight lines. Decimal:  A real number on the base ten standard numbering system. Denominator:  The denominator is the bottom number of a fraction—the top number is called the numerator. The denominator is the total number of parts. Degree:  The unit of an angle, angles are measured in degrees shown by the degree symbol:  ° Diagonal:  A line segment that connects two vertices in a polygon. Diameter:  A chord that passes through the center of a circle. Also the length of a line that cuts the shape in half. Difference:  The difference is what is found when one number is subtracted from another. Finding the difference in a number requires the use of subtraction. Digit:  Digits are a characteristic of numerals. 176 is a 3-digit number. Dividend:  The number that is being divided. The number found inside the bracket. Divisor:  The number that is doing the dividing. The number found outside of the division bracket. Edge:  A line that joins a polygon or the line (edge) where two faces meet in a three-dimensional solid. Ellipse:  An ellipse looks like a slightly flattened circle, also known as a plane curve. Planetary orbits take the form of ellipses. End Point:  The point at which a line or a curve ends. Equilateral:  All sides are equal. Equation:  A statement showing the equality of two expressions usually separated by left and right signs and joined by an equals sign. Even Number:  A number that can be divided or is divisible by 2. Event:  Often refers to the outcome of probability. Answers questions like What is the probability the spinner will land on red? Evaluate:  To calculate the numerical value. Exponent:  The number that gives reference to the repeated multiplication required. The exponent of 34 is the 4. Expressions:  Symbols that represent numbers or operations. A way of writing something that uses numbers and symbols. Face:  The face refers to the shape that is bounded by the edges on a 3 dimensional object. Factor:  A number that will divide into another number exactly. The factors of 10 are 1, 2 and 5. Factoring:  The process of breaking numbers down into all of their factors. Factorial Notation:  Often in combinatorics, you will be required to multiply consecutive numbers. The symbol used in factorial notation is ! When you see x!, the factorial of x is needed. Factor Tree:  A graphical representation showing the factors of a specific number. Fibonacci Sequence:  A sequence whereby each number is the sum of the two numbers preceding it. 1, 2, 4, 8, 16, 32 is a Fibonacci sequence. Figure:  Two dimensional shapes are often referred to as figures. Finite:  Not infinite. Finite has an end. Flip:  A reflection of a two dimensional shape, a mirror image of a shape. Formula:  A rule that describes the relationship of two or more variables. An equation stating the rule. Fraction:  A way of writing numbers that are not whole numbers. The fraction one-half is written 1/2. Frequency:  The number of times an event can happen in a specific period of times. Often used in probability. Furlong:  A unit of measurement that is the side length of one square of an acre. One furlong is approximately 1/8 of a mile, 201.17 meters and 220 yards. Geometry:  The study of lines, angles, shapes and their properties. Geometry is concerned with physical shapes and the dimensions of the objects. Graphing Calculator:  A larger screen calculator thats capable of showing/drawing graphs and functions. Graph Theory:  A branch of mathematics focusing on the properties of a variety of graphs. Greatest Common Factor:  The largest number common to each set of factors that divides both numbers exactly. The greatest common factor of 10 and 20 is 10. Hexagon:  A six sided and six angled polygon. Hex means 6. Histogram:  A graph that uses bars where each bar equals a range of values. Hyperbola:  One type of conic section. The hyperbola is the set of all points in a plane. The difference of whose distance from two fixed points in the plane is the positive constant. Hypotenuse:  The longest side of a right angled triangle, and always the side thats opposite of the right angle. Identity:  An equation that is true for values of their variables. Improper Fraction:  A fraction whereby the denominator is equal to or greater than the numerator, such as 6/4. Inequality:  A mathematical equation containing either a greater than, less than or not equal to symbols. Integers:  Whole numbers, positive or negative including zero. Irrational:  A number that cannot be represented as a decimal or as a fraction. A number like pi is irrational because it contains an infinite number of digits that keep repeating; many square roots are irrational numbers. Isoceles:  A polygon having two sides equal in length. Kilometer:  A unit of measure that equals 1000 meters. Knot:  A curve formed by an interlacing piece of string by joining the ends. Like Terms:  Terms with the same variable and the same exponents/degrees. Like Fractions:  Fractions having the same denominator. (Numerator is the top, denominator is the bottom) Line:  A straight infinite path joining an infinite number of points. The path can be infinite in both directions. Line Segment:  A straight path that has a beginning and an end, known as endpoints. Linear Equation:  An equation whereby letters represent real numbers and whose graph is a line. Line of Symmetry:  A line that divides a figure or shape into two parts. The two shape must equal one another. Logic:  Sound reasoning and the formal laws of reasoning. Logarithm:  A power to which a base, [actually 10] must be raised to produce a given number. If nx a, the logarithm of a, with n as the base, is x. Mean:  The mean is the same as the average. Add up the series of numbers and divide the sum by the number of values. Median:  The Median is the middle value in your list or series of numbers. When the totals of the list are odd, the median is the middle entry in the list after sorting the list into increasing order. When the totals of the list are even, the median is equal to the sum of the two middle (after sorting the list into increasing order) numbers divided by two. Midpoint:  A point that is exactly half way between two set points. Mixed Numbers:  Mixed numbers refer to whole numbers with fractions or decimals. Example 3 1/2 or 3.5. Mode:  The mode in a list of numbers refers to the list of numbers that occur most frequently. A trick to remember this one is to remember that mode starts with the same first two letters that most does. Most frequently Mode. Modular Arithmetic:  a system of arithmetic for integers, where numbers wrap around upon reaching a certain value of the modulus. Monomial:  An algebraic expression consisting of a single term. Multiple:  The multiple of a number is the product of the number and any other whole number. (2,4,6,8 are multiples of 2) Multiplication:  Often referred to as fast adding. Multiplication is the repeated addition of the same number 4x3 is the same as saying 3333. Multiplicand:  A quantity multiplied by another. A product is obtained by multiplying two or more multiplicands. Natural Numbers:  Regular counting numbers. Negative Number:  A number less than zero. For instance  - a decimal .10 Net:  Often referred to in elementary school math. A flattened 3-dimensional shape that can be turned into a 3-D object with glue/tape and folding. Nth Root:  The nth root of a number is the number needed to multiply by itself n times in order to get that number. For instance: the 4th root of 3 is 81 because 3 X 3 X 3 X 3 81. Norm:  The mean or the average, or an established pattern or form. Numerator:  The top number in a fraction. In 1/2, 1 is the numerator and 2 is the denominator. The numerator is the portion of the denominator. Number Line:  A line in which points all correspond to numbers. Numeral:  A written symbol referring to a number. Obtuse Angle:  An angle having a measure greater than 90 ° and up to 180 °. Obtuse Triangle:  A triangle with at least one obtuse angle as described above. Octagon:  A polygon with 8 sides. Odds:  The ratio/likelihood of an event in probability happening. The odds of flipping a coin and having it land on heads has a 1/2 chance. Odd Number:  A whole number that is not divisible by 2. Operation:  Refers to either addition, subtraction, multiplication or division which are called the four operations in mathematics or arithmetic. Ordinal:  Ordinal numbers refer to the position: first, second, third etc. Order of Operations:  A set of rules used to solve mathematical problems. BEDMAS is often the acronym used to remember the order of operations. BEDMAS stands for brackets, exponents, division, multiplication, addition and subtraction. Outcome:  Used usually in probability to refer to the outcome of an event. Parallelogram:  A quadrilateral that has both sets of opposite sides that are parallel. Parabola:  A type of curve, any point of which is equally distant from a fixed point, called the focus, and a fixed straight line, called the directrix. Pentagon:  A five-sided polygon. Regular pentagons have five equal sides and five equal angles. Percent:  A ratio or fraction in which the second term on denominator is always 100. Perimeter:  The total distance around the outside of a polygon. The total distance around is obtained by adding together the units of measure from each side. Perpendicular:  When two lines or line segments intersect and form right angles. Pi:  The symbol for Pi is actually a greek letter (Ï€). Pi is used to represent the ratio of a circumference of a circle to its diameter. Plane:  When a set of points joined together form a flat surface, the plan can extend without end in all directions. Polynomial:  An algebraic term. The sum of two or more monomials. Polynomials include variables and always have one or more terms. Polygon:  Line segments joined together to form a closed figure. Rectangles, squares, pentagons are all examples of polygons. Prime Numbers:  Prime numbers are integers that are greater than 1 and are only divisible by themselves and 1. Probability:  The likelihood of an event happening. Product:  The sum obtained when any two or more numbers are multiplied together. Proper Fraction:  A fraction where the denominator is greater than the numerator. Protractor:  A semi-circle device used for measuring angles. The edge is subdivided into degrees. Quadrant:  One quarter (qua) of the plane on the Cartesian coordinate system. The plane is divided into 4 sections, each section is called a quadrant. Quadratic Equation:  An equation that can be written with one side equal to 0. Asks you to find the quadratic polynomial that is equal to zero. Quadrilateral:  A four (quad) sided polygon/shape. Quadruple:  To multiply or to be multiplied by 4. Qualitative:  A general description of properties that cannot be written in numbers. Quartic:  A polynomial having a degree of 4. Quintic:  A polynomial having a degree of 5. Quotient:  The solution to a division problem. Radius:  A line segment from the center of a circle to any point on the circle. Or the line from the center of a sphere to any point on the outside edge of the sphere. The radius is the distance from the center of a circle/sphere to the outside edge. Ratio:  The relation between to quantities. Ratios can be expressed in words, fractions, decimals or percents. E.g., the ratio given when a team wins 4 out of 6 games can be said a 4:6 or four out of six or 4/6. Ray:  A straight line with one endpoint. The line extends infinitely. Range:  The difference between the maximum and the minimum in a set of data. Rectangle:  A parallelogram which has four right angles. Repeating Decimal:  A decimal with endlessly repeating digits. E.g., 88 divided by 33 will give a 2.6666666666666 Reflection:  A mirror image of a shape or an object. Obtained from flipping the image/object. Remainder:  The number that is left over when the number cannot be divided evenly into the number. Right Angle:  An angle that is 90 °. Right Triangle:  A triangle having one angle equal to 90 °. Rhombus:  A parallelogram with four equal sides, sides are all the same length. Scalene Triangle:  A triangle with three unequal sides. Sector:  An area between an arc and two radii of a circle. Sometimes referred to as a wedge. Slope:  The slope shows the steepness or incline of a line, determined from two points on the line. Square Root:  To square a number, you multiply it by itself. The square root of a number is the value of the number when multiplied by itself, gives you the original number. For instance 12 squared is 144, the square root of 144 is 12. Stem and Leaf:  A graphic organizer to organize and compare data. Similar to a histogram, organizes intervals or groups of data. Subtraction:  The operation of finding the difference between two numbers or quantities. A process of taking away. Supplementary Angles:  Two angles are supplementary if their sum totals 180 °. Symmetry:  Two halves which match perfectly. Tangent:  When an angle in a right angle is X, the tangent of x is the ratio of lengths of the side opposite x to the side adjacent to x. Term:  A part of an algebraic equation or a number in a sequence or a series or a product of real numbers and/or variables. Tessellation:  Congruent plane figures/shapes that cover a plane completely without overlapping. Translation:  A term used in geometry. Often called a slide. The figure or shape is moved from each point of the figure/shape in the same direction and distance. Transversal:  A line that crosses/intersects two or more lines. Trapezoid:  A quadrilateral with exactly two parallel sides. Tree Diagram:  Used in probability to show all of the possible outcomes or combinations of an event. Triangle:  Three sided polygon. Trinomial:  An algebraic equation with three terms, a specific type of polynomial. Unit:  A standard quantity used in measurement. An inch is a unit of length, a centimeter is a unit of length a pound is a unit of weight. Uniform:  All the same. Having the same in size, texture, color, design etc. Variable:  When a letter is used to represent a number or number in equations and or expressions. E.g., in 3x y, both y and x are the variables. Venn Diagram:  A Venn diagram is often two circles (can be other shapes) that overlap. The overlapping part usually contains information that is pertinent to the labels on both sides of the Venn diagram. For instance: one circle could be labeled Odd Numbers, the other circle could be labeled Two Digit Numbers the overlapping portion must contain numbers that are odd and have two digits. Thus, the overlapping portions shows the relationship between the sets. (Can be more than 2 circles.) Volume:  A unit of measure. The amount of cubic units that occupy a space. A measurement of capacity or volume. Vertex:  A point of intersection where two (or more) rays meet, often called the corner. Wherever sides or edges meet on polygons or shapes. The point of a cone, the corners of cubes or squares. Weight:  A measure of how heavy something is. Whole Number:  A whole number doesnt contain a fraction. A whole number is a positive integer which has 1 or more units and can be positive or negative. X-Axis:  The horizontal axis in a coordinate plane. X-Intercept:  The value of X when the line or curve intersects or crosses the x axis. X:  The roman numeral for 10. x:  A symbol most often used to represent an unknown quantity in an equation. Y-Axis:  The vertical axis in a coordinate plane. Y-Intercept:  The value of y when the line or curve intersects or crosses the y axis. Yard:  A unit of measure. A yard is approximately 91.5 cm. A yard is also 3 feet.