Organizational Design, Growth and Challenges Research Paper

Organizational Design, Growth and Challenges - Research Paper Example This is an acronym used to depict the Strengths, Weaknesses, Opportunities and Threats of an organization. The four components are separate yet integrated; in this regard, the best way to carry out SWOT analysis entails identifying the strengths and weaknesses of any organization prior to tackling the opportunities and strengths. This paper analyses the strengths, weaknesses, opportunities and threats of Wal-Mart Stores. Wal-Mart Stores Inc. is a renowned American multinational retailer corporation operating chains of large discount warehouse and departmental stores. It is currently the biggest private employer in the world with slightly over 2 Million employees. Wal-Mart was founded in 1962 by Sam Walton. It was incorporated in 1969 and began to publicly trade in the New York Stock Exchange in 1972. Wal-Mart’s headquarters is based in Bentonville, Arkansas, USA. It has eminently expanded over the years. Currently, Wal-Mart runs 8,416 stores located in 15 different countries. With the view of understanding the entire environment of Wal-Mart, it is important to critically analyze its strengths, weaknesses, opportunities and threats (Oldham, 1980). As evidenced by its incredible success, Wal-Mart has abundance of strength. For instance, Wal-Mart offers a wide variety of merchandise at very competitive prices. Due to their large purchases they receive exorbitant discounts from their suppliers, which is passed down to the customers. Strength of Wal-Mart is in fact that they manufacture their own brands and supply goods from local suppliers to retailers. Wal-Mart’s large size and high purchasing power is also strength on its own. It has an incredible team of executives who form its leadership. This has equipped Wal-Mart with a management of high caliber. The company spends its resources carefully with the aim of maximizing their margins (Burton, 2012). With regards to weaknesses, Wal-Mart, being a large multinational company, has a large pool of employ ees. Managing all these employees is never an easy task. It, therefore, poses a major challenge to Wal-Mart’s management. Quality of goods sold is another major concern. Owing to its low prices, customers sometimes question the quality of goods. Customer satisfaction is, therefore, not guaranteed. As with opportunities, Wal-Mart has been able to expand into other countries and has formed partnerships with other companies. However, there are still some markets that are yet to be reached by Wal-Mart. Another opportunity is that of taking over some overseas companies, such as ASDA in the United Kingdom. With the escalated trend of internet shopping, Wal-Mart has the opportunity to develop strategies that will enhance home delivery of goods whose orders are placed via the internet. Another opportunity is that of creating convenience stores. This could enable Wal-Mart to overcome local restrictions, as well as travel costs. The most prevalent threat facing Wal-Mart is competition. Local, as well as international competition, has posed a major threat to Wal-Mart. Wal-Mart has been vulnerable to attacks regarding ethical issues as well. In this purview, they have been accused in providing low pay and poor working conditions to its workers. Environmental issues also threaten Wal-Mart’s success. Company/Organization Name: Wal-Mart Stores STRENGTHS WEAKNESSES Large market share Discounts by suppliers Price leader Large variety of

One Hundred Years of Solitude Essay Example | Topics and Well Written Essays - 1250 words

One Hundred Years of Solitude - Essay Example Ideally, Marquez was brought up by her paternal grandparents in Aracataca, Colombia. His childhood tales talks about a big home that are filled with ghouls, discussions in secret code, and relatives who could prophesy their own deaths (Villad 40-50). Through reading this book One Hundred Years of Solitude, one observes many elements of Marquez’s childhood. Conversely, the perspective for the book is Marquez’s own personal reminiscence for childhood, for his grandparents, for a big house overflowing with ghouls and endless laughter. Also, the context of the book is Marquez’s political viewpoint and the brutal realism of growing up in a predominantly turbulent developing country. Colombia has a long and tragic socioeconomic history, in which Marquez acquired knowledge about politics and economics. Intermittent absentmindedness, particularly of the critical happenings that shape Macondo town remains a structural persistent right through the novel, apparent in recurr ence and circularity. This repetitive behavior traits and names of the Buendia offspring; the outwardly endless civil wars; the succeeding refuge of annihilated Aureliano in the bare practice of making little gold fish, melting down and remaking them; the stages of dissatisfaction, lack of accomplishment and tragic death that curses pedigree. This novel appears to be suggesting that the failure to learn from one’s blunders, the lack of historical awareness, becomes the primary curse called upon Macondo’s history and therefore a critical element in the series of dealings surrounding the killing of the banana workers (Browitt 16-33). The chronological burden of wars, economic distress, consecutive ethical failures and political betrayal, ultimately leads to devastation. One Hundred Years of Solitude chronicles historical facts from the inside. Garcia Marquez adeptly avoids the melodramatic style of former socialist realisms by placing the storyline focalization within th e community of Macondo. He ingeniously permits the Colombian bourgeoisie to conceal its profligacy through its own dealings. Garcia Marquez’s technique around classical realists is basically to locate the story-telling height of popular culture, focalizing dealings in the course of their understanding of the townspeople, who through their discerning memory re-live the past. Furthermore, Garcia Marquez does not â€Å"problematise† the language of illustration; his magical realism changes the entity of representation itself, permitting the magical and superstitious world of oral folk mores to stand for itself. This novel makes use of eminent uniqueness of the Latin American modernist tradition (Browitt 16-33). The first thing the reader notices when reading Marquez’s novel is the mere quantity of dealings it covers, therefore making it a daunting task to provide a brief synopsis of the plot. Even though the novel rests on an impossible to read manuscript given to a family by a strange gypsy, there are many tangents and twirls as we realize the events of the Buendia’s in their home town of Macondo. This seemingly makes the novel a tad too difficult to follow, with family disputes, civil war, incestuous relationships and industrialization, tossing the story-line into many numerous directions. The political wars and quarrels in the novel reflect the taut relationship between the liberals and the conservatives throughout Colombian History, where the exertion for

A factor that effect normal speech development Essay

A factor that effect normal speech development - Essay Example At 2 years of age, the child is able to utter 2- word phrases. By 3 years, the child is able to form sentences, uses plurals and past tense, can make sentences with 3 to 5 words and 90% of the talk is understood by strangers. At 4 years of age, the child can make sentences with 6 words, can converse and tell stories. At 5 years of age, the child can make sentences with 6- 8 words, can name 4 colors and can count ten pennies correctly (Schwartz, 1990; qtd. in Leung & Kao, 1999). Delay in the development of speech is a major concern to both parents and pediatricians. Speech delay can occur with or without delay in other milestones. A child is considered to have delay in the development of speech when the speech milestone attained is significantly lower than that which is normal for that age. It is important to identify, investigate and institute appropriate intervention in speech delay because; this can have significant impact on the social, academic, personal and vocational life of th e individual. There are many causes for delayed development of speech. The most common cause of speech delay is mental retardation. Infact, it accounts for more than 50% cases of speech delay (Leung & Kao, 1999). Most often, speech delay occurs due to inadequate stimulation of the child. An older dominating sibling may steal all the attention of the elders of the house. Various hereditary factors can affect speech development. Delayed speech in parents can result in delayed speech in the offspring also. Many genetic diseases which lead to global developmental delay or mental retardation can contribute to delayed speech. Exposure to many languages at a time or frequent changes in the childs environment can contribute to delayed speech. Chronic ear infections, effusions and impacted wax can lead to hearing debility and hence delayed speech. Intact hearing is vital to speech and language development in the first few years of life.

Ethical Decision Reflection Essay Example for Free

Ethical Decision Reflection Essay To let go of someone you dearly love is very painful to do. The pains cause by ending relationship is very unbearable. Some people may find their world tear apart when they realize that their relationship with their partner is not going well. I have had this relationship in the past that truly marks in my heart and in my mind. I do love this person very much despite of his weaknesses and flaws but many people around us do not like the idea of being us together. At first, I try not to give ear to their comments and opinions because of my love for my partner. But in a long run, I decide to call it quits because I find out that my partner is having an affair with other man; take note, it’s a â€Å"man. † It truly hurts me a lot because he exchanges me to a man! It is a big slap my on face. That is the first factor I consider when I break up with him. He is not trustworthy and faithful. I just strongly believe that a woman is meant to be with a man and a man is meant to be with a woman. Though I live in a liberated world but I cannot just take and stand with this kind of idea that is having an affair with same sex. When I break up with him, I feel so much freedom that I never been experiencing when we are still together. I don’t know why I feel that way, but that is how I really feel. I feel like a bird being imprison in a cage for a long time and has the chance to be released. When my friends especially my parents learn about it, they are very happy and relieve. They don’t just like my partner because they can smell something fishy on him. After the break, I feel such joy in my heart and feel more beautiful inside.

Vitamin D Impact on the Liver and Kidney

Vitamin D Impact on the Liver and Kidney Revised vitamin D copy Sources and forms of vitamin D Vitamin D, also termed calciferol, is a fat-soluble secosteroid compound that is an essential regulatory factor for calcium and phosphate metabolism in humans and animals. Its biological functions involve a physiological action in bone formation and mineralization, muscle contraction, nerve signal modulation and transmission as well as many cellular metabolic effects in various organs. There are two forms of vitamin D that are metabolically important; vitamin D2 or ergocalciferol and vitamin D3 or cholecalciferol. The nutritional sources of both forms are limited to certain types of foods that naturally contain vitamin D and therefore it is added to some foods as a supplement. 1.1.1- Exogenous (Diet) Both forms of vitamin D (D2 and D3) are exogenously obtained in low quantities from some types of food in the diet. Vitamin D2 is rare as it is produced from fungal and plant sources such as mushrooms and cereals, as a result of irradiation, by ultraviolet photons, of the plant sterol ergosterol. When these foods are ingested, ergocalciferol is absorbed into the blood. Vitamin D3 , on the other hand, is available in very low amounts from animal sources including oily fish such as salmon and mackerel; other sources include meat, liver, cheese, cod liver oil, eggs and fortified foods such as margarine and milk (Holick, 2006; Engelsen et al., 2005; Nowson et al., 2004). Farmed salmon, for example, contains only 25% of the vitamin D levels present in wild salmon, however, the amount of vitamin D in canned food may affected by modern processing methods (Chen et al., 2007). 1.1.2- Endogenous In humans the principal precursor of vitamin D3 is cholesterol which is obtained from the diet. Cholesterol is initially converted to 7-dehydrocholesterol, provitamin D3, through the action of enzymes termed the mucosal dehydrogenase complex, present in the small intestine. Provitamin D3, is then incorporated within chylomicrons and transported to the skin where temperature dependent photoisomerisation processing of 7-dehydrocholesterol takes place in epidermal cells resulting in the production of D3. Within the epidermal cells, vitamin D3 undergoes photocoversion to its isomers 5,6-transvitamin D3 and suprasterol, a process which relies on the amount of ultraviolet radiation absorbed; inadequate sunlight exposure compromises this process (Holick, 2003; Iqbal, 1994). Sunlight exposure is therefore a crucial element in the regulation and enhancement of endogenous cholecalciferol production (Dusso, et al., 2005; Iqbal, 1994; Reichel, et al., 1989; Smith, 1988). Once photoconversion is completed, cholecalciferol binds to Vitamin D Binding Protein (VDBP) and transported to the liver for further metabolic processing. Vitamin D metabolism Both forms of vitamin D (D2 and D3) undergo similar metabolic activation in the liver and kidney respectively to produce the physiologically active form 1,25-dihydroxyvitamin D3. 1.2.1- Skin The skin is characterized by two layers, the outer epidermal region, consisting of several strata, and the inner dermal layer. Skin exposure to UVB rays in sunlight, characterized by a wavelength of 290 nm to 315 nm, allows the initial steps of vitamin D synthesis to occur using the substrate 7-dehydrocholesterol (7-DHC) as illustrated in step 1 of Figure 1. UVB absorption by 7-DHC is thought to occur actively in the stratum basale and stratum spinosum regions of the epidermal layer. The substrate 7-DHC is an important intermediate of cholesteryl ester biosynthesis from squalene. During the reaction, 7-DHC forms procholecalciferol through B ring opening of the steroid structure. This transition state is relatively unstable and can further undergo photocatalyzed reactions to form lumisterol and tachysterol (Wolpowitz and Gilchrest, 2006). Lumisterol and tachysterol have been shown to prevent vitamin D reaching intoxicating levels and do not have any direct vitamin D effects (Bouillon et al., 1998). In addition to this protective mechanism, previtamin D poisoning is also prevented because this is an equilibrium reaction that allows cholecalciferol to revert back to 7-DHC (Webb, 2006). Cholecalciferol (previtamin D3) is produced upon double bond rearrangement of procholecalciferol and remains in the extracellular space where it becomes bound to the ubiquitous VDBP (Holick, 2005). Figure1. Sources and steps of vitamin D synthesis in the three major sites: skin, liver and kidney (Figure obtained from Wolpowitz and Gilchrest, 2006). 1.2.2- Liver Cholecalciferol that has been transported to the liver undergoes the first step of its bioactivation, the hydroxylation of carbon 25 (Dusso, et al., 2005) by two hepatic enzymes; the microsomal and mitochomdrial 25-hydroxylases (Deluca et al., 1990). In hepatic cellular microsomes and mitochondria, vitamin D3 is hydroxylated at carbon 25 and transformed to 25-hydroxyvitamin D3 by both 25-hydroxylase enzymes. This enzyme complex requires the presence of essential catalytic cofactors including nicotinamide adenine dinucleotide phosphate (NAPDH), flavin adenine dinucleotide (FAD), ferredoxin and molecular oxygen for this reaction to proceed (Sahota and Hosking, 1999; Ohyama et al., 1997; Kumar, 1990). Recently, large numbers of hepatic cytochrome P-450 enzymes exhibiting 25-hydroxylase action have been identified in vitamin D activation pathways; these enzymes include CYP27A1, CYP3A4, CYP2D25 and CYP2R1 (Dusso, et al., 2005; Cheng et al., 2003; Sawada et al., 2000). However, CYP2R1 is b elieved to be the principal enzyme in the hepatic pathway and the presence of a genetic mutation in its gene may compromise the outcome of this process; both CYP27A1 and CYP2D25 demonstrate high capacity and low affinity features, therefore, their activity is considered insignificant in this pathway (Dusso, et al., 2005; Cheng et al., 2003; Sawada et al., 2000). This metabolic step is inefficiently regulated, i.e. the levels of 25-hydroxy vitamin D are elevated as dietary intake of vitamin D increases. Consequently, over 95% of 25-hydroxyvitamin D in serum circulates as 25-hydroxyvitamin D3 which has a half-life of approximately three weeks, and is therefore used in the assessment of vitamin D status (Dusso, et al., 2005; Reichel et al., 1989). The metabolically inert 25-hydroxyvitamin D3 is then transported to the kidney for the second step of its bioactivation. 1.2.3- Kidney The second step of vitamin D3 bioactivation takes place at the proximal convoluted tubule of the kidney. Hydroxylation occurs at C-1 of 25-hydroxyvitamin D3 whereby the highly active 25-hydroxyvitamin D3 1-ÃŽ ±-hydroxylase (CYP27B1) incorporates a hydroxyl group to Carbon-1 of the first ring to form the biologically active metabolite 1,25-dihydroxyvitamin D3 (Holick,2006; Dusso, et al., 2005; Deluca et al, 1990; Reichel, et al., 1989). The high activity of 1-ÃŽ ±-hydroxylase (CYP27B1) present in kidney is not unique to this organ and can also be found in some other organs (Bouillon, 1998). The renal hydroxylation of 25-hydroxyvitamin D3 is the rate-limiting step in the production of 1,25-dihydroxyvitamin D3 and is well regulated. An alternative pathway of hydroxylation of 25-hydroxyvitamin D3 within renal mitochondria takes place at Carbon-24 to form 24,25-dihydroxyvitamin D3 which is metabolically inert. This process is catalyzed by renal 24-ÃŽ ±-hydroxylase in response to 1-ÃŽ ±-hy droxylase suppression. However, 24-ÃŽ ±-hydroxylase not only initiates the attachment of the hydroxyl group at Carbon-24 but also enhances the dehydrogenation of 24,25-dihydroxyvitamin D3 and hydroxylation at Carbon 23 and 26 (Sahota and Hosking, 1999; Bouillon, 1998; Reichel, et al., 1989). Renal hydroxylases require the presence of catalytic cofactors that enhance their synthetic activities during this process. Figure 2 shows the details of vitamin synthesis including the enzymes and cofactors required for each step. Figure2. Enzymes, cofactor and intermediates compounds of vitamin D metabolism (Bouillon et al. 1998) 1.2.4- Regulation of vitamin D metabolism Numbers of factors have been demonstrated to be important in the regulation of vitamin D metabolism; particularly significant its regulation through renal production. The factors involved in this regulation comprise parathyroid hormone (PTH), calcitonin, dietary calcium and phosphate, insulin and insulin-like growth factor and 1,25-dihydroxyvitamin D3 itself (Holick,2006; Deluca, 2004; Sahota and Hosking, 1999). Key interactions of vitamin D with its receptor are known to initiate gene regulation. These mechanisms have been studied using vitamin D analogues which have revealed the mechanism of assembly of transcriptions factors and promotion of gene regulation by this molecule (Cheng et al., 2004; Wu et al., 2002). Figure 3 shows the effect of various regulators on vitamin D metabolism. Figure 3: Alternate pathway for vitamin D3 under different metabolic conditions of low mineral Ca and P levels, PTH concentration and secretion of GH / IGH (Figure obtained from Gomez, 2006). 1.2.4.1- Parathyroid Hormone Parathyroid hormone (PTH) is the primary regulator of renal 1,25-dihydroxyvitamin D3 formation (Holick, 2006; Dusso et al., 2005; Bouillon et al., 1998; Issa et al., 1998). PTH regulates 1,25-dihydroxyvitamin D3 production directly through enhancing 1-ÃŽ ±-hydroxylase activity within kidney cells and increasing the genetic transcription rate of renal proximal tubular 1-ÃŽ ±-hydroxylase both of which result in an increase in the renal 1,25-dihydroxyvitamin D3 production rate. High levels of 1,25-dihydroxyvitamin D3 suppress the enzyme transcription activity and PTH concentration. Thus, renal 1,25-dihydroxyvitamin D3 has a negative feedback response on PTH secretion, providing an efficient regulatory control of renal 1,25-dihydroxyvitamin D3 homeostasis (Dusso, et al., 2005; Holick,2003; Sahota and Hosking, 1999; Reichel, et al., 1989; Iqbal, 1994). 1.2.4.2- Calcium Dietary calcium exhibits a direct regulatory influence on renal 1-ÃŽ ±-hydroxylase activity via fluctuating serum calcium concentration and indirectly via its effect on serum PTH concentration. Calcium exerts its effect through calcium-sensing receptor (CaR) activation within the parathyroid gland and renal proximal tubules cells in response to low calcium concentration. Thus, the low intracellular calcium levels lead to increased production of 1,25-dihydroxyvitamin D3 within renal cells (Ramasamy, 2006; Bland et al., 1999; Chattopadhyay et al., 1996). On the other hand, it has been shown that high calcium concentrations markedly impair renal 1,25-dihydroxyvitamin D3 formation in human nephrotic cell cultures and in parathyroidectomised animals (Bland et al., 1999; Chattopadhyay et al., 1996). An increase in extracellular calcium indirectly suppresses 1,25-dihydroxyvitamin D3 production at the proximal convoluted tubule by inhibiting PTH release (Deluca, 2004; Carpenter, 1990). Howev er, the detailed mechanism of calcium-sensing receptors (CaR) activation is not yet fully understood (Dusso, et al., 2005; Hewison, et al., 2000). 1.2.4.3- Phosphate Dietary phosphate intake and serum phosphate concentrations exhibit regulatory effects on 1,25-dihydroxyvitamin D3 production in proximal renal tubules. This effect has been demonstrated in several studies which showed that a decrease in dietary phosphate accelerated renal formation of 1,25-dihydroxyvitamin D3, but did not directly affect 1, 25-dihydroxyvitamin D3 catabolism. Conversely, elevated serum phosphate and increased phosphate intake led to decreased production of 1, 25-dihydroxyvitamin D3 (Carpenter, 1989; Reichel et al., 1989). Several studies have shown that inorganic phosphate levels have no significant direct effect on mitochondrial 1-ÃŽ ±-hydroxylase activity in cultured renal cells in the short term, suggesting that the action of inorganic phosphate is not mediated via changes in PTH and Calcium concentrations and is possibly inducted by other hormones such as growth hormone, insulin and insulin-like growth factor (Khanal et al., 2006; Dusso et al., 2005; Carpenter, 1 989). In recent studies, fibroblast growth factor 23 (FGF-23), frizzled-related protein 4 (FRP-4) and matrix extracellular phosphoglycoprotein (MEPE) have all been identified as potent and key regulatory factors of 1-ÃŽ ±-hydroxylase activity in renal cells. These factors act through a biphasic mechanism on renal phosphate homeostasis and modulate the circulating levels of 1, 25-dihydroxyvitamin D3 produced by proximal renal tubules (Dusso et al., 2005; Inoue et al., 2005; Mirams et al., 2004). 1.2.4.4- Calcitonin Calcitonin belongs to a family of calcium regulating hormones that is produced in the parafollicular cells of the thyroid gland, also known as C cells. It is a short and linear polypeptide with a molecular weight of only 3.7 kD. It is characterized by 32 amino acids and a disulfide bridge in the N terminal portion of the peptide. Calcitonin is secreted in response to increased free Ca2+ in blood and acts on osteoclasts, the bone resorbing cells, as a suppressor of bone dissolution. Although calcitonin decreases Ca+2 and inorganic phosphate in blood, it also has the ability to recruit phosphorus into other cells. In addition to these metabolic functions, it is also involved in the upregualtion of CYP27B hydroxylase through the protein kinase C pathway (Yoshida et al., 1999) via a phosphorylation cascade that activates cAMP and induces the expression of hydroxylase thereby activating the transformation of 25(OH) D3 to 1,25(OH)2 D3. In addition to the significant role as a calcium regulating hormone, calcitonin is also known to stimulate the production of vitamin D in tandem with PTH (Yoshida et al., 1999; Wongsurawat and Armbrecht, 1991). Previous studies revealed that 1-ÃŽ ±-hydroxylase mRNA expression, 1-ÃŽ ±-hydroxylase activity and the production of 25(OH)D and 1,25(OH)2D3 all increased in rat kidney cells following the administration of calcitonin (Yoshida et al., 1999; Galante et al., 1972; Rasmussent et al., 1972). However, in cases of diabetes, it is postulated that the kidney becomes immune to the effect of this hormone in diabetic rats which lead to increase vitamin D production (Wongsurawat and Ambrecht, 1991). 1.2.4.5- Growth hormone, Insulin and Insulin-like growth factor-1 Growth hormone (GH) has many regulatory actions in various metabolic processes in humans and mammals and its effect on mineral homeostasis in target organs such as bone and renal cells is well documented. While the regulatory effects of GH on dietary calcium and phosphate metabolism in different tissues have been established, its effect on vitamin D metabolism remains controversial. However, many studies have shown that GH increases the expression of 1-ÃŽ ±-hydroxylase and 1, 25-dihydroxyvitamin D3 in cultured cells and experimental animals (Gomez, 2006). Wu and colleagues reported that serum1, 25-dihydroxyvitamin D3 increases after GH administration in hypophysectomized rats fed with a phosphate depleted diet. Short-term studies in healthy humans have shown that GH raises 1-ÃŽ ±-hydroxylase enzyme activity and promotes 1, 25-dihydroxyvitamin D3 synthesis without changes in PTH, calcium and phosphate concentrations, suggesting that the increasing circulating levels of 1, 25-dihydroxy vitamin D3 following GH administration is not mediated by PTH action (Wu et al., 1997; Bianda et al., 1997; Wright et al., 1996). GH has also been shown to lead to increased production and serum concentration of 1, 25-dihydroxyvitamin D3 in pigs and in renal impaired prepubescent children. These are thought to be a result of the direct and indirect effects of GH on 1-ÃŽ ±-hydroxylase expression, and on calcium and inorganic phosphate homeostasis in renal tubules cells (Strife and Hug, 1996; Denis et al., 1995). However, the action of GH on vitamin D metabolism in vitro remains uncertain and may involve other regulatory factors such as PTH and Insulin-like growth factor-1 (IGF-1). It has been shown that GH does not raise 1, 25-dihydroxyvitamin D3 levels directly in cultured cells obtained from aged-rats; yet it stimulates calcium absorption and the expression of calcium binding proteins in vitro indicating that the effect of GH is mediated through the action of other factors such as IGF-1 (Fleet et al., 1991). Insulin is another key factor with a role in vitamin D homeostasis. Insulin significantly decreases renal hydroxylase activity and renal synthetic capacity of 1, 25-dihydroxyvitamin D3 in insulin deficient patients or those receiving insulin therapy (Armbrecht et al., 1996). However, a study of different routes of therapeutic insulin administration in human diabetic subjects concluded that insulin induces the hepatic hydroxylation of 25-hydroxyvitamin D3. This effect is related to the fact that insulin is a potent inducer of the vast majority of liver hydroxylases enzymes (Colette et al., 1989). This study also showed that there was no significant difference in circulating levels of 1,25-dihydroxyvitamin D3 between different methods of insulin administration. Serum 1,25-dihydroxyvitamin D3 is maintained at normal concentrations in those subjects on long term insulin therapy; however, continuous intraperitioneal infusion procedure (CPII) may augment hepatic 25-hydroxlase activity (Col ette et al., 1989). Similarly insulin has shown a significant effect on stimulating 1,25-dihydroxyvitamin D3 production through 1,25-dihydroxyvitamin D3 and PTH stimulation with no concomitant action on 24-hydroxylase expression in rat osteoblast cells when these cells were cultured with known concentrations of 1,25-dihydroxyvitamin D3 and PTH (Armbrecht et al., 1996). Insulin-like growth factor-1 (IGF-1) is a relatively small peptide that is primarily expressed in hepatic cells and to a lesser extent in some other cells and tissues. It has been identified as one of the potent regulatory components of mineral metabolism in humans and mammals. Recent studies on the metabolic effect of IGF-1 revealed that the administration of IGF-1 to aged laboratory animals, fed on a calcium- and phosphate- deficient diet, can restore 1-ÃŽ ±-hydroxylase activity and enhance the production of 1,25-dihydroxyvitamin D3. In contrast, there was no significant effect of IGF-1 on enzyme activity and 1,25-dihydroxyvitamin D3 levels in adolescent or elderly rats fed on a calcium and phosphate fortified diet concluding that the expression of IGF-1 is not age related but related to the dietary calcium and phosphorus status. (Gomez, 2006; Wong et al., 1997; Wu et al., 1997). In healthy human subjects, a significant effect of IGF-1 on renal 1,25-dihydroxyvitamin D3 synthesis wa s observed after short term infusion with IGF-1. There was no noticeable alteration of the levels of circulating calcium, phosphate and PTH highlighting the role of IGF-1 in stimulating renal expression of 1-ÃŽ ±-hydroxylase and 1,25-dihydroxyvitamin D3 formation in conjunction with GH, independently from PTH (Bianda et al., 1997). In vitro studies have shown that IGF-1 influences the expression of 1-ÃŽ ±-hydroxylase and 1,25-dihydroxyvitamin D3 synthesis in cells cultured from non renal human tissues. Halhali and colleagues demonstrated that IGF-1 noticeably elevates both the enzyme activity and 1,25-dihydroxyvitamin D3 levels when added into cultured syncytiotrophoblast cells obtained from human placental sources. This study demonstrated that IGF-1 strongly enhances the ability of non renal cells to produce 1,25-dihydroxyvitamin D3 without involvement of GH and PTH (Halhali et al., 1997). 1.2.4.6- 1, 25-dihyroxy vitamin D3 The circulating levels of 1,25-dihydroxyvitamin D3 modulate its production by renal cells through an indirect negative feedback mechanism. This mechanism appears to reduce the likelihood of vitamin D toxicity by inhibiting 1,25-dihydroxyvitamin D3 synthesis by an indirect mechanism that controls the 1-ÃŽ ±-hydroxylase gene expression at the molecular level rather than inhibiting 1,25-dihydroxyvitamin D3 synthesis directly. However, the exact mechanism is not yet fully understood (Dusso et al., 2005; Deluca et al., 1990). A recent study examined the effect of 1,25-dihydroxyvitamin D3 on 1-ÃŽ ±-hydroxylase production by cultured human keratinocytes. Keratinocytes were cultured with labeled 25-hydroxyvitamin D3 and different concentrations of 1-ÃŽ ±-hydroxylase mRNA and 24-hydroxylase- suppressed proteins. The 1,25-dihydroxyvitamin D3 did not suppress either the 1-ÃŽ ±-hydroxylase activity or the rate of gene transcription. The study implied that metabolic regulation of 1,25-dihydroxyvi tamin D3 is related to the molecules biodegradation in response to augmented 24-hydroxylase activity rather than 1,25-dihydroxyvitamin D3 formation by 1-ÃŽ ±-hydroxylase (Xie et al., 2002). In addition, Wu and colleagues demonstrated a possible alternative mechanism of 1,25-dihydroxyvitamin D3 synthesis linked to the fact that both 24-hydroxylase and 1-ÃŽ ±-hydroxylase enzymes share equivalent metabolic capability and they proposed the possibility of protein- protein interaction between intracellular vitamin D binding protein and 1-ÃŽ ±-hydroxylase (Wu et al., 2002). 1.2.5- Vitamin D Transport, receptors and mechanism of action Vitamin D receptor (VDR), also known as calcitriol receptor, is a member of the steroid family and belongs to the nuclear receptor superfamily (NHR). Human VDR until recently was thought to comprises four functional units with a total of 427 amino acids residues with an estimated molecular weight of about 48 kDa. These units are the DNA binding domain (DBD) or C domain, the D domain and the ligand binding domain (LBD) or E domain. More recently, a carboxy-group with undefined function, known as the F region has been identified (Christakos et al., 2003; Aranda and Pascual, 2001; Rastinejad et al., 2000). These units as, shown in figure 4, are also known as A/B domain. The A/B region of VDR contains a low number of amino acids that participates in essential ligand-independent receptor stimulation (Aranda and Pascual, 2001; Issa et al., 1998). It is not yet clear if the deletion of A/B domain from VDR will compromise ligand binding, DNA binding or its transactivation features (Issa et a l., 1998). In contrast, the structure of the DNA binding domain or C region among NHRs comprises 40% unique amino acids sequences and a domain of more than 67 resemble amino acids residues (Rastinejad et al., 2000). Moreover, the core structure of DBD comprises between 22 and 114 amino acid residues, nine of them are cysteines. Eight of cysteine residues orchestrate with zinc atoms in tetrahedral fashion to form a dual â€Å"zinc-like finger† DNA binding configurations containing approximately 70 amino acids with a carboxy-terminal extension (CTE). This encloses T and A boxes in a dual helix molecule in which one helix is essential for definitive interaction with the main domain on DNA while the second helix takes a part in receptors structural properties (i.e. receptor dimerization) (Aranda and Pascual, 2001; Issa et al., 1998). However, the integration of the structural amino acids of the DBD ÃŽ ±-helix one, at the site of the first zinc atom, determines the selectivity and specificity of recognition of DBD and forms an area known as the â€Å"P Box†. Similarly; the integration of amino acids at the position of the second zinc atom modulates the formation of a configuration termed the â€Å"D Box† which forms a dimerization interface zone (Aranda and Pascual, 2001; Rastinejad et al., 2000; Issa et al., 1998). Furthermore the vast majority of DBD amino acid units are basic amino acids which enhance the non-covalent binding of the DNA helix at the negatively charged phosphate group (Issa et al., 1998). The ligand binding domain (LBD) or E domain has a spherical configuration with many functional regions composed of 12 cohered helix anchors defined as H1 to H12. LBD itself comprises a net of 427 amino acids which contribute to homodimerization and heterodimerization and the interaction of hormones and costimulaotors by a crucial transactivational mechanism (Aranda and Pascual, 2001; Weatherman et al., 2000; Issa et al., 1998). Crystallograp hic studies show that LBD have two cohered and integrated domains, the Ti or â€Å"signature motif† and the carboxy or C terminal AF-2 providing the self-ligand transcriptional properties; hence a higher degree of attraction of 1,25 dihydroxyvitamin D3 binding is observed at 382 to 402 of LBD amino acid sequence and any genetic aberration at this particular amino acids sequence will diminish the interaction capability of LBD (Aranda and Pascual, 2001; Issa et al., 1998). Figure 4: The primary structure of the vitamin D receptor (VDR) and the binding of retinoid X receptor (RXR)-VDR heterodimers to vitamin D response elements (VDREs) in the form of DR3 and ER6 motifs. (Figure from Lin and White, 2003) 1,25-dihydroxyvitamin D3, has been identified as steroid hormone with a mechanism of action similar to other steroid hormones, causing new protein expression in various target organs. Based on the nuclear receptors structural studies, calcitriol is known to exert its biological action through binding with VDR in the cell nucleus to mediate a cascade of transcriptional and translational processes resulting in either the regulation or inhibition of new protein expression in target tissues or the binding to plasma membrane receptors without stimulating new protein synthesis (Nezbedova and Brtko, 2004; Reichel and Norman, 1989). Two different receptors for 1,25-dihydroxyvitamin D3 have been recognized in different target cells; identified as genomic VDRnuc and typical VDRmem .These receptors provide the best dynamical conformational forms for calcitriol interaction and to evoke its genomic and non-genomic effects (Norman et al., 2002). The binding of 1,25-dihydroxyvitamin D3 to VDRnuc e nhances the interaction with an undistinguished protein known as the nuclear accessory factor (NAF) and to the caroxy-terminal of VDR. This interaction leads to a structural conversion pattern of the C-terminal of VDR allowing the AF-2 domain to attach with other transcriptional elements such as SCR-1, calcium binding protein (CBP) and P300. This promotes the binding of the heterodimer molecule with DNA at the vitamin D response sites (VDRE) and directs its transcriptional gene activity (Jones et al., 1998; Iqbal, 1994). In addition, these coactivators play a role in DNA configurational changes through histone acetyl transferase activation pathway of the core components of histones. This results in mechanical instability of the DNA structure and enhances the net binding capacity of the coactivators with their corresponding receptors at nucleosomal histone level and leads to the upregulation of these transcriptional coactivators which in trun, accelerate the net gene transcriptional rate to promote the synthesis of the analogous protein (Lipkin and Lamprech, 2006; Jones et al., 1998). Conversely, the non-genomic or classical effect of 1,25-dihydroxyvitamin D3 is modulated through its binding with the surface cellular membrane receptor known as mVDR which initiates an immediate response in various target tissues with no genomic transcriptional activity. Many studies demonstrate the rapid effect of calcitriol in rapidly increasing both the level of circulating calcium and its absorption rate in animal intestines, evoking phosphoinoisitide bioactivation, cyclic guanosine monophosphate (cGMP) elevation, activation of protein kinase C and triggering the mitogen activated protein kinase pathways and involving the chloride gates action potential in different organs (Dusso et al., 2005; Nezbedova and Brtko, 2004; Boyan and Schwartz, 2004; Norman et al., 2002). The entire mechanism, as shown in figure 5, for the rapid effect of calcitriol remains doubtful, however; the proposed mechanism is mediated through the interaction with mVDR leading to a series of intracellular sig naling events. Signaling is orchestrated by the activation of various metabolic pathways involving different transportation mechanisms of certain mineral components of target organs. (Pedrozo et al., 1999; Norman et al., 1999; Revelli et al., 1998). However, other studies reveal that the genomic effect of 1,25-dihydroxyvitamin D3 is independent of its non-genomic mechanism (Dusso et al., 2005). Figure 5: Cellular mechanism of action of 1,25(OH)2D3 (Figure from Horst et al., 1997) 1.3- Biological actions of Vitamin D on target tissues and Systems The active form of vitamin D, 1,25-dihydroxyvitamin D3 is well recognized as a member of steroid hormones that mediates several metabolic and non-metabolic processes in various organs in human and animals as shown in figure 6. 1.3.1- Intestine Mineral absorption in the intestines is increased in the presence of the hormone 1,25(OH) vitamin D. However without this, only 10 to 15% of dietary calcium and 60% of phosphorus is absorbed from the diet (De Luca, 2004). Ca2+ and HPO42- are also absorbed when intestinal cells interact with the vitamin D- VDR- RXR complex. The latter enhances the expression of the epithelial calcium channel and calcium-binding protein which recruits calcium and phosphorus (Holick, 2007). Knock out mice experiments studying the effect of VDR gene deletions also show that the size of the small intestines is related to the levels of calcitriol and dietary calcium availability. Vitamin D deficient mice fed with diets low in calcium exhibited the largest small intestine to large intestine ratio (Cantorna et al., 2004). VDR knock-out mice experiments also aid in the discovery of calcium channels, the route for Ca absorption, in the intestine (Peng et al., 1999). Calbindin is a potent calcium transporter in mammals which characterized by a high affinity for calcium ions. Therefore, the binding of vitamin D to VDR and RXR signals an increased production of calbindin which facilitates systemic Ca2+ ions transportation and prevent the occurrence of calcium toxicity in the intestines. Figure 6: Schematic diagram of the effects of Vitamin D on different tissues and organs (Figure from Holick, 2007). 1.3.2- Bone Takeda et al. (1999) studied the role of vitamin D and VDR in bone cells using knock out mice experiments. Their results showed that bone cells formation triggering mechanisms such as cell to cell interaction between osteoblast and osteoclast progenitors and stromal cells induced by 1,25(OH)2 vitamin D3 and provoke the formation of osteoclasts. In their capacity as bone resorbing cells, osteoclasts can be triggered by low serum calcium levels, to break down bone and free calcium back in to the blood thus redistributing calcium throughout the body. However, this does not occur without the expression of VDR and without vitamin D complexing with its receptor. This study emphasizes the important role of recognition sites on the VDR and the structural implications that the receptor-ligand binding has on VDREs and transcription initiation. Although the effects of PTH

A Family Vacation to Canada :: Summer Vacation Essays

This is the actual story of a trip I took with Smith Family into Canada. The total head count was 19, including myself. The trip took 8 days to complete. We left on Saturday, June 24 at 12:00am and got back on Sunday July 1, around 3:00pm. The great Canadian adventure started at 12 noon on Saturday to pack the bus and truck. The bus is an old school bus with a big rack on top to hold canoes, and screens over all the windows. Inside there are 8 bunks in the back for sleeping. The middle is where the food is kept. The front has two tables on each side for playing cards. As soon as I got there I started meeting people. I had only met Craig, Renee, and Amber before at Cameron Smith’s graduation party. There were 3 well fed dogs running around. The first person Tyler pointed out was Harry, his grandpa. He was getting the gas together for the boats and there were about 5 others standing around him. One was Troy and the other was Larry. It was easy to see that Craig and Troy were brothers, they were rigging the bus to carry 5 canoes. Others were busy helping to get ready. I helped put the motor rack in Tyler’s truck. After the bus and truck had all of the canoes on, Jeff, Tyler, and I went back to Tylerâ₠¬â„¢s house to take showers and eat. The plan was to meet Craig at Cash Wise at 8:30 to buy the food. Craig’s Eagle got a flat tire on the way to Willmar. Tyler, Jeff, and I got there at 9:30 but the shopping was already done. As we were leaving Willmar, on our way back to Harry’s, we were able to see fireworks from the â€Å"Works over Water† display on Foot Lake. When we got to Harry’s, there were several cars in the yard. Tyler and I went to the house were I met Erin and Allison for the first time. Erin was eating a pizza and at first glance I thought she was Emily Smith. I could not get over how much Erin, Allison and Amber looked like Emily. Little kids were running everywhere. In the living room, were about 25 people I had never met or seen before, who seemed to be having a good time together.

Tale Tell Heart and Goose Girl

Jack Mitchell Mr. Glen Smith English1302 Oct 10,2012 Compare/Contrast Essay Assignment #2 The unnamed narrator in Edgar Allan Poe’s â€Å"A Tell- Tale Heart† and the chambermaid in the Grimm Brothers â€Å"The Goose Girl† both possess strikingly similar characteristics. Both show aggression and use violence to get what they want but are very careful of how they go about it and covering it up. In Poe’s story, the unnamed narrator kills an elderly man that he is caring for because the old man has a foul looking eye that is covered with a white film.This is what is slowly driving him insane but afterwards he ingeniously decides to hide the body incase someone heard the noise of the olds man body. This is so he does not get arrested for his murder and when the police do stop they believe his story and do not suspect anything, until he gives them a reason. The chambermaid on the other hand forcefully and violently makes the princess, who she knows wont stand up for her self, switch places with her simply because she wants to live the life of the princess.She also makes the princess swear to secrecy so she never has to worry about her true identity being unveiled. Later, she cleverly kills the princess’s talking horse, which was the only witness to what happened between the chambermaid and the real princess’s. In Poe’s â€Å"The Tell-Tale Heart† the unnamed narrator is caring for an elderly man who isn’t capable of taking care of himself. The elderly man has a bad eye that has a silky film over the top of it. The narrator becomes sickened and essentially afraid of the eye.He decides that the only way he can get rid of these feelings is to kill the old man thus getting rid of the eye forever Originally, he is hesitant to actually go through with his plan, but he knows it is the only way to end his torture. â€Å"I made up my mind to take the life of the old man, and thus rid myself of the eye forever† (303). He waits until the time is right when the eye is open to kill him â€Å"I did for seven long nights every night just at midnight, but I found the eye always closed; and so it was impossible to do the work† (303).He feels he must kill the man with the evil eye open because â€Å"for it was not the old man who vexed me, but his Evil Eye† (303). Once he finally kills the man, he decides to hide the body incase someone heard the noise or the beating of the man’s heart, which is now driving him even more insane. However, when he was finished cleaning up someone rang his doorbell and when he opened it, â€Å"There entered three men, who introduced themselves, with perfect suavity, as officers of the police† (305). The narrator gave the police a very believable story and they were satisfied.He was almost scott free, but then he starts to hear the thumping of the mans heart and starts going crazy. Convinced the police heard the noise too he ripped up th e planks revealing the body of the elderly man. In the Grimm Brothers â€Å"The Goose Girl†, the chambermaid of the princess so desperately wants to the live the lavish care free life of the princess she decides to test her fate by taking action. This is when her violent behavior is seen for the first time, when she decides to forcefully and violently begin to curse at the princess to dress up as a chambermaid so she can take the princess’s place.She also made the princess to swear to never tell anyone what happened. â€Å"Then with many harsh words, the chambermaid ordered the princess to take off her own royal clothing and put on the chambermaid's shabby clothes. And in the end the princess had to swear under the open heaven that she would not say one word of this to anyone†¦Ã¢â‚¬ (406) When she finally arrives at the castle and marries the king, she asks him for a favor. â€Å"Send for the knacker, and have the head of the horse which I rode here cut off. â €  (408) This is her way of making sure that there are no loose ends and that there is no one or thing that can revel her true identity.However, she does not know the horse can still talk after its’ been beheaded. This small overlooked detail is the root cause to her downfall. The Narrator is portrayed as an insane man who starts to lose control of whatever sanity he has left once he comes into contact with the elderly mans grotesque eye that he thinks is evil. Even though he is portrayed as crazy, in reality he has not lost his mind completely, in he fact that he actually watches the man, investigates the room, and checks the eye to see if it is open â€Å"every night just at midnight†(303). He did this for seven nights, hich clearly shows that he has not completely lost his grip on reality. By waiting for the perfect chance to strike shows patience, mentally and physically. Another sign the narrator was not totally insane was that he had a face-to-face conversatio n with three police officers. In the end, â€Å"The officers were satisfied† and believed his alibi. There is no way a person said to have lost his mind completely could have fooled three trained police officers. On the other hand, the chambermaid in â€Å"The Goose Girl† is seen as a cunning, tough character throughout the story.However, towards the end of the story her true colors begin to shine. By her sending out the knacker to â€Å"have the head of the horse which I rode here cut off, for it angered me on the way. †(306). This shows that she has started to worry and stress over her secret getting out. By her having everything and everyone who could tell her secret around her taken away is the first sign of weakness from her. It is a sign of weakness because she is doing everything possible to save herself and only herself.Lastly, the reason why both the chambermaid and the narrator both got caught and failed to get away was due to them. The narrator was ho me free until he started to panic, thinking the guards could hear what he was hearing he finally lost it â€Å"dissemble no more! I admit the deed! —tear up the planks! here, here! —It is the beating of his hideous heart! † (306). The chambermaid had it done what she had set out to do. However, if she would have stopped and trusted the promise the princess gave her from the beginning she would have been fine.She instead decided to take things into her own hands and had the talking horse beheaded. Finally, the reader can see that both of the characters used every means necessary to get what they wanted which included violence to get what they want but are also very careful of how they go about it and covering it up.Work Cited Grimm, Jacob and Wilhelm Grimm. â€Å"The Goose-Girl. † Kinder-und Hausmarchen. 7th ed. D. L. Ashilman, trans. Berlin: n. p. , 1857. Print Poe, Edgar Allan. â€Å"The Tell-Tale Heart. † The complete Tales and Poems of Edgar All an Poe. New York: Random House, 1975. Print.