MAMLD1 Mutation and Phenotypes of Hypospadias

MAMLD1 Mutation and Phenotypes of Hypospadias The relationship between clinical phenotypes and mutations of MAMLD1 in children with hypospadias Yong-fen Lv, Lu-lu Cui, Pin Li* Department of Endocrinology, Shanghais Children Hospital, Shanghai Jiaotong University Acknowledgements: The work was financially supported by the key project of Shanghai municipal health bureau (2011111), youth project of Shanghai municipal health bureauà ¯Ã‚ ¼Ã…’major issue subprojects of Shanghai science and technology commission (12411952408), Yangtze river delta research project of Shanghai science and technology commission (13495810300). Abstract Purpose: To verify the relationship between clinical phenotypes of hypospadias and mutations of MAMLD1. Methods: Seventy-two patients were diagnosed to be hypospadias in department of endocrinology and department of urinary surgery in our hospital. Among all the patients, 69 were with normal karyotype and enrolled as the studied group. Fifty healthy boys were employed as the controls. Peripheral Blood were collected for DNA extraction. For the studied group, PCR primer was designed and direct sequencing was performed for screening for MAMLD1 mutations in six coding exons and the flanking region. Those mutated exons were examined for the control group. Results: Thirty-five of all the 72 patients (48.6 %) were isolated hypospadias. The other 37 cases (51.4%) were complicated by other genitourinary system malformations, including 12 cases with micropenis and/or underdeveloped testicles. Abnormal karyotype was identified in 3 patients, and all were karyotype as 46, XX (SRY+ in 1 case and SRY- in 2 cases). Six types of MAMLD1 mutations were detected in exon 2, 3, 5, 7 in studied group, including c.5A>G (p.D2G), IVS4-364C/A, c.1910A>Gà ¯Ã‚ ¼Ã‹â€ p.N637S), c.2208T>C, c.2227 G>A (p.E742K) and IVS8-144C/T. All were single nucleotide polymorphism except c.5A>G (p.D2G), a newly discovered point mutation. The frequency of IVS4-364C/A was significantly different between patients and controls, and it was also significantly different between patients with and without micropenis and/or underdeveloped testicles. Conclusion: Chromosome abnormality is not the leading cause of other genitourinary system malformations complicated with hypospadias. Mutations of MAMLD1 maybe closely related to hypospadias in Chinese. c.5Aà ¯Ã‚ ¼Ã… ¾Gà ¯Ã‚ ¼Ã‹â€ p.D2Gà ¯Ã‚ ¼Ã¢â‚¬ °is the newly discovered point mutation in this work. IVS4-364C/A is associated with underdeveloped testicles and/or micropenis in hypospadias patients. Introduction Hypospadias is one of the most common congenital genitourinary system malformations in males, with incidence 1†°Ãƒ ¯Ã‚ ½Ã… ¾1%. As one of the Juvenile-types of testicular dysgenesis syndrome,(1-3) the prevalence of hypospadias is obviously increasing in these years. From 1987 to 2001, the prevalence rate was doubly increased in China.(4) Hypospadias will lead to different degrees of genital malformation, and the clinical phenotypes vary when with other complications. For instance, besides the general signs of hypospadias, e.g., ectopic ureteral orifice, phallocampsis, redundant dorsal prepuce, etc, the patient may be also suffered from other malformations including penoscrotal transposition, cryptorchidism, hydrocele, oblique inguinal hernia, micropenis and underdeveloped testicles. Hypospadias is a complicated disease due to various causes. The causes of most cases are not able to be verified, especially for those mild cases. For these cases, environmental factors, endocrine fa ctors and abnormal gene expression may be the leading causes.(5) The sex differentiation of males is a continuous series of processes related on the balancing and interaction of various genes like SRY, WTl, ATF3, SF-1, etc. MAMLD1, which is previously called chromosome X open reading frame6 (Cxorf6), is the important candidate gene widely studied recently. This gene is located in Xq28,(6,7) with molecular length of 157898 bp and containing 8 exons, among which exon 2, 3, 4, 5, 6, 7 are coding exons. MAMLD1 is initially detected in patients with X-linked myotubular myopathy. The reproductive systems of patients are normally developed with mutations in Myotubularin MTM-1, while different degrees of malformations occur in cases with deletion of MTM1 gene.(8-11) The subsequent experiments indicated that, for patients with 46, XY disorder of sex development (DSD), except MAMLD1, no other candidate genes were found in the deletion region. These results indicate that MAMLD1 is the perfect candidate gene for the study of 46, XY DSD, especially for hypospa dias. This work aimed to evaluate the mutations of MAMLD1 and clinical phenotypes in children with hypospadias in China, and thus to illustrate the role of MAMLD1 mutation in hypospadias. Methods Patients Seventy-two children with hypospadias admitted to Shanghai Childrens Hospital Affiliated to Jiaotong University from March 2011 to December 2012 were enrolled in this study. Definite diagnosis was based on the clinical signs, and patients with adrenogenital syndrome were excluded through clinical examination. Clinical examination Clinical survey was performed including patient’s complain, present medical history, past medical history, personal history, family history, birth history, mother’s medical history in pregnancy, previous exposure to environmental pollution, etc. Physical examination was performed to measure the hight, weight, heart rate, blood pressure and the status of gonad development, etc. For adolescent, the development of secondary sexual characteristics was also assessed. Regular auxiliary examinations were performed including blood and urine routine test, biochemistry test, gonadal hormone level, adrenal cortex function and abdominal ultrasound exam, etc. Karyotype analysis and detection of SRY gene Lymphocytes were isolated from peripheral blood of patients, cultured and smeared on slides, and G-bands were produced by treatment with trypsin. Thirty split-phases were selected for each case, and karyotype analysis was performed according to ISCN-1995. SRY gene detection was performed for all the patients. Screening for MAMLD1 mutations The gene sequence of MAMLDI was obtained from National Center for Biotechnology Information (NCBI), which was the same as obtained from Ensembl Genome Browser: NC_000023.10 (NCBI) versus ENSG00000013619 (Ensembl release 70-January 2013). Primers were designed for the coding exon 2, 3, 4, 5, 6, 7 of MAMLD1. DNA extraction was performed using TIANamp Blood DNA Kit (TIANGEN Biotech (Beijing) Co., Ltd, China) and purity test was done. Ploymerase chain reaction (PCR) was performed with use of LONGgene A300 PCR and Premix Ex Taq Version2.0 (TaKaRa D332A), GC buffer (TaKaRa DRR20GC1) and rTag (TaKaRa DR001BM), 35 cycles of denaturation at 94à ¢Ã¢â‚¬Å¾Ã†â€™ for 30 seconds,extension at 72à ¢Ã¢â‚¬Å¾Ã†â€™ for 60 seconds. Mutations were identified in the six coding exons and flanking regions of MAMLD1, and those mutated exons were examined for the control group. Statistical analysis The SPSS 18 software was used for statistical evaluation. Chi-square test was used to compare the two groups, frequency of single nucleotide polymorphism between the two groups was analyzed using Fisher Exact test, and differences were considered statistically significant when the p-value was G (p.D2G), IVS4-364C/A (rs1209024), c.1910A>G (p.N637S), c.2208T>C, c.2227 G>A (p.E742K, rs5925166) and IVS8-144C/T (rs658748). Two types of mutations were detected in exon 5 and 7 in all healthy controls, including c.1910 A>G (p.N637S, rs2073043) and c.2208T>C. Among all the mutations, c.5A>G (p.D2G) was a newly discovered point mutation, others were all single nucleotide polymorphism. The studied group compared to the control group, the frequency analyzed by Fisher Exact test, the P value for IVS4-364C/A, c.1910A>G (p.N637S), c.2208T>C, c.2227 G>A (p.E742K) and IVS8-144C/T were 0.002, 0.638, 0.362, 1 and 0.509 respectively. Therefore, the frequency of IVS8-144C/T was significantly different be tween the two groups, and the frequency of the other 4 SNPs were not significantly different between the two groups. Relationship between mutations of MAMLD1 and clinical phenotypes of hypospadias One case with c.5A>G (p.D2G) was isolated hypospadias, the urethral opening position was located at the middle segment of penis. Due to the limited number of mutation cases, the sample size should be increased to study the relationship between c.5A>G (p.D2G) and phenotypes of hypospadias. Analyzed by Chi-squared test with Yates continuity correction, the frequency of IVS4-364C/A was significantly different between patients with and without micropenis and/or underdeveloped testicles (p=0.001). Discussion Chromosome abnormality and karyotype change is one of the causes of hypospadias. Till now, ten types of chromosome abnormalities were confirmed involving chromosome 1, 4, 6, 8, 11, 13 19, 20, 21, X, Y, etc. In the studied 72 patients, abnormal karyotype was identified in 3 patients, and all were karyotype as 46, XX (SRY+ in 1 case and SRY- in 2 cases). For these three patients, uterus and ovary were not found through the laparoscopic exploration. Therefore, they were diagnosed to be 46, XX male sex reversal syndrome. Karyotype analysis is important for hypospadias patients with sex reversal syndrome in exploring candidate gene and pathogenesis, in clinical diagnosis as well as in making therapeutic plan. However, there are only 3 cases with karyotype abnormality in the 72 patients studied, which means chromosome abnormality is not the leading cause of hypospadias. MAMLD1 is initially detected in patients with X-linked myotubular myopathy. The reproductive systems of patients are normally developed with mutations in Myotubularin MTM-1, while different degrees of malformations occur in cases with deletion of MTM1 gene.(8-11) Except MAMLD1, no other candidate genes were found in the deletion region. These results indicate that MAMLD1 is the perfect candidate gene for the study of 46, XY DSD, especially for hypospadias. In the works of Fukami et al., three nonsense mutations were detected, i.e., p.E124X, p.Q197X and p.R653X, in 4 XY DSD cases, involving micropenis and hypospadias with urethral opening position located on scrotum and the joint at penis and scrotum.(12) Kalfa et al. have studied the mutations of MAMLD1 in hypospadias patients and discovered 3 mutations, including p.V432A, p.E109fsX121 and P.531ins3Q, and they proposed that 10 percent of all the severe hypospadias cases was caused by mutations of MAMLD1.(13) In the study of Chen et al., three mutations of MAMLD1 were discovered, i.e., p.Q529K, p.D686D and noncoding region c.2065+8a>t, in 99 Swedish with hypospadias.(14) However, this is not the case in China. Qian et al. have studied the mutations of MAMLD1 in 100 cases of isolated hypospadias,(15) where 200 healthy participants were randomly selected as control. In their work, two point mutations, c.1699C>T and c.1985A>G, were detected and all were SNPs, and statistical analysis revea led that MAMLD1 is not the candidate gene for isolated hypospadias in China. The different results may be due to the different inclusion criteria of studied population between China and abroad, i.e., the studied populations of foreign works were mostly composed by hypospadias cases complicated by other genitourinary system malformations, including gonadal dysgenesis, while mostly isolated hypospadias cases were selected in the works of Chinese. In this study, a new point mutation c.5A>G was detected in exon 2 of one patient, and this mutation was not found in controls. The mutation makes the second amino acid position, originally the hydrophilic negatively charged aspartic acid, substituted by a neutrally charged glycine. For various species, the second amino acid position in exon 2 of MAMLD1 is highly conserved, and analyzed via polyphen, the mutation c.5A>G (p.D2G) of MAMLD1 is predicted to be probably damaging with a score of 0.996 from HumDiv and 0.993 from HunVar, which indicates that c.5A>G (p.D2G) is highly related to hypospadias. SIFT predicts that the mutation can affect protein function, since there is no protein diversity on the site (supplementary figure 20). The case with c.5Aà ¯Ã‚ ¼Ã… ¾G was isolated hypospadias, and the urethral opening was located in the middle segment of penis. A big sample size and the information of the exact protein function are required to elucidate whether c.5A>G (p.D2G) of MAMLD1 is the cause of isolated hypospadias and its role in human sexual differentiation. The meaningful SNP detected in this work is the full mutation in introns close to exon 3, i.e., IVS4-364C/A (rs1209024), in 12 patients, which is not found in controls. The 12 cases including 2 cases with anterior hypospadias, 9 cases middle urethral openings and 1 case posterior urethral opening. Among all the 12 patients, 6 were complicated by 2 other malformations, 8 cases were complicated by micropenis and/or underdeveloped testicles. Generally, introns are non-coding sections of a gene, which are removed before the mature mRNA can be transported, thus do not exist in the mRNA sequence. However, there may be several mini genes in some introns, the so called genes-within-genes. The frequency of IVS4-364C/A was significantly different between patients and controls, and it was also significantly different between patients with and without micropenis and/or underdeveloped testicles. Therefore, two possibilities could be speculated, the first is that there may be coding sequence relat ed to micropenis and/or underdeveloped testicles in the introns close to exon 3 of MAMLD1, the second is that the mutation could affect mRNA shear mode, thus lead to the change of protein function. Next step of our study plan is to verify whether the mutation could affect mRNA shear mode through reverse transcription, amplification and sequencing of extracted mRNA. References 1. Skakkebaek NE, Rajpert-De ME, Main KM. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod 2001;16:972-8. 2. Sharpe RM. Pathways of endocrine disruption during male sexual differentiation and masculinization. Best Pract Res Clin Endocrinol Metab 2006;20:91-110. 3. Sharpe RM, Skakkebaek NE. Testicular dysgenesis syndrome: mechanistic insights and potential new downstream effects. Fertil Steril 2008;89(2 Suppl):e33-8. 4. Wu YQ, Dai L, Wang YP, Liang J, Zhu J, Wu DS. Secular Trends of Hypospadias in Chinese Perinatals. J Sichuan Univ (Med Sci Edi) 2005;36:274-6. 5. Liang WQ, Ji CY, Zhang JM, et al. The correlation between the type of hypospadias and external genital system malformations. Chin J Urol 2011;32:126-9. 6. Laporte J, Kioschis P, Hu LJ, et al. Cloning and char acterization of an alternatively spliced gene in proximal Xq28 deleted in two patients with intersexual genitalia and myotubular myopathy. Genomics 1997;41:458–62. 7. Laporte J, Guiraud-Chaumeil C, Vincent MC, et al. Mutations in the MTM1 gene implicated in X-linkedmyotubular myopathy. ENMC International Consortium on Myotubular Myopathy. European NeuroMuscular Center. Hum Mol Genet 1997;6:1505-11. 8. Bartsch O, Kress W, Wagner A, et al. The novelcontiguous gene syndrome of myotubular myopathy(MTM1), male hypogenitalism and deletion in Xq28: report of the first familial case. Cytogenet Cell Genet 1999;85:310-4. 9. Bates PA, Kelley LA, MacCallum RM, et al. Enhancement of protein modeling by human intervention inapplying the automatic programs 3D-JIGSAW and3D-PSSM. Proteins 2001;S5(Suppl 5):39-46. 10. Biancalana V, Caron O, Gallati S, et al. Characterisation of mutations in 77 patients with X-linked myotubular myopathy, including a family with a very mild phenotype. Hum Genet 2003;112:135-42. 11. Hu LJ, Laporte J, Kress W, et al. Deletions in Xq28 in two boys with myotubular myopathy and abnormal genital development define a new contiguous gene syndrome in a 430 kb region. Hum Mol Genet 1996;5:139-43. 12. Fukami M, Wada Y, Miyabayashi K, et al. CXorf6 is a causative gene for hypospadias. Nat Genet 2006;38:1369-71. 13. Kalfa N, Liu B, Klein O, et al. Mutations of CXorf6 are associated with arrange of severities of hypospadias. Eur J Endocrinol 2008;159:453-8. 14. Chen Y, Thai HT, Lundin J, et al. Mutational study of the MAMLD1-gene in hypospadias. Eur J Med Genet 2010;53:122-6. 15. Qian C, Lin HW, Sun P, et al. Research of MAMLD1 gene in Hypospadias. J Clin Pediatr Surg 2012;11:106-11. Figure Legends Figure 1. Mutations of MAMLD1, the number represents the exon serial number, the black area represents the coding region. Table 1à ¯Ã‚ ¼Ã… ½Clinic phenotypes of 72 patients with hypospadias Table 2. Patients complicated by other genitourinary system malformations Table 3. Mutations of MAMLD1 gene screened in patients and controls

Disorder in King Lear Essay -- King Lear essays

Disorder in King Lear   Ã‚  Ã‚  Ã‚  "Order from disorder sprung." (Paradise Lost)   Ã‚  Ã‚  A [kingdom] without order is a [kingdom] in chaos (Bartelby.com). In Shakespeare's tragic play, King Lear, the audience witnesses to the devastation of a great kingdom. Disorder engulfs the land once Lear transfers his power to his daughters, but as the great American writer, A.C. Bradley said, "The ultimate power in the tragic world is a moral order" (Shakespearean Tragedy). By examining the concept of order versus disorder in the setting, plot, and the character King Lear, Bradley's idea of moral order is clearly demonstrated by the outcome of the play.       "By removing a 'degree' or not acting according to the 'natural' social order, disorder and disharmony in the whole of the universe are inevitable" (Sarah Doncaster). Bradley's idea of moral order is evident from the setting of the play. An excellent example from the play would be that of the storms. By using the technique of pathetic fallacy, Shakespeare creates a storm raging in the sky to reflect the storm raging inside of Lear. Upon the heath, Shakespeare intertwines this idea of disorder in the universe and disorder within Lear. King Lear says,       Rumble they bellyful! Spit, fire! spout, rain! Nor rain, wind thunder, fire, are my daughter: I tax you not, you elements, with unkindness; I never gave you kingdom, call'd you children... (3, ii, 14-17)       Lear's feelings in this passage parallel the disorder of the storm. To bring order to the universe, Lear must start by bringing order to himself. This occurs when he becomes lawful and puts his daughters on trial. Soon after, Lear says, "When the rain came to wet me once and the wind ... ... statement because of the "innocent" deaths, it is these innocent deaths which further support the fact that moral order is supreme. The Phrygian Stoic philosopher, Epictetus said it best, "Since it is order which shapes and regulates all other things, it ought not itself to be left in disorder" (Epictetus)       Works Cited Bradley, A.C. Shakespearean Tragedy. London: Macmillan, 1905 Doe, John. "Open Quote" Bartelby.com http://www.bartleby.com/81/14917.html Doncaster, Sarah. "Discuss the Representation of Nature in Shakespeare King Lear." Shakespeare Online.   http://www.shakespeare-online.com/essays/learandnature.asp 04 May. 2000 Epictetus. Discourses. Boston: Harvard University Press, 1928 Milton, John. Paradise Lost. Oregon: University of Oregon, 1997 Shakespeare, William. King Lear. Oxford: Oxford University Press, 1998

Corporal Punishment in Schools Essay -- Essays Papers

Corporal Punishment in Schools I wrote this paper for Contemporary Moral Issues class. This was an assignment of our choice and I chose to do this topic, because the week before in Intro to Education we had discussed discipline methods and I was astonished to learn that corporal punishment still existed in schools. I am hoping that by including this piece of work on my webfolio others will become aware that corporal punishment is alive and used often in our schools. In the following paper I will discuss the controversial issue of the use of corporal punishment in schools. Supporters for corporal punishment say that it is a deterrent to misbehavior and delinquency, is needed to maintain discipline, and is not a form of child abuse. The position against corporal punishment says that it is of limited effectiveness, has potentially serious side effects, is a form of child abuse, and should be abolished in all schools. I think the position against corporal punishment should become the social or public policy. Corporal punishment should not be used as a form of discipline, because it leaves psychological and physical harm on children. The first key argument against corporal punishment that I will present is the argument that corporal punishment is a form of child abuse. The Policy Statement of the American Academy of Child and Adolescent Psychiatry states, "corporal punishment is a discipline method in which a supervising adult deliberately inflicts pain upon a child in response to a child's unacceptable behavior and/or inappropriate language" (1). If one is deliberately inflicting pain on another, then that is for sure a form of abuse. Many students are physically and psychologically assaulted... ...htm 1. Committee on Psychosocial Aspects of Child and Family Health. Guidance for Effective Discipline." American Academy of Pediatrics 101 (April 1998) Database on-line. Available from ERIC, American Academy of Pediatrics. 1. Flynn, Clifton P. "Exploring the link between corporal punishment and children's cruelty to animals." Journal of Marriage and Family 61 (November 1999). Database on-line. Available from ProQuest. 3. Hyman, Irwin A. "Using research to change public policy: reflections on 20 years of efforts to eliminate corporal punishment in schools." Pediatrics 98 (October 1996). Database on-line. Available from ProQuest, Expanded Academic ASAP. 2-4. Hyman, Irwin A. and Pamela A. Shook. Dangerous Schools: What We Can Do about the Physicaland Emotional Abuse of Our Children. San Francisco, California: Jossey-Bass, 1999. 3.

Aerospace Outsourcing

Title of Assignment: Outsourcing and the AeroSpace Industry Table of Contents The origin of outsourcing in the Aerospace Industry†¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦ †¦.. . Page 3 Barriers to entry in the Monopoly and Oligopoly Industry†¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦. .Page 4 Types of Outsourcing†¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦. . Page 4 The Demand for Outsourcing†¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦. . Page 6 S. W. O. T. Analysis of Outsourcing†¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦. . Page 7 Gross Domestic Product †¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢ € ¦Ã¢â‚¬ ¦.. †¦.. . Page 9 The future of Outsourcing†¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦. Page 10 Is it Outsourcing or Offshoring†¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦. . Page 12 References†¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦.. †¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦ . Page 13 PowerPoint Presentation Slides The origin of Outsourcing in the Aerospace Manufacturing The term outsourcing is frequently used to describe a movement away from vertical integration – moving an activity outside the firm that formally was done within the firm. The term outsourcing also is used to describe an ongoing arrangement where a firm obtains a part or service from an external firm {text:bibliograp hy-mark} . Outsourcing is not a new concept, for hundreds of years businesses have outsourced their needs; however, during the industrial evolution the US economy begun to acquire a greater need for outsourcing as costs of manufacturing became a concern, this move begun in the 1950’s and continued aggressively to the 1980’s and 1990’s as global competition placed a greater strain on the economic growth {text:bibliography-mark} . Outsourcing was not formally identified as a business strategy until 1989 (Mullin, 1996). In the beginning of this acclaimed activity, firms outsourced what was deemed essential; however, as the evolution of outsourcing occured – fueled by the need to ‘cut-cost’ continued, other functions which were important but not relative to the core competencies of the firm begun to be outsource as well. From an economic perspective outsourcing is an industry in itself which can be viewed from a micro-economic and macro-economic perspective, this indicates its demand and supply curve moves in respective directions as the need for it grows or diminishes just as any other markets within an economy. In saying this it can be a very broad subject and can carry large discussions; this paper will deviate towards outsourcing’s role in the commercial aerospace manufacturing industry which begun in 1954 with Boeing and remained dominated by Boeing, Airbus and Bombardier since 1986. Barriers to entry Barriers to entry are one of the key incentives of the monopoly and oligopoly industry. The Aerospace industry, which is dominated by three main players, Boeing, Airbus and Bombardier is considered to be an oligopoly industry, because of the â€Å"Market Power† that is held by these firms. The industry has high fixed cost and is excessively capital intensive and time consuming, which serves as the key restriction not to be attractive for competition. In order to create value and share risk, the industry has fostered the idea of outsourcing. Outsourcing is using the facilities and services of a third party to supply good that would otherwise be created by the organization. Figure 1 details the major difference between a market with perfect competition and one that does not: {draw:frame} Types of Outsourcing The outsourcing framework begins with the decision to ‘make or buy,’ this would lead to ‘_insourcing__’_ (make) or outsourcing (buy). Outsourcing has two major components, ‘_inshoring_’ (in-land) or ‘_offshoring_’ (distant land). Offshoring has three major component, ‘_nearshore__’_ which indicates the work is outsourced to a nearby country to the parent company as opposed to farshoring; whereas, ‘_captive centers__’_ are overseas subsidiaries set-up to serve the parent company {text:bibliography-mark} . The framework of outsourcing can be very complex and arriving at the decisions can cause a material change in the supply curve of a manufacturing firm as the process of outsourcing is very costly and burdensome, if done improperly it can have a an unfavorable ROI. {draw:frame} Jobs outsourced Job functions outsourced fall in two major categories, Information Technology (IT) and Business Process Outsourcing (BPO). Under BPO, essential components or parts are being outsourced where it once was manufactured in-house. In the Commercial Aerospace manufacturing industry, it became more prevalent that manufacturing all parts of a commercial airplane was time consuming and costly, this brought about the demand for outsourcing. The demand of outsourcing Outsourcing is an exponential concept in business that has an impact on both the provider and consumer. When this aspect is viewed through the business lenses, the focus is on value creation. The intrinsic benefit of outsourcing is twofold, in that, the consumer gets to reap the benefit of economies of scale, where-as the provider get’s to charge for the product supplied. The exchange of these transactions create value for the parties involved as well as contribute to the participants gross domestic product (GDP). O_ffshoring_ of the general maintenance as well as parts for assembling new airplanes has heightened, which seems to have a negating effect of the domestic manufacturing industry. As airlines have rushed to slash costs, aircraft maintenance outsourcing has increased significantly from 37% of maintenance expenditures for major U. S. airlines in 1996 to 64% in 2007 ( At-A-Glance. 2008 December). The law of demand states that consumer will increase their consumption once there is a benefit to be gained. The increase in demand for outsourcing will result in a downward sloping demand curve, as outsourcing of maintenance continues to decimate the highly skilled aircraft labor force which will eventually have adverse economic effect – reduction in the wetware of the industry. The law of demand – Quantity demanded increases as price reduced {draw:frame} Technical knowledge is being shared with the players of the industry, thereby leading to increase competition in the near future. Boeing's partners in Japan and Italy will be building composite structures that include sophisticated sub-systems that are already certified, tested and ready for final assembly. (Manufacturing and Technology News, Feb 2007). There are benefits to be gained from the new phenomenon, â€Å"Outsourcing†. In the business arena benefits are offset by weaknesses, which need to be evaluated and planned for accordingly. S. W. O. T analysis of outsourcing has economic and financial benefits for the end user. S. W. O. T Analysis of outsourcing – The consumer perspective Financial Benefits No major capital outflow Contractual cost are treated as sunk cost – assist in decision making Less wear and tear on assets – longer life and high ROI Risk is shared with suppliers Lower unit cost Concentrate on creating value to customer No expense is incurred with equipment maintenance Pricing technique is enhanced, Marginal cost is known Variable costs are known which help to allocate resource Plan, coordinate and manage corporate resources An outward shift signifies an increase in demand The financial gains of outsourcing will force firms to build this aspect into their strategy; this will create a shift in demand for the commodity, thereby shifting the curve to the right. An increase in demand will cause shift in demands as oppose to a movement along the curve which is the result of a reduction in price. {draw:frame} Gross Domestic Product of domestic and foreign economy India’s economy is the twelfth largest in the world by nominal value, and ranks fourth in purchasing power parity. In 2008, India had established itself as the world’s second fastest growing major economy. The service industry in India accounts for 62. 6 percent of the country’s GDP followed by the industrial and agricultural sectors which contribute 20 percent and 17. 5 percent. India’s GDP in 2008 was 3. 344 compared to the US GDP which was 1461 in 2008. GDP graph of India and the United States {draw:frame} Outsourcing is the practice of using a service from an outside supplier. There are many pros and cons when it comes to outsourcing; however, many big name airline companies based in the US weigh their opportunities. India has become the leader in outsourcing, gathering interest of companies looking to save money. India is well known for their IT, science, and technology, giving companies like those in the airplane industry a reason to consider outsourcing. Those who wish to outsource reap the benefits of paying lower wages: however, it can come at a cost of language barriers and cultural differences. In some circles the language barrier is considered a pro not a con because many Indian vendors invest money in cross cultural training. There is also the uncertainty of the outsourcing company being able to stay in business. In today’s economy many airlines are using outsourcing by purchasing goods at a lower rate than they would if they were to buy them domestic. Many of the major players in the airline industry are finding it more beneficial to purchase the materials that they are using for their business via outsourcing. The airplane manufacturing industry as a whole is expected to grow between 150 billion and 225 billion by the year 2020 in total offshore engineering. India provides aerospace firms both aircraft design and on board electronics systems such as flight control and engine control. The Future of Outsourcing The future of outsourcing appears to be unswerving as processes will remain available to any firm that needs to utilize the activity. However, there are benefits and challenges to major component of selecting the correct provider. These are _appropriate offshore locations, selections of ideal outsourcing partner, dynamic Challenges and outsourcing in-house problems_, are key factors which will determine the future of outsourcing for both supplier and consumer. The future of outsourcing is contingent on the ability to outsource a need effectively, this is empirical to the future of the economy in which outsourcing is a major contributor, for example Boeing and many other firms outsourced to China for years and China’s economy grew due to the decisions that were made. Outsourcing is economically smart on a micro-economic perspective; however, it can be devastating on a macro-economic perspective if the goal is purely capitalistic. {text:bibliography-mark} Priorities for selecting an outsource partner _ _On a scale of 1 to 5 (where 1 = extraneous and 5 = vital) {draw:frame} Selection of appropriate offshore location {text:list-item} {text:list-item} {text:list-item} Selection of ideal outsourcing partner {text:list-item} {text:list-item} {text:list-item} {text:list-item} {text:list-item} {text:list-item} {text:list-item} Dynamic challenges text:list-item} {text:list-item} {text:list-item} {text:list-item} {text:list-item} {text:list-item} Outsourcing in-house problems {text:list-item} {text:list-item} {text:list-item} {text:list-item} {text:list-item} Kate Vitasek speaks of the decision to outsourcing and the approach to successfully outsourcing. In her views that is the goal of Vested Outsourcing, and this is accomplished by implementing five basi c rules explained in her book. Focus on outcomes, not transactions. Focus on the WHAT, not the HOW. 3. Agree on clearly defined and measurable outcomes. Optimize pricing model incentives for cost/service trade-offs. 5. Governance structure provides insight, not merely oversight. Is it Outsourcing or Offshoring? There are some anti-outsourcing trend booming in the US, but the US Chamber of Commerce (USCC), has evidently come out sturdily in favor of outsourcing as it considers it good for the US economy and it has reportedly decided to fight legislative moves against outsourcing of jobs to countries where jobs are being outsourced. text:bibliography-mark} . With the large amount of lay-offs which have occurred and the many more which may come about, outsourcing is on the hot-plate of a political split, many agree and many disagree with outsourcing; however, is it outsourcing that is the problem or ‘offshoring,’ there are many who agree on a macro-economic perspective that ‘offshroring’ is unhealthy for the economy and have argued their point. The Aerospace industry has ‘offshored’ since the 1960’s and have not collapse the US economy in doing so; however, it has placed itself in dear competition with China who now makes their own planes and gained experience from having been Boeing’s major outsourcing partners. References

How does human cruelty darken Browning’s poetry? Essay

On the one hand, some people agree that the recurring theme of human acts of cruelty, such as murder and deceit, throughout his poetry instils a sense of darkness. An example that supports this is the joy and delight that the female narrator feels in ‘The Laboratory’- â€Å"invisible pleasures†, which gives an impression of uncontainable excitement as she helps concoct her deadly poison for which she has high admiration, as it finally allows her to get her revenge, emphasising a sinister tone in the poem as the woman revels in the pain she is about to cause, holding no remorse. This can be compared to the similar way in which the persona of the duke in ‘My Last Duchess’ also shows no remorse or guilt for the presumed murder of his duchess, darkening the air of the poem as, combined with the warning implications of further intentions to keep his next duchess exactly where he believed she was supposed to be within society, he seemingly has no fear of be ing caught and if so, punished, showing the danger in the immense amount of power he holds. On the other hand, I partly disagree with this statement as Browning also incorporates social realism and satirical comedy into his work, to portray the hypocritical yet casual nature of cruelty within society, such as in ‘The Pied Piper of Hamelin’. The brutality of humans within this poem is represented by the contrast between the theoretical behaviour of a jester-like figure and a well-dressed mayor, and the actual way in which they behave showing that a person cannot be judged by appearances, in a comedic manner. This is similar to ‘The Patriot’ as Browning used a consistent rhyming scheme to represent the way in which society has and never will change over time, and people will always look for someone to blame life’s problems on. Another reason for my opposition to this statement, based on Browning’s ‘Pied Piper of Hamelin’ is that the cruelty portrayed within the poem is not necessarily a result of human behaviour, but rather an otherworldly being; â€Å"no guessing his kith or kin†, which suggests that nobody could distinguish where he had come from as he was so different to everybody else. On the contrary to this, many would agree with the statement that human acts of cruelty darken Browning’s poetry because the pied piper abducts the innocent children of Hamelin for a crime they themselves had not committed, emphasising how truly evil his actions were. By taking the children, the piper literally took the fresh, new life out of the town, which has connotations of light and happiness, therefore meaning the piper managed to take the light out of the town and poem. Furthermore, darkness descends upon Browning’s work as a result of the introduction of human cruelty, especially in ‘The Patriot’ in the way that society so easily turned against their leader after he had failed to give them what they wanted, despite his best intentions in trying to give them everything that was best for them, and punished him by seeing him die up close from the best possible view in a humiliating and demeaning public execution. On other hand, some disagree: Laboratory- sympathy felt for the poisoner, so some justification felt/admiration of her strength as only female narrative MLD- charismatic duke/ justification of his actions.

Has the law proven effective regulating the banking industry or are the limits of a bankers business too complex to be laid down by the law.

Introduction It will be determined in this study whether the limits of a bankers business can ever be laid down by the law or whether a bankers business should in fact be left undefined. This will be done in light of the recent financial crisis so that a determination can be made as to whether banking law has proven effective in regulating bankers or whether unnecessary risk are still being taken. In doing so, the powers and responsibilities of the Financial Services Authority (FSA) will be examined in order to decide whether the activities currently being undertaken by the FSA are sufficient enough to regulate the financial market. Literature Review The main objectives of a bank is to provide financial services to individuals and organisations by allowing money to be either borrowed or deposited whilst at the same time acting as a means for credit to be created. Nevertheless, given the complexity of the modern banking business, it seems as though a lack of regulation exists which is especially evident in light of the recent financial crisis. This is because; banks appear to have taken extortionate risks without any intervention which is highly detrimental to both the economy and consumers. It is quite difficult to determine what a bankers business should consist of, however, which is why great difficulty remains when trying to assess how they ought to be regulated. And, although some attempt to define a bankers business has been made by the courts; Commissioners of the State Savings Bank of Victoria v Permwan & Anor (1914) 19 CLR 45 and United Dominions Trust Ltd v Kirkwood [1966] 1 QB 783 a bankers business still remains ill-de fined. It is unclear whether a bankers business should be laid down by the law, however, since the activities undertaken by banks are often to wide-ranging to classify. This would impose too much restriction on banks and certain activities would be prevented from being undertaken; Woods v Martins Bank (1959) 1 QB 55. Despite this, it is important that some form of restriction is in place so that unnecessary risks are avoided. This was highlighted by Benston and Kaufman (1996, p. 1) when they pointed out that; â€Å"to protect our money, banks should not be allowed to take great risks that might cause them to fail.† Therefore, some restrictions are needed so that banks are not free to do as they wish as this would be extremely damaging to the economy. The Financial Services Authority (FSA) was in fact introduced in order to regulate the activities of bankers, yet it remains arguable whether this has been successfully achieved. This is because, although the FSA has been provided with s tatutory powers under the Financial Services and Markets Act (FMSA) 2000 to regulate the financial services industry more effectively, given the recent financial crisis, it is questionable just how efficient the FSA is. However, as noted by the FSA themselves; â€Å"as a risk-based regulator, our approach is based on a clear statement of the realistic aims and limits of regulation.† Not all agree with this, however, and instead it has been argued that the FSA are no longer relevant in today’s society (House of Commons Treasury Committee, 2009, p. 4). In view of this, it has thus been noted by Awrey that; â€Å"perhaps most glaringly, conventional financial theory failed to adequately account for the complexity of modern financial markets and the nature and pace of financial innovation.† This signifies how the FSA have been unable to keep up-to-date with the advances that are continuously being made within society and that further regulatory procedures are thereby required if the banking industry is to be restored to an acceptable state. Modern financial markets thereby appear to complex for the FSA and so it is important that more stringent regulatory practices are instilled upo n the banking industry so that banks do not abuse their powers and responsibilities. Proposed Methodology In acquiring the relevant information for this study, various academic opinion, case law and legal theory will be analysed. These will be acquired by accessing text books, journal articles, governmental reports and online legal databases. Secondary research will be the main forma of research used for this assignment so that existing data can be collected and analysed in order to reach a conclusion. This will be a more cost effective and time saving way of undertaking the research, which is applicable for this assignment given the difficulty in obtaining primary research from large organisations such as the FSA. Quantitative and qualitative research methods will be used so that information can be gathered that is in numerical form, whilst also gathering information that is not in numerical form but which contains descriptive data. Outline of the WorkOverview of the Banking Industry A brief overview of the banking industry will be provided here in order to determine the main objectives of bankers and the effects in which their activities can have on the economy.Powers and Responsibilities of Bankers It will be considered here whether a bankers business can be defined by the law or whether the activities are too complex to be defined.Regulation of the Banking Industry An evaluation as to whether the banking industry ought to be regulated more efficiently will be made by looking at the existing regulatory procedures and considering whether they have so far been effective or whether more needs to be done in order to prevent further financial crisis’ from arising.Financial Services Authority’s Powers and Responsibilities The powers and responsibilities of the FSA will be considered in order to determine whether additional powers ought to be conferred upon the FSA or whether modern banking is too compl ex to enable the FSA to regulate financial activities. Thus, it will be shown that whilst banking activities do remain complex, the FSA should still be provided with the ability to regulate the banking industry so that a robust system is in place. If the activities of bankers were not was in needed so that any problems that are likely (FSA, 2009, p. 5). Hence, it is vital that the risks taken by bankers are severely limited since much ambiguity would ensue if restraints were not being imposed upon the financial sector and as noted by Johnston (1960, p. 347; â€Å"the difficulty is increased by the fact that banking, like other forms of business, continues to develop and expand its activities to meet its competitors and provide wider services for the public with the result that any attempt to squeeze the concept into the confines of a definition may prove successful today but inadequate tomorrow.†Are the Powers and Responsibilities of the FSA acceptable in today’s soci etyHere, it will be discussed whether the powers and responsibilities of the FSA are acceptable in today’s society where modern banking is more complex than ever. Hence, it will be shown that the FSA has come under much scrutiny since the financial crisis was first instigated, yet rather than taking a step back, the FSA need to take a more interventionist approach so that future financial crisis’ can be prevented. It has thereby been said that the FSA should investigate â€Å"how financial services firms manage their Information Security Risks; how these risks are evolving; the risks they pose to our objectives; and the role industry and government bodies play in assisting regulated firms to address these Information Security Risks† (FSA, 2004, P. 3). If a more interventionist approach is undertaken by the FSA, financial crimes similar to those that caused the economic crisis will be more easily identified and therefore dealt with appropriately. Strong financial crime deterrent messages[1] will also be sent out by the FSA and financial crime will inevitably be reduced. References Awrey, D. (2011) Complexity, Innovation and the Regulation of Modern Financial Markets, Harvard Business Law, Oxford Legal Studies Research Paper No 49/2011, [Online] Available: http://papers.ssrn.com/sol3/papers.cfm?abstract_id=1916649 [14 February, 2013]. Benston, G. and Kaufman, G., (1996) Why Regulate Banks, Res, [Online] Available: http://www.res.org.uk/society/mediabriefings/pdfs/1996/July/benston.pdf [13 February 2013]. FSA. (2004). Countering Financial Crime Risks in Information Security, Financial Crime Sector Report, [Online] Available: www.fsa.gov.uk/pubs/other/fcrime_sector.pdf [14 February, 2013]. FSA., ‘Delivering a Reduction of Financial Crime’ (2011) FSA Annual Report 2011/12, [Online] Available: www.fsa.gov.uk/pubs/annual/ar11-12/section5.pdf [14 February, 2013]. FSA. (2009) The Turner Review; A Regulatory Response to the Global Banking Crisis, Financial Services Authority, [Online] Available: http://www.fsa.gov.uk/pubs/other/turner_review.pdf [14 February, 2013]. FSA., (2012) What we Do: Regulatory Approach, Financial Services Authority, [Online] Available: http://www.fsa.gov.uk/pages/about/what/approach/index.shtml [13 FEBRUARY, 2013]. House of Commons Treasury Committee. (2009) Banking Crisis: Dealing with the Failure of UK Banks, Seventh Report of Session 2009-09, Report Together with Formal Minutes, HC 416, [Online] Available: http://www.publications.parliament.uk/pa/cm200809/cmselect/cmtreasy/416/416.pdf [14 February, 2013]. Johnston, C. C. (1960) Judicial Comment on the Concept of Banking Business. 2 Osgoode Hall 347. [1] FSA., ‘Delivering a Reduction of Financial Crime’ (2011) FSA Annual Report 2011/12, fsa.gov.uk/pubs/annual/ar11-12/section5.pdf> [Accessed 20 August, 2012].

Reflection Week Essay

Apply ratio, vertical, and horizontal analyses to financial statements Ratio analyses are used by companies to gather information in a company’s financial statement. Ratios and numbers from a company’s current year are compared to previous years and sometimes even the economy to judge the company’s performance. There are several ratios such as profitability ratios, liquidity ratios, activity ratios, leverage ratios and market ratios that can be used to calculate financial information. In vertical analyses, each entry of the assets, liabilities and equities in a balance sheet is represented as a proportion of the total account of the financial statement. In horizontal analysis a company’s ratios are compared in the financial statements over a period of time. Horizontal analysis can be used from revenues to earnings per share. Prepare a statement of cash flows using both direct and indirect methods. When preparing a statement of cash flows, there are two different methods that can be used; there is the direct method, and there is also the indirect method. The direct method shows operating cash receipts and payments, making it more consistent with the objective of a statement of cash flow, while the indirect method adjusts net income for items that do not affect cash. The FASB allows both methods to be used because in the end the results of the total amount for net cash provided by operating activities arrive in the same way. Companies use numerous adjustments when preparing such statements so following a proper guide such as the direct method or indirect method will help to ensure that everything is properly in order the way it should be. Prepare journal entries associated with the issuance of preferred and common stocks and the declaration and payment of dividends The issuance of common stock affects only paid-in-capital accounts. Always record common stock at its par or stated value. Debit Cash and credit Common Stock. Preferred stock has preference over common stock. However, preferred stockholders do not have voting rights. The entry is debit to Cash and credit to Preferred Stock. For a corporation to issue cash dividends there must be: retained earnings, adequate cash, and a declaration of dividends. A company does not pay dividends unless its board of directors decides to do so, then it is deemed declared. When it is declared then it becomes a liability. Three important dates are observed with dividends: declaration date, record date, and the payment date. Declaration commits a corporation to legal obligations.