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

Noli me tangere reflection Essay

Noli Me Tangere. It is a novel written by Filipino writer and national hero Jose Rizal and was first published in 1887 in Berlin, Germany. This novel was written to remind us the bad things that Jose Rizal experienced during his time by the Spanish. From the very start of this novel, the first plan of our national hero is, to write this novel with the help of his countryman that is also suffering to the hands of the Spanish, but suddenly he failed to do it with the help of his countryman, because his countryman lose their hope in fulfilling their dreams to have freedom in the hands of the Spanish colonies. Jose Rizal, did not give up, because he continue write this novel without the help of his countryman, and he decided to write it by himself only. The first chapter of this novel was entitled â€Å"the paging†, where in, in this chapter stated the lifestyle of Don Santiago de los Santos also known as Kapitan Tiago, he was from Binondo and he was the step father of Maria Clara according to this chapter. In this chapter, the other characters was Padre Sibyla, Padre Damaso, and Tenyente Guevarra.According to this chapter, kapitan tiago invited the said characters to go to his house and have asimple gathering, but suddenly it came to a fight between Padre Damaso and Tenyente Guevarra because of the ereheng namatay. Padre Sibyla stops the rivalry between the two. The second chapter was entitled â€Å"Ang binatang si Crisostomo†. Where in in, this chapter, Kapitan Tiago present Don Crisostomo Ibarra to the priest, the son of his deceased friend named Don Rafael Ibarra.

Karl Marx and The Russian Revolution Essay example

Karl Marx, a German philosopher, is known for his revolutionary political ideas during the Russian Revolution. He established the idea of â€Å"materialist conception of history†, meaning how society and the economy is organized is determined by changes material conditions. He published this thesis in his manuscript called The German Ideology. While writing The German Ideology, Marx also joined the Communist League, an international proletarian organization, and wrote a polemic against P.J. Proudhon’s idealistic socialism. Vladimir Lenin was a theorist and communist philosopher during the Russian Revolution and a serious follower of many of the Marxist ideals. He is remembered as one of the greatest revolutionaries in history for many reasons,†¦show more content†¦Trotsky lost and was exiled, then assassinated. Bolsheviks were members of a section of the Russian Social-Democratic Worker’s party. The section was led by Vladimir Lenin, who helped the group seize control of Russia, beginning the Soviet Union. Bolsheviks were founded when supporters of Lenin fought for restriction of membership to professional revolutionaries, and won. They maintained a highly consolidated, well-ordered, and professional party. The group became gradually popular among workers and solders after Lenin demanded peace and insisted that the soviets, worker’s councils, should be in power. This rise in popularity is what drove the Bolsheviks to take over the Russian government and set a dominant power, the Soviet Union. Czar Nicholas II was the last supreme leader of Russia. He was opposed to any and all social reform and stood rooted in his traditional principles. He was considered an incompetent leader, forcing outdated policies upon the Russian people, especially since he ruled during such a revolutionary time. His neglect of the Russian citizens and their needs is what established the beginnings of the revolution. In 1917 he was ousted and went into exile. Stalin’s Secret Army, also known as the KGB, was a secret organization that handled Russia’s internal security and intelligence. It began under Lenin’s rule as the Cheka, which was used to defend the Bolsheviks from the White Army. Right from the beginning, the groupShow MoreRelated The Warnings in George Orwells Animal Farm Essay1248 Words   |  5 Pagesevents surrounding the Russian revolution that took place in 1917. Orwells tale of Animal Farm is seemingly a story of how a group of farmyard animals plot to overthrow their owner and seize control of the land. The novel seems to be a simple story, however Orwell wrote this book as an allegory, a story that has a clear secondary meaning beneath is literal sense. Everything in Animal Farm is used to represent people and events that took place during the Russian revolution from 1917-1939. OrwellRead MoreSimilarities between Animal Farm and the Russian Revolution874 Words   |  4 Pagesï » ¿The Russian Revolu tion Animal Farm Animal Farm is a satirical novella by George Orwell, and it can also be understood as a modern fable. The book is about a group of animals who drive away the humans from the farm which they live on, and it is primarily based on the Russian Revolution. Animal Farm is well known as an allegory. Most fables have two levels of meanings. On the surface, the fable is about animals. But on the second level, the animals stand for types of people or ideas. The way theRead MoreKarl Marx, The Philosopher, And Revolutionary Socialist1068 Words   |  5 PagesKarl Marx was the philosopher, social scientist, and revolutionary socialist during the 19th century. He was born in Prussia, on May 5, 1818, into a wealthy middle-class family. His father was disqualified from being a lawyer because he was Jewish so he converted to another religion. Karl attended a Lutheran Elementary School, but later became a non-believer of any God and a person that believes physical matter is all that is real. Karl graduated from Friedrich Wilhelm Gymnasium at the age seventeenRead MoreCharacters In Animal Farm, By George Orwell1079 Words   |  5 PagesLondon,United Kingdom. George Orwell published Animal Farm on August 17,1945. The setting of Animal Farm is on a farm in England. The characters in Animal Farm are based off of leaders or people during a Russian political upheaval. The book reflects on the events leading to the Russian Revolution of 1917. George Orwell uses different characters and themes in Animal Farm such as leadership,corruption, and class conflict. Old Major is one of the leaders of the pigs. Old Major is a prize Middle WhiteRead MoreThe Russian Revolution Of 19171563 Words   |  7 PagesThe Russian Revolution of 1917 swept the country into an entirely new epoch, changing a monarch-led country into the Soviet Union and spreading the red of communism in waves through generations. A powerful team of Vladimir Lenin and Leon Trotsky organized the Bolsheviks, or Red Army, in political and military strategy against the Menshevik White Army. Part of their success came from the lack of unification of the Mensheviks. While the White Army banded together under a simply ‘anti-Bolshevik’ policyRead MoreGeorge Orwell s Animal Farm922 Words   |  4 Pagesboar of the farm, Old Major, mimics Karl Marx, the â€Å"Father of Communism,† and Vladimir Lenin, a Russian communist revolutionary. George Orwell introduces direct parallels between the respected figures through their mutual ideas of equality and profoundly apprecia ted qualities. Furthermore, his utilization of dialect and descriptions represent the key ideas of the novel. Throughout the novel, Orwell continues to show comparisons between Old Major and Karl Marx/ Vladimir Lenin that reveal their representationRead MorePolitical Issues In Russia1071 Words   |  5 PagesRussian Federation has a long and interesting history. Many different events the structure and development of the country. Nowadays, Russia plays one of the most important roles in our world. Russia is located at the intersection of different cultures and contains multinational population and ethno-cultural diversity. Russia is an interesting country to discuss its issues of ethnicity and religion, try to predict the future development and economics of the country. How different country’s issuesRead MoreAnimal Farm: a Compare and Contrast on Karl Marx Communist Manifesto1037 Words   |  5 PagesTopic: Research the life of Karl Marx. What were the fundamentals of his Co mmunist Manifesto and how do they compare to the ideas expressed by Old Major in Animal Farm. Animal Farm is a novella written by George Orwell in 1945. This particular story by George Orwell reflects on the events leading up to and during Stalin era in Russia. During the time he wrote, the work of Karl Marx’s Communist Manifesto was being followed by the Russian leaders, and some of Marx’s ideas can be foundRead More Symbolism and Interpretation in Animal Farm Essay808 Words   |  4 PagesANIMAL FARM, and the real-life counterparts they appear to represent. Consider how each character could also be interpreted to have a larger, broader meaning. Farmer Jones : The farmer stands for the Russian Czar Nicolas II who was forced to abdicate after the successful February Revolution. In addition, Mr. Jones symbolizes the evils of capitalism, and the moral decline of men under this type of society. Humans: The humans stand for the capitalists, who exploit the weak. The gradual transformationRead MoreMarx And Engels : An Old Meeting Place Of Voltaire And Diderot856 Words   |  4 PagesIn August of 1844, 26-year-old Karl Marx and 23-year-old Friedrich Engels met in Paris for an aperitif at the Cafà © de la Regence – an old meeting place of Voltaire and Diderot. Their ensuing discourse lasted ten intense days and resulted in a lifelong friendship. This transformative relationship is evident in the publishing of The Communist Manifesto in 1848, during a period of widespread European revolution. Although Marx and Engels agreed that revolution was justified to create a communist society

Alphabetical Phrasal Verbs Reference List

Phrasal verbs are verbs that are made up of a main verb and followed by particle, usually prepositions. Most phrasal verbs are two or three words and can be quite challenging for English learners as they can be literal or figurative in meaning. In other words, sometimes it is easy to understand the meaning (such as get up), but in the case of figurative meanings can be quite confusing (such as pick up). Begin learning phrasal verbs with a limited list. The list below provides a good starting point for intermediate level English learners. Teachers can use this introducing phrasal verbs lesson plan to help students become more familiar with phrasal verbs and start building phrasal verb vocabulary. Finally, there are a wide variety of phrasal verb resources on the site to help you learn new phrasal verbs and test your understanding with quizzes. This ESL phrasal verb reference guide is intended for English learners. The guide contains some of the most important phrasal verbs used in everyday English. There are many, many more phrasal verbs, but I have chosen these verbs as a good starting point for English learners. Each phrasal verb is defined, has an example sentence for context, and states whether the definition is separable or inseparable, transitive or intransitive. For more information on how to use phrasal verbs, read the phrasal verb guide on this site. Important phrasal verbs in English starting with the letter A. Includes examples and whether the phrasal verb is separable / inseparable, transitive / intransitive. S Separable IS Inseparable T Transitive IT - Intransitive account for explain, be the reason for His lack of interest accounts for his poor grades. IS T act on take an action Tom acted on the information. IS T add to increase the size This chair will add to the furniture we already have. S T add up make sense Your guess adds up based on all the facts. IS IT agree with have the same opinion as someone I agree with Tom about the need for better schools. IS T allow something for provide time, money, or other resource for something You need to allow two hours for traffic. S T answer for something be responsible for something The director answers for the drop in sales last quarter. IS T argue something out discuss all the details to come to an agreement We argued our differences out and signed a contract. S T arrive at something agree upon something We arrived at a contract last week. IS T ask after somebody ask how someone is doing I asked after Kate last week and her mother told me she was doing well. IS T attend to something take care of something you need to do Peter attended to preparations for the party while his wife cooked the dinner. IS T average something out arrive at the average figure I average the contracts out and well make a profit of $250,000. S T

History Begins At Home Remember - 1917 Words

History Begins at Home Remember. Upon hearing this word, a weathered widow thumbs a tarnished locket resting in the hollow of her throat. A wistful child nestles a tattered teddy bear into his chest. A shellshocked veteran flicks open the blade of a corroded Swiss Army Knife. Every life is a story composed of memories— of recollections enhanced by physical objects that evoke fervent feelings of these moments. Because of this, any thing can mean something to anyone, regardless of its surface value or outward appearance. This stirs up quite a bit of controversy in the world of conservation. Most will concur that historic preservation is about more than simply maintaining bricks and mortar. The practice acknowledges that built history serves†¦show more content†¦But vernacular buildings are not exactly places that coincide with the popular definition of what is worth saving. Yet, upon closer inspection, it is these haggard monuments to the toils of previous proletariats that hold the most poig nant stories of the past. Take Pine Street Historic District in Montclair, New Jersey for example. It is filled with â€Å"vernacular single-family homes and masonry apartment buildings but appears to be nothing more than a run-down ghetto in need of extensive renovation. The more pressing concern is that its preservation impedes the development of Montclair Connection, a proposed 1,200-foot train track that would shorten the commute of thousands of employees who work in Manhattan. But these houses they would so readily see demolished convey the story of the caretakers, gardeners and maintenance people who tended to Montclair’s more ostentatious estates (Galant). Just because the homes in the district are not grand does not mean that they do not hold cultural significance. Every place has its secret history, its hidden accounts of desire and diversity. Imagine the gardener’s daughter meeting up with the son of the landed gentry on her back porch to engage in a c landestine affair under the summer stars. The past is told the way people choose to remember it. And who is to say that the previous bourgeoisie should fade into oblivion simply because they

Between the Wars Free Essays

The event that had significant impacts during the interlude between the First and Second World Wars would be the Great Depression. The effect of this financial crisis, not only in the United States but also in other parts of the world, was apparent both in the domestic front and in the international community. The Great Depression started during the late 1920s and would stretch until the next decade. We will write a custom essay sample on Between the Wars or any similar topic only for you Order Now This historical turning-point was triggered by Black Tuesday, which was the day when the stock markets had a major downturn. (Rothbard, 2000) The impact of this event, both positive and negative, was massive indeed as the country was forced into a state of great recession and then reassessment of economic and social policies. (Mcelvain, 1993) In the ground level, the people experienced difficulties, as employment becomes scarce, thereby leading to poverty and hunger, which was prevalent during that decade. The citizens in the grassroots were the ones that was most affected, for the depression was deeply felt by everyone. The length, lasting 10 years, was overwhelming indeed; the extent of the crisis was equally devastating. The agriculture and primary sectors industries experienced economic slumps even bankruptcies, which in turn burdened the people whose wages declined and employment opportunities disappeared. The end of this Great Depression coincided with the start of the Second World War. The implication of the financial crisis was not only social but also political, as policies were forced to be reassessed and eventually changed. The New Deal policy was a result of the crisis. Also, government officials debated the liberal policies in economics, as many abandoned liberal economics, and advocated more protectionist policies. The impact of the Great Depression is far-reaching and vast, as it is political, social and economic. References Mcelvaine, Robert. (1993). The Great Depression: America 1929-1941. United States: Three Rivers Press. Rothbard, Murray. (2000). America’s Great Depression. United States: Ludwig Von Mises Institute. How to cite Between the Wars, Papers

Brand Management Apple Inc

Question: Discuss about theBrand Managementfor Apple Inc. Answer: Introduction The modern economic structure of the world operates in a complex organizational structure and it is the duty of every firm functioning in this environment to introduce innovative strategies to make their product or service unique. This study is concerned with the organization named Apple Inc, which is the creation of Steve Jobs and his friend Steve Wozniak, who were school buddies. Their innovative and creative ideas and thoughts while working for Hewlett and Packard, was the motivation to start- off such a renowned organization of the present time. Apple now is a producer of different innovative products like the iPod, iPad, iPhones, Mac books, laptops. Apple TV etc. it is also a supplier of hardware and software processors to different other firms all around the world. Apple is faced with tough competition in this industrial sector as it has big players like Google, Amazon, Microsoft, HP etc. It is known that Apple is a young organization with respect to the above mentioned organizations in the IT industry but it has beaten all its rivals with respect to the products they manufacture (Apple. 2016). This way the comparative brands of Google, Microsoft etc have not been effective enough to dethrone the products of Apple. Analysis The marketing strategy of Apple includes the various points, which will result in the success are like campaigns to be implemented by the people who interact with the customers about their products and motivate them for excessive use of their products. The firm also aims to improve the brand name to an extent of 60%. The revenue and sales per year also needs to be increased by 20%. The other important objectives and mission of the organization are to eliminate intermediaries from the market thus reducing the price of the product and selling the product directly to the consumers. Apple is also focused on producing its own storage products and computer accessories to reduce the cost of production. They are also with an objective to expand its network all over the world to become the number one company in terms of profit and customer base. The organization is also functioning powerfully in the sector to present its expertise through the products and implements production technology for the development of the network of distribution. Apple concentrates over almost every sections of the society to extend customer base and to increase market share. The firm also focuses on targeting the vertical markets being experts in their stream, uses modern technologies to enhance the industry, which is helpful for Apple to be known in the global market (Raut, and Brito, 2014). The values and objectives of Apple have always been to emphasize mainly on the innovation, which will be beneficial for the development. They also focus on simplicity as it of forms an intrinsic part of the organizations approach for product design and approach. They focus on supplying user-friendly products, which enables the consumers to improve their daily activities. Apples value also consists of proper selection of markets, which enables the firm to take business decisions more efficiently. Apple also limelights collaboration of employees and efficiency of their employees as an essential element for its business thus always takes the initiative to create a proper organizational culture. Competitive Analysis All these firms invest a significant amount of capital in the research and development and marketing. The reason behind the highly competitive nature of the market is due to its low switching cost. Thus, creation of new product is what Apple doing to maintain its share in the market position (Grant, 2016). The brand of Apple consists of their list of innovative products and services and with the introduction of these products in the market, the life of the consumers have become smoother and faster. These innovative products as a result have increased their market share and have also increased their customer base. Apple as result has created a brand name of itself and almost every consumer globally is aware of the products and the name Apple. Such a big impact in the market from Apple has urged its competitors to implement new and improved techniques for the production of newer products and thus competing with Apple. Analysis with the CBBE Model Brand building is one of the primary aims of every organization. This question related to this keen interest in brand building is answered through the CBBE model (Customer-Based Brand Equity). Identity The identity can be created through a proper brand salience, which relates to the customer awareness aspect. Customers are well aware about the products of Apple and are thus able to link the brand logo name and products in their memories. Meaning Meaning refers to the image of Apple, which is created through proper performance of the products of Apple. The performance is evaluated through the primary and secondary features of their products along with the product reliability, durability, efficiency and service effectiveness of the products of Apple. The style and design along with the price also puts a mark in the mind of the consumers and Apple with its innovative products have thus implanted deep in the minds of the consumers (Andajani, Hadiwidjojo, and Rahayu, 2014). Responses The response or the feedback of the customers is an essential part of any firm. Apple also looks into the responses of the customers. The customers generally respond depending upon the brand quality, consideration, superiority, credibility etc. All the mentioned adjectives are best suited for Apple as they hold tight hold on the market and the customers through its innovative product and quality services through fun, excitement and warm feelings (Apple. 2016). Relationship This step identifies the relationship and the level of knowledge the customers have about Apple brand. It shows the synch between the firm and the customers through behavioral loyalty, having a sense of community, and sentimental attachment. Active participation on the part of the customers to invest time towards the product and the firm creates a sense of attachment. Apple has that place in the minds of the customers and thus they hold a strong place in the minds of the heart (Thompson, et al. 2013). Recommendation The analysis brings out a lot of ideas and a marketing plan can be recommended. The recommendations to Apple are as follows: Apple should concentrate and invest more in the research and development department and should implement advanced techniques to generate innovative techniques from time to time in order to maintain its competitive edge. The company should also focus on providing customer satisfaction through quality products and an efficient after sales service. Apple also requires to shape out new designs and concepts to propel them pass the competition of the rivals. It needs to support the hopes and dreams of the consumers and needs to function diligently to make their technology user friendly. They also need to assess their work process from time to time and needs to monitors the functions of its competitors in order to remain a step ahead of them. Therefore, an effective monitoring of the internal and external atmosphere is what is recommended to Apple in order to move forward in business. Reference List Andajani, E., Hadiwidjojo, D. and Rahayu, M., 2014. Customer Experience Model: Social Environment, Retail Brand and Positive WOM.Research in Business and Management,2(1), pp.25-41. Apple. (2016).Apple. [online] Available at: https://www.apple.com [Accessed 15 Oct. 2016]. Dess, G.G., Lumpkin, G.T. and Eisner, A.B., 2014.Strategic Management: Text and Cases. Fogliasso, C.E. and Williams, A., 2014. Analysis Of The Business, Societal And Governmental Relationships Of Apple Inc.Leadership Organizational Management Journal,2014(1). Grant, R.M., 2016.Contemporary strategy analysis: Text and cases edition. John Wiley Sons. Heracleous, L., 2013. Quantum Strategy at Apple Inc.Organizational Dynamics,42(2), pp.92-99. Raut, U.R. and Brito, P.Q., 2014.An analysis of brand relationship with the perceptive of customer based brand equity pyramid(No. 526). Universidade do Porto, Faculdade de Economia do Porto. Thompson, A., Peteraf, M., Gamble, J., Strickland III, A.J. and Jain, A.K., 2013.Crafting Executing Strategy 19/e: The Quest for Competitive Advantage: Concepts and Cases. McGraw-Hill Education.