Life of Frederick Douglass essays

Life of Frederick Douglass expositions In this short entry by Frederick Douglass, called Narrative of the Life of Frederick Douglass, he portrays prime instances of an unadulterated Machiavellian. Douglass gives us knowledge on Mrs. Hamilton, a slave proprietor, who simply like Machiavelli clarifies in The Qualities of the Prince gives us what precisely Machiavelli was discussing. Mrs. Hamilton is remorseless to her slaves so as to keep them steadfast and is never quiet during inactive occasions so as to maintain her slaves at her favorable position. Douglasss experiences with Mrs. Hamilton again show us precisely how Machiavelli needed a pioneer to control the individuals and with this Douglass gives us how Mrs. Hamilton being the pioneer, controls the slaves which are her subjects. At the point when Frederick Douglass initially acquaints us with Mrs. Hamilton he gives us an all around created visual on how she rewarded her slaves. Mrs. Hamilton would sit in the room in a huge seat with a substantial dairy animals skin close by. She would then whip the slaves, as they would pass by her while she hollered at them, and called them names. Mrs. Hamilton would likewise call Mary pecked than by her name. I consider this to be of treatment as full Machiavellian from Mrs. Hamilton. Machiavelli in his work The Qualities of a Prince recommends to pioneer that they ought to be brutal to their subjects so as to keep them faithful. I sense that by what Mrs. Hamilton was doing to her slaves might be taken a gander at from an unexpected route in comparison to by downright merciless. It shows to me that she was simply keeping her slaves faithful to her by whipping them and calling them names. Also, this to me shows that she adopted a strategy utilizing an organized Machiavellia n style. On the off chance that Mrs. Hamilton didn't practice this sort of treatment to her slaves they would most likely feel that on the off chance that they chose to escape for opportunity toward the North, Mrs. Hamilton would not have rebuffed them for it and let them to free. Mrs. Hamilton additionally utilizes another of Machiavellis proposals. M ... <!

HRM practice in USA and Russia Coursework Example | Topics and Well Written Essays - 1500 words

HRM practice in USA and Russia - Coursework Example Culture assumes a huge job regarding planning human asset the executives practice. HRM practice in Russia is profoundly particular from that of USA. Socio-political nature and social setting are diverse in these nations. This investigation will be partitioned into two portions. In initial segment human asset the board rehearses in Russia and USA will be examined and the subsequent part will manage impacting factors influencing human asset the board practice. Human asset the executives practice in United States is one of a kind since the nation centers around obtaining gifted people ready. The enrollment framework which is executed by the nation is neither position based nor vocation based. Direct application technique is used while enlisting for open area. Outer candidates can without much of a stretch go after various authoritative jobs. In setting of enlistment, no decent variety approaches are empowered yet more inclination is offered explicitly to military veterans. Motivating forces or rewards are planned by offices while pay-scale is organized by the administration. Business cost file is answerable for computing base compensation and there is no exchange empowered at group or individual level. Compensation level is balanced on premise of status positions. Advancements at all conceivable staff level is on premise of capabilities. Execution examination plan or experience isn't viewed as indispensable elements with regards to advancem ent (Paauwe, 2004). Occupation postings are accessible to all workers and HR office or appraisal focuses are exclusively answerable for determination of candidates. Progressive evaluations are not mulled over while giving advancements. Training meetings are likewise facilitated for advancement of crippled, ladies or other minority segment. Inward versatility level is steady inside United States. Preparing programs are sorted out for all colleagues

The Changes of Europe in the 1700s

The Changes of Europe during the 1700s Since the time the very beginning, people’s lives have been changing as people keep on learning new ideas of life. This paper looks at a portion of the progressions experienced in Europe during the 1700s. The entire of Europe is noted to have experienced assorted changes in course of the eighteenth century. Promoting We will compose a custom exposition test on The Changes of Europe during the 1700s explicitly for you for just $16.05 $11/page Learn More In this paper, I will inspect a portion of the progressions experienced in the mainland in respect of different significant parts of the human life, for example, wellbeing and social insurance, illness, training, and farming as the principle wellspring of nourishment and occupation for some individuals in those occasions. This paper likewise talks about in detail the fundamental contemplations and thoughts behind the incomparable Scientific Revolution just as the edification ingrained by early scholars and essayists in the distr ict. The eighteenth century would be a time of assorted changes in the entire of Europe. This period was generally alluded to as ‘the Age of Enlightenment’ and would be described by numerous progressions in different areas of life. This would be an increasingly bound together learned development across Europe among a gathering of savants or scholars who shared a dynamic enemy of strict point of view. This degree be that as it may, would be more noteworthy than it was initially accepted and it activated numerous positive just as negative changes over the locale. Both the Scientific Revolution and the Enlightenment would significantly change the essence of the landmass and come the 1700s, different changes would be clear in numerous countries over the mainland. One remarkable change that would affect other noteworthy changes would be the high populace rates saw across Europe during the 1700s. Numerous nations, for example, England and France expanded their populaces at th e quickest rate. Despite the fact that wellbeing and instructive offices were experiencing outstanding changes to the better, the administrations would be poor attributable to the increasing socioeconomics. High populaces would regularly glue different consequences for the human life among them sicknesses. During the 1700s, the Europeans would be subjects to numerous infirmities and sicknesses, for example, bubonic plague, measles, and little pox. Irresistible sicknesses stayed endemic in towns and the urban areas. The whole mainland had been portrayed by a fast improvement of clinics and over the span of this period, medical clinics would be opened in the bigger urban areas. These anyway would not be sufficient to provide food for the government assistance of the flooding populations.Advertising Looking for article on history? We should check whether we can support you! Get your first paper with 15% OFF Learn More The century was in fact one of the most enticing crossroads througho ut the entire existence of most European nations. Over the span of this period, Europe populaces would stay helpless before starvations and rehashed gather disappointments and this combined with the common ailments would force extraordinary enduring on peoples’ lives. In any case, regardless of these difficulties agribusiness was as yet rehearsed for thriving despite the fact that futile attributable to the dynamic starvation of the period. Bread was the staple nourishment for some individuals however it was once in a while accessible in many pieces of the locale. For this situation, most dinners would establish of peas and beans soup enhanced with vegetables and roots. In any case, regardless of these disappointments, the century would observer a few upgrades in the variety of yields and in the eating routine. Rural upheavals were likewise seen in certain parts, for example, England and Netherlands where horticulture would be directed in an increasingly logical way. Most Rev olution and Enlightenment scholars and masterminds had extraordinary contemplations and thoughts with respect to the idea of Europe and this would be the power behind the assorted changes in the mainland around then. One of the most well-known methodologies among scholars would be the possibility of legitimate and sound thinking. Another significant thought normal with illumination scholars and journalists would be the inquiry in regards to acknowledged convictions which added to new logical hypotheses. Clever and engaging style of composing was likewise utilized by scholars to impact individuals in understanding the illumination strategic. There were likewise different thoughts that would be founded on good, induction, and logical request and all these would come to impact advancement ways of thinking and monetary standards in the European history.

The Iliad Achilles Essay - 1925 Words

The Iliad: Achilles (Research Paper Sample) Content: THE ILIAD: ACHILLESThe Iliad is a piece of European literature that talks about the rage that erupted between Achilles and Agamemnon in the Greek Camp during the ninth year of the ten year Trojan War. The dispute was over possession of war-prized women. As a result of this rage, many lives are lost in the camp as Greek gods are involved too. Achilles is a Greek hero viewed as an embodiment of the grief of the people. He was the son of Nereid Thetis and Peleus who ruled the Myrmidons. According to the Achilleid, when Achilles was born, Thetis tried to make him immortal by dipping him in the river Styx. However, Achilles was left vulnerable at the heel where his mother had held him.Achilles wrath and anger can be said to be a representation of how the Greeks felt. It is provoked by his sense of honor and is evident all throughout Homerà ¢Ã¢â€š ¬s Iliad. First, Agamemnon, the greedy king takes Chrysies without approval of her father. Achilles feels dishonored and drops out as the commander of the Achaean forces. Agamemnon further triggers Achilles anger by ordering that his battle prize, Briseis be brought to replace Chrysies. Some literature materials state that Achilles may have been in love with her. Angered by this, he convinces Zeus to help Trojans regain their honor. What follows is a series of endless wars and retaliation attacks. Second, though Agamemnon tries to appease him by offering gifts and his Briseis back, Achilles rejects all that and further attacks the Greeks. In the process, his friend Patroclus who had worn Achillesà ¢Ã¢â€š ¬&trad...

William Shakespeare s Romeo And Juliet - 1960 Words

The play, Romeo and Juliet, is a tragedy written by William Shakespeare in 1592 and is set in Verona, Italy. It is about two young star-crossed lovers. The play explores the themes of friendship, loyalty, family, love, hate, fate and fortune. It includes literary and dramatic techniques such as imagery of light and dark, poetic language in iambic pentameter, soliloquies, oxymorons, sonnets, characterisations, juxtapositions, similes, metaphors and puns. Romeo falls in love with Juliet at first sight. However, their love is forbidden, as Romeo comes from the Montague family and Juliet from the Capulet family. The two families have an ongoing feud that prevents the lovers from ever being together. To get their way, they go against their parents’ wishes which in the end results in a double suicide. This quote by Juliet (Act 2, scene 2) â€Å"Romeo, Romeo wherefore art thou Romeo?† is her expressing her feelings towards Romeo being a Montague. She continues to say â€Å"de ny thy father and refuse thy name. Or, if thou wilt not, be but sworn my love And I’ll no longer be a Capulet.† Juliet is asking herself, why Romeo has to have the name Montague because if he did not, they could be together happily. In Romeo and Juliet, family means more than husband, wife and children. Family includes everyone from the head of the household (Capulet and Montague) down to their servants. Romeo and Juliet’s love is forbidden and is a betrayal against their families because of the Capulet and Montague’sShow MoreRelatedWilliam Shakespeare s Romeo And Juliet1287 Words   |  6 PagesLizzy Baginski English Composition 2 Mr. Spera March 10, 2015 Romeo and Juliet Research Paper The movie Romeo and Juliet is a modern classic film that took place in 1996. Overall this is a timeless story that everyone should go and watch. This movie has an intriguing plot line that tells the story of two feuding families, The Montagues and The Capulets, and how the children of these two different families fall in love. The two children overcome various obstacles such as hiding their chemistry fromRead MoreWilliam Shakespeare s Romeo And Juliet 966 Words   |  4 Pages Beauty Over Gold â€Å"Beauty provoketh thieves sooner than gold.--William Shakespeare, 1623. In his book As You Like It, William Shakespeare pointed out the supremacy of love rather than the want of gold and wealth. Truly, beauty is more important to thieves than wealth. Many of the thieves in this world would rather have an elegant woman than to obtain precious rubies. After all, what good is a prosperous man if he doesn’t have a charming woman? Two famous men grab my attention who didn’t fear forRead MoreWilliam Shakespeare s Romeo And Juliet Essay1024 Words   |  5 PagesRomeo and Juliet is a tragedy written by William Shakespeare early in his career about two young star-crossed lovers whose deaths ultimately reconcile their feuding families. It was among Shakespeare s most popular plays during his lifetime and, along with Hamlet, is one of his most frequently performed plays. Today, the title characters are regarded as archetypal young lovers. Romeo and Juliet belongs to a tradition of tragic romances stretching back to antiquity. The plot is based on an ItalianRead MoreWilliam Shakespeare s Romeo And Juliet1124 Words   |  5 PagesThe play Romeo and Juliet is a tragedy written by William Shakespeare early in his career about two young star-crossed lovers whose deaths ultimately reconcile their feuding families. It was among Shakespeare s most popular plays during his lifetime and, along with Hamlet, is one of his most frequently performed plays. Today, the title characters are regarded as archetypal young lovers. Romeo and Juliet belongs to a tradition of tragic romances stretching back to antiquity. Its plot is based onRead MoreWilliam Shakespeare s Romeo And Juliet861 Words   |  4 Pagesgreatly shown in the play Romeo and Juliet by William Shakespeare. It was love at first sight with Romeo Montague and Juliet Capulet. Meeting at a party and falling in love to get married without even spending quality time with each other. Romeo and Juliet couldn t tell there parents because the Capulets and Montagues are long term rivals. Both Romeo and Juliet had to find different ways and excuses to make this marriage work. A big problem was developed. Romeo kills Juliet s cousin and is banishedRead MoreWilliam Shakespeare s Romeo And Juliet1770 Words   |  8 Pagesof Romeo and Juliet. The story of two destined lovers who were killed by their own doing. But what if they weren t two destined lovers who got unlucky, but doomed partners that were never going to have a good-life to begin with.William Sha kespeare gives us a view of early signs of gang conflict in the early age of Verona, Italy. He gives us a perspective of the norms and customs of Italy during the Setting of William Shakespeare s most famous story. Romeo and Juliet, by William Shakespeare, givesRead MoreWilliam Shakespeare s Romeo And Juliet1616 Words   |  7 Pageslove can also cause some of life s most controversial battles. These battles could stem from lack of patience, disagreement of moral values, and in some cases, an absence of attraction overall. In Romeo and Juliet by William Shakespeare, the issues that drive Romeo Montague and Juliet Capulet s to each of their dreadful misfortunes are inevitable. When it comes to many of Shakespeare s plays, Aristotle s theory is used to describe them as tragedies. Romeo and Juliet is known by many as a tragedyRead MoreWilliam Shakespeare s Romeo And Juliet1264 Words   |  6 Pagestheater-going public the most important dramatist in English literature, Shakespeare oc cupies a well-known position in the world of talented authors. His canon contains thirty-seven plays, written in the late sixteenth and early seventeenth centuries. Additionally, throughout the years, they continue to sustain critical attention, with the majority of his works circling tragedies, one being Romeo and Juliet. William Shakespeare s Romeo and Juliet speaks to the timeless appeal of star-crossed lovers. Their loveRead MoreWilliam Shakespeare s Romeo And Juliet924 Words   |  4 PagesWilliam Shakespeare’s Romeo and Juliet is a tragedy that follows the so-called love of two teenagers. The two fall in love at a masked ball and have a secret marriage. Throughout the play, their actions show how ridiculous love is, and how it is a danger to anyone who become twisted in its choking grasp. However, in the death of the youth and survival of the elders, an alternative explanation for the tragic events may be found. Although Shakespeare seems to be mocking love throughout the play, itRead MoreWilliam Shakespeare s Romeo And Juliet1279 Words   |  6 Pagesour lives. The great, classic writers teach timeless, valuable life skills. Shakespeare was the greatest writer of all time. His writings mainly consisted of dramas and sonnets. Romeo and Juliet, as well as, A MIdsummer Night’s Dream were written about the same time period. He was able to inter relate everything that wrote. For example, the tale of Pyramus and Thisbe could possibly be an advertisement for Romeo and Juliet. The basic structure of the two dramas is the same; two forbidden lovers meet William Shakespeare s Romeo And Juliet - 1960 Words Romeo and Juliet is a play that focuses on a tragic love story of two teenagers. Romeo comes from the Montague family and Juliet from Capulet family. As the play begins, Romeo the main character is depicted as a boy who is immature and who believes that he is in love with Juliet. There is a conflict between the Montague family and Capulet family and the character Juliet becomes an obstacle between the two families. The play ends with a tragic death of the two love birds. Romeo’s changes throughout the play from an immature to a mature young man; this can be observed by his actions. He blooms in love; his love for Juliet develops very quickly, and so does his hasty character. He matures throughout the play Romeo and Juliet with his†¦show more content†¦Romeo feels depressed because he does not understand himself; he talks to his cousin Benvolio about how he loves a woman, but at the same time he feels sad. He tells him how he has lost himself with this love: â€Å"Tu t! I have lost myself; I am not here, this is not Romeo, he is some other where† (Act, scene 1) In scene one, Romeo is obsessed with Rosaline and that he is not able to decide who he is and which way he wants his life to go. His love for Rosaline is short lived, despite his love for Rosaline; she is not able to reciprocate the love. (I, 4, 13-28) â€Å"If love is rough with you, be rough with love; Prick love for pricking, and you will beat love down,† Mercutio says this to Romeo after seeing him sorrowful. Romeo then meets Juliet at a party in Capulet house; he suddenly forgets everything about Rosaline. He quickly changes from being sad and depressed, to a happy man who is in love again (Eger). Romeo says that he has been struck by love at first sight when he meets Juliet; he then realizes that his love for Rosaline was not sincere and that he did not understand why he was with her. He wonders where his heart has been, for he has not seen this kind of beauty until to night. In Scene I Act III, we see how Romeo is not able to control his emotions. His rage and anger drive him to kill someone without thinking through his actions. He is invited to fight Tybalt, but he refuses because of their relationship now through his marriage to Juliet. Mercutio takes

The University Of Arkansas Fort Smith - 815 Words

Gardner The University of Arkansas Fort Smith (UAFS) was established in 1928 as an extension of the public school system in Fort Smith, Arkansas. It was known originally as Fort Smith Junior College until 1950, and it initially only occupied 15 acres. Today, the UAFS campus has approximately thirteen buildings in which classes are held in. There are several buildings that are on campus that do not hold classrooms for learning such as the Smith-Pendergraft Campus Center, the Boreham Library, the Business Center, the Recreation and Wellness Center (RAWC), and the Lion’s Den. There is a total of 66 campus buildings and facilities on and off campus, and there is 1.16 million building square feet maintained by UAFS (â€Å"Why UAFS†). Each building on campus illustrates something different; there are several buildings that are new to our campus also. One building that is not new to our campus, but certainly grabs the eye of many students by either a positive or negative way is the bu ilding Gardner. Gardner is one of the oldest buildings on the UAFS campus, but besides the unusual layout that can be an inconvenience at times, the building has history, character, and beauty that out ways the negative any day. The building Gardner is one of the most inconvenient buildings on campus. It has two sets of double doors on the first floor, and it has two sets on the second floor also. The building seems to be divided right down the middle, literally. It does not matter which set of doubleShow MoreRelatedLife In The Us Essay1279 Words   |  6 Pagesa Chinese bakery place called Lily Bloom Bakery to help support his family. Lins first experience with schools in the United States was much different from what he expected. Lin started his junior year in Brooklyn, New York at a high school called Fort Hamilton High school. Lin said â€Å" the way the school system here works is totally new to me, nothing was like how it was in China, everything was so unfamiliar† there were many major differences like how the classroom setting was, how you stay in theRead MoreIs The American Dream Creating An American Nightmare?1381 Words   |  6 Pages60% of jobs in America will require a college degree. (Carnevale, Smith and Strohl) Because of the American-dream mentality and the statistics of needing a college degree, many assume that going to college for any degree will result in a lifetime of prosperity and happiness. This thought process is far from the truth. Not all college degrees are created equal, and the national average cost of a bachelor’s degree at a public university is $96,244, regardless of the chosen field of study. (What s theRead MoreEssay about Designated Smoking Areas Needed for College Campus1209 Words   |  5 PagesThe perfect solution is to construct a few sites on campus away from buildings and crowds for the smoking students. There is no evidence to show a decline in smoking after banning tobacco use. Tobacco use is a habit, not an easy thing to quit. If universities primary goal is to rid students of smoking then they are on the wrong path. More effect methods would be to provide smoking cessation products, counseling, and support groups. There is a way for a campus to be accepting of all professors and studentsRead MoreShould Students Be Digitally Public Schools?906 Words   |  4 Pages Should Students Be Digitally Connected in Public Schools? Alta M. Lockley University of Arkansas Fort Smith Should Students Be Digitally Connected In Public Schools? Education is ever-changing and students need to be confident, creative, connected and active lifelong learners. Digital technologies are very important to our student’s world as they use them to connect with each other, learn new skills and pursue their interest. Luckey (2009) stated â€Å"For students in particular,Read MoreThe Massacre of Captain John Gunnison and his Explorers in 18531494 Words   |  6 Pagesbetween the Great Plains and the Pacific Coast states—a northern route between St. Paul, Minnesota and Puget Sound; a 35th parallel route from Fort Smith, Arkansas through the Mojave Desert to California; and two explorations along a southern route, the first leg to include from the Red River in Texas to the Rio Grande and the second leg from the Rio Grande to Fort Yuma, Arizona. The fifth route was assigned to Captain John W. Gunnison, who was already familiar with the areas he was about to exploreRead MoreEssay on Women in William Shakespeares A Midsummer Nights Dream780 Words   |  4 Pagesin our society, women have been given the same rights and freedom as men; therefore changing the tradition of the weak woman to the one just as powerful as a man. Works Cited Koci, Katherine. â€Å"Feminism in a Patriarchal Society.† University of Arkansas – Fort – Smith. http://www.uafortsmith.edu. Nov. 10, 2009. Shakespeare, William. A Midsummer Night’s Dream. Austin, TX: Holt, Rinehart, Winston, 1993.Read MoreSusan Lewellyn s Life With Her Mother Essay1414 Words   |  6 Pageswith her until the age of 13. Her mother would only be with Susan when it was convenient for her, and that turned out not very often. Her mother lived in Fort Smith, AR which was also an issue, because Susan lived in Jonesboro with her father. Susan would spend spring break vacations and occasionally holidays with her mother in Fort Smith. Her mom eventually moved back to Jonesboro in late 1999 and a year later, Susan moved in with her. Susan moved in and out of her mother’s home several timesRead MoreThe Importance Of Nutrition On Health, Health And Well Being Of Our Population Essay1093 Words   |  5 Pages The Importance of Nutrition in Health Madison Aynes University of Arkansas Fort Smith NUTR 25230E1  According to the World Health Organization nutrition is defined as â€Å"the intake of food, considered in relation to the body’s dietary needs.† This topic is often overlooked by many Americans and its relationship with a healthy life is often never understood. From before life begins in the embryonic stages to the final stages of life nutrition plays a vital role in the life a person. PoorRead MoreThe Federal Express Air Carrier Service2093 Words   |  9 PagesAbstract Federal Express is a company that was founded on the idea from a term paper created by a Yale Undergraduate student, Frederick Smith. 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Environment on Childrens Growth and Development- myassignmenthelp

Question: Discuss about theEnvironment on Childrens Growth and Development. Answer: Introduction Several factors influence growth and development of a child. One of these is the environment. The essay below is a literature review on how the environment acts as a third educator as far as growth and development of children are concerned. Despite the many environments that shape children behavior, of importance or consideration in this literature review is largely the physical environment. Children interact with the physical environment in many ways. One way is through playing. A lot of playing marks early childhood and various ways are playing influences a child learning and development (Payne Isaacs, 2017). Additionally, the finding of recent research develops a way forward that is useful in describing the role that the environment plays in the early childhood development and learning. Lastly, the literature stipulates the issues that need to be addressed for future studies and research on the same to be more inclusive and useful. The environment on children To start with, there are set of environments that children interact with as he or she develops. These include but are not limited to prenatal environment, physical environment, social or cultural environment, learning environment and emotional environment. The prenatal environment consists of influences that a mother can pose to a child as a result of chemical or other elements in her body (Cutter-Mackenzie Edwards, 2013). The biological study has time and again shown that chemical in the body of a mother, such as the use of alcohol or use of drugs may injure fetus and affect how a child grows. In addition to that, cultural environment consists of values and beliefs that in one way or another regulate the manner in which a child grows. The physical environment consists of the nutritional value of children which has been shown to have the potential to influence the health status of a child or lead to accident, abuse or disease (Davis, 2014). On the other hand, the learning environmen t is described as one that has the potential to promote the childrens cognitive development. In addition to that, the emotional environment is portrayed as one that shapes the personality of an individual in that sense of children. Some of the traits influenced by the environment include self-esteem and personal resilience. Most researchers agree that playing instills health benefits to children of all ages. In addition to that, playing offer children with an opportunity to discover their self (Roberts, LoCasale-Crouch, DeCoster, Hamre, Downer, Williford, Pianta, 2015). Moreover, through playing, children learn to interact with others thus building their social skills. There exist several theories that describe the playing of children. Theories on the role of the environment on children The first one is classical theories. These theories take the philosophical look at the importance of playful activities. There are several theories under these categories. The first one is the surplus energy theory. According to this theory, play act as the opposite of work, in that, a person uses playing activities to give away the energy available after meeting the one needed for survival (Coughlin, 2010). Another theory under this category is relaxation theory which suggests that individual need to play for relaxation, especially after work. Also, there is recapitulation theory which suggests that children play to prepare them for adult life (Harms, Clifford Cryer, 2014). Lastly, is the pre-exercise theory suggested that children play to emulate the roles of adults. However, modern researchers dispute the importance of the theories because, for one, the theories form their bases from philosophical principles instead of empirical studies (Haywood Getchell, 2014). In addition to t hat, they fail extensively to elaborate on the theoretical facts to prove their point (Wood, 2010). Thus, modern researchers have come up with contemporary theories that aim at explaining the importance of playing, and by extension children interaction with the environment through playing and how this influences their growth and development. Firstly, Sigmund Freud believes that play is essential for children as it helps them in their emotional development. Specifically, playing has a therapeutic effect in children. They can heal themselves from negative emotion and instill positive ones (Kolb, 2014). Thus, his study reveals that children can avoid distressing activities and start embracing those that motivates them. Secondly, there is arousal modulation as a theory which stipulates that through playing, children can learn the world around them and form their view. The theory by Berlyne suggests that playing stimulates childrens nervous system which in turn stimulates their urge for diverse exploration. Moreover, there is a metacommunicative theory which suggests that children adopt the make-believe behavior when playing and tries to make the reality be in tandem with their behavior (Konig, 2009). Thus, through this approach, children can grow intellectually. Lastly, is the cognitive theory, Piaget, and Vygotsky, the people behind the theory suggested that children acquire knowledge through two main ways, that is, assimilation and accommodation. To start with assimilation, the theory suggests that children learn things that are in outside world and start adopting and fitting into them and in effect make them their existing knowledge. On the other hand, accommodation makes it possible for children to adapt the new information that they get from the environment (Thompson, 2014). However, as far as playing is concerned, assimilation takes precedence in the sense that is children tend to acquire new ideas but not to accommodate what they have for a long time continue to see or hear about. Therefore, it is important to plan and organize effectively learning the environment or learning areas (VanHoorn, Nourot, Scales Alward, 2014). For instance, there is evidence that shows that learning areas offer children with the opportunity to discover mo tor skills, creativity, and health benefits. Research and Findings Research findings have demonstrated a lot of impacts on the impact of physical environment on children and more specifically childrens development. Gary Evans, a development psychologist from the University of Cornell, suggest that the influence of overcrowding, housing, and noise level play a pivotal role in children development, in particular, psychosocial characteristics. In effect, these affect academic achievement and parenting behavior (Evans Hygge, 2007). To start with noise, Evans notes that there is a notable delay in reading for those children living in noisy areas such as airports. In addition to that, Evans notes that children exposed to noise register an increase in blood pressure and hormone related to stress. The other aspect of the environment that affects children development is crowding. Evans research demonstrates that children aged 10-12 tend to withdraw in an environment that is overcrowded. In addition to that, Evans notes that concentrating a lot more children in any activity leads to distraction among preschool-aged children (Evans Hygge, 2007). Another factor that Evans considers is housing and quality that one neighbors. In his studies, he reveals that there is a therapeutic effect that is associated with children living in a natural setting. In addition to that, the setting reduces the possibility of children having chronic stress. However, there are ways that Evans suggests that one can be able to manage these environmental conditions that may hinder childrens development and growth. Firstly, is to ensure that there are no unnecessary noises that are emanating both from the inside or the outside of the house (Evans Hygge, 2007). Secondly, is to monitor the volume level of electronics, which is, keeping the volume low. Additionally, is to modify the environment and to consider the schooling environment, and if possible, admit him or her to a relatively quiet school. Conclusion Therefore, the findings suggest that a lot need to be done in making the environment conducive for the betterment of childrens growth and development. There are various ways that this can be achieved. Firstly, children need not play in a crowded environment. It is crucial to consider this as it has the potential to scare them away. In addition to that, there is need to ensure that children go to schools that are well managed and organized as this will increase their development and growth (Nind Hewett, 2012). Moreover, it is good to ensure that children play in an organized environment that is familiar to them or one that they desire. These can encourage them to start playing and in effect increase their creativity, motor skills, and all that playing benefits a child. Furthermore, Recommendations for future Research In addition to that, it is important that more study to be carried out on the behavior of children under a different condition as this will make it easier to determine what is best for them and their growth. For instance, what type of teacher can make a child develop better or worse. In addition to that, it is important to do more research on ways that children can be taught to adapt to various environmental conditions that are not so conducive for them. For instance, if loud volume or noise affects children, what are some of the ways that children can still develop and grow in such a loud area. Moreover, it is difficult to always control the company of children between the ages of 10-12, to avoid crowds or crowded area. Therefore, in as many studies indicate that crowded areas are not fit for childrens development, should they find themselves in such situations, research needs to point ways to cope up with the situation. Lastly, future research ought to identify the best games or th e best way for children to play or interact with the environment. It is prudent to avoid generalization and specify the specific way that will ensure children prevents all those interactions that seem beneficial to their growth and development but not necessarily helpful. References Coughlin, P.K., 2010. Making field trips count: Collaborating for meaningful experiences.The Social Studies,101(5), pp.200-210. Cutter-Mackenzie, A. and Edwards, S., 2013. Toward a model for early childhood environmental education: Foregrounding, developing, and connecting knowledge through play-based learning. The Journal of Environmental Education, 44(3), pp.195-213. Davis, J.M. ed., 2014. Young children and the environment. Cambridge University Press. Evans, G. and Hygge, S., 2007. Noise and cognitive performance in children and adults. Harms, T., Clifford, R.M. and Cryer, D., 2014. Early childhood environment rating scale. Teachers College Press. Haywood, K. and Getchell, N., 2014. Life Span Motor Development 6th Edition. Human Kinetics. Kolb, D.A., 2014. Experiential learning: Experience as the source of learning and development. FT press. Konig, A., 2009. Observed classroom interaction processes between pre-school teachers and children: Results of a video study during free-play time in German pre-schools. Educational and Child Psychology, 26(2), p.53. Nind, M. and Hewett, D., 2012. Access to communication: Developing the basics of communication with people with severe learning difficulties through intensive interaction. Routledge. Payne, V.G. and Isaacs, L.D., 2017.Human motor development: A lifespan approach. Routledge. Roberts, A.M., LoCasale-Crouch, J., DeCoster, J., Hamre, B.K., Downer, J.T., Williford, A.P. and Pianta, R.C., 2015. Individual and contextual factors associated with pre-kindergarten teachers responsiveness to the MyTeachingPartner coaching intervention. Prevention Science, 16(8), pp.1044-1053. Thompson, R.A., 2014. Stress and child development. The Future of Children, 24(1), pp.41-59. VanHoorn, J., Nourot, P.M., Scales, B. and Alward, K.R., 2014. Play at the center of the curriculum. Pearson Higher Ed. Wood, E., 2010. Developing integrated pedagogical approaches to play and learning. Play and learning in the early years, pp.9-26.

The Matrix Essays (1072 words) - Futurology, The Matrix,

The Matrix In the science fiction movie The Matrix people are ruled by Artificial Intelligence (AI), machines made by men to make life easier on the human race. This form of industrialization has also begun in our world today. We have given birth to a host of machines that think for themselves, hoping they would make our lives easier and less taxing on our bodies. In the movie the machines have taken control of the humans and rule over them by hiding from them the real world. In today's society machines have begun a hostile take over of the lives of humans. Ironic, is it not, that in the movie, and in our lives today, machines have become rulers over the humans who made them. In the time when the movie takes place, the humans of the world are being governed by the machines they created. At first the machines, after becoming fed up with working for the humans, attacked the humans through technological warfare. The humans countered by destroying what they thought to be the only source of energy for the machines, the sun. When the machines lost the power of the sun, they had to find a new source of energy. The machines learned that the human body itself can produce the kind of energy necessary to sustain their lives. But humans would never just bow down to their enemies and so the machines had to devise a way to detain the humans so that they could extract that energy. The machines created a computer program called The Matrix. In the movie this marvel displays the digital image of a human's mental self along with that of other humans and a mock up of the world as it was at the highest point in human history. While some humans were detained in the matrix to b e used for energy, other humans were fed intravenously to them. Humans became crops to the machines, they were grown in massive fields and harvested like wheat until they were ripe enough to be fed to the other humans. The living humans merely lived out what they thought were their real lives, not knowing that they were powering their own enemies through a war. Ironic that the humans became slaves to those they created as slaves is it not? In the modern world we find humans churning out new inventions constantly. AI is one of the most recent of these inventions and was invented for the sole purpose of making the lives of humans less hectic. However, different duties call for different machines. For example, the machine inside your automobile is not as smart nor as quick as the one inside a government-spec supercomputer. Recently humans devised a way to interconnect the thoughts of these machines and to allow them to hook up to and speak with one another. This wonder of the modern world is called networking. What if a few of the smarter machines found a way to network themselves together through this web of computers? They could begin to change the chain of commands going in and coming out of other machines, in effect taking control of those machines. Considering how much impact machines have on the daily lives of humans, could these smarter machines not bring the world to a sudden standstill? Think what would happen if machines began to make their own commands and would not allow even the slightest input from humans. Our lives would soon be governed by what the machines told us to do. You wouldn't be able to cash a check at the bank or put gas in your car. These machines would soon learn how to command those used to assemble other machines and they would begin churning out new machines day in and day out. The machines would then have a foothold for the beginning of their attack on the human race, which leaves us at the beginning of the movie, The Matrix. Humans are setting themselves up for a fall by allowing machines so much freedom. Ironic is it not that humans make themselves so vulnerable to attack from the one enemy they could never stop? Imagine for a second that all the machines

When I arrived to college Essays - Free Essays, Term Papers

When I arrived to college Essays - Free Essays, Term Papers When I arrived to college, I was very eager and excited to start school and having the opportunity to be away from my mother, and living the independent life I desired. But as I approach the weeks into the college life, and gaining an insight in terms of the role you have to potentially play as a college student, which portrays the adulthood. College life carries all of the responsibilities just like commentary adult. I thought I was ready for the college life until I encountered many responsibilities as an adult. On the other hand, not having my parent assistance. I have to provide for myself while in college.. First day I came to my school, I walk through the clear shaped, black window of Indiana State University. I felt very welcomed. I was preparing for an appearance to walk into my dorm room. I enter the build with a cheesy, bright white smile that made a representative glanced back, as I walk smoothly up the stair. As I passes several rooms, I get closer to minds, making my smile even wider because of the excitement of living the college life I desire. So after moving of my things, I introduced myself to some freshmen inside of my dorms. I wanted to make new friends, and when I had that chance I did not intend to let it go. I ended up hanging out with those guys for long period of time. Things were starting to get excited. The next couple of days, we decide to go out to a party that was hosted near our school. The party was consider to be one of the greatest welcome back party for college students. I was frankly urged to attend that party, and when I didI got arrested for drinking underage. I was sent to a police station behind black and gray cell bars with the accommodation of a cold white toilet on the wall. I insisted calling my Mother or Father to bomb me out. Unfortunately, they did want to because of the poor decision I made, and the responsibility I should be accountable for myself. That was one of the scariest moments in my lifetime. Not having the support of my parents after encountering adversity in my life. However, eventually my parents bonded me out, and informed that they are no longer providing for me. This was a major shock for me. I did not anticipated this to happen to me. The next week, I woke up in an ideal world, wishing everything was just a myth. I delighted to have freedom, and allow to go back to college. But living on my own was not intriguing. One of the main thing I had to do was find a job and manage my money, which was something I was not good at doing. Since I am independent college student, I had to provide for myself such car note, cell phone, clothes, hygiene products that was needed on a daily basis, etc. I had to take initiative to supply for myself. As a result to my problem, I learned to become more self-reliant individual, and develop the ability to make wise decision independently. I realized taking care of myself allowed me to become more advanced for the adult world and effective adult.

Corporate Governance Law Paper Term Example | Topics and Well Written Essays - 1750 words

Corporate Governance Law - Term Paper Example Mr. Morrison similarly indicated the importance of selecting the right person for the job based on experience, personal qualification and perspective since these are the benchmarks that would be used in guiding the company during the executive’s incumbency. Ilene Gordon Ms. Gordon spoke about the importance of â€Å"transition† that could lead to the loss of good senior to mid-level executives if not good projects or initiatives that will become lost as the new Chief Executive Officer assumes his post and get acclimated in his new role. Ms. Gordon emphasized that picking the right candidate often times involves hiring with the least amount of â€Å"collateral damage† or â€Å"unintended consequences† or what the board does not want to happen. It is equally important for a chief executive officer to have a viable plan or a good strategy in place within a finite amount of time or within the next 365 days after assuming office. It will not do any corporation any good if the Chief Executive Officer will be dilly dallying on what is the right plan to implement to stabilize the organization. Richard L. Thomas Mr. Thomas discussed the selection process that was adopted by First Chicago, wherein the candidates were rotated and given essentially several tasks that involved all aspects of the operation of the organization. ... When the â€Å"winning† Chief Executive Officer was finally announced, those involved in the carnage that supported other candidates resigned. It should be noted that some of those executives involved good executives who were caught in the crossfire. J. Erik Fyrwald Mr. Fyrwald described two scenarios that he has experienced directly in his career. One involved a succession planning that resulted in an internal candidate being picked, as the new Chief Executive Officer, and that went well for the organization. The other case involved a search that was directed inwards, however, the tumultuous circumstances within the company at the time prevented the search for a good Chief executive officer. The search, therefore, dragged on for several years leaving the company without any direction. After introspection, it was established that the problem was the weakened executive team that was decimated during the exciting years that Nalco has to go through. Challenges Involved in Chief E xecutive Officer Succession Several points were discussed by the speakers to amplify the challenges that they have experienced directly or indirectly in Chief Executive Officer’s succession planning or the lack of it. In the same breadth, I will likewise indicate my observation on these points that may be congruent if not contrary to the opinion of the speakers. The chief executive officer has no easy task and responsibility. Primordial of this responsibility is to ensure that the interest of the stockholders is not only upheld at all times, but it is also his responsibility to ensure that the company remains and becomes a good corporate citizen while complying with fealty to applicable government

Human Rights and Women Essay Example | Topics and Well Written Essays - 500 words

Human Rights and Women - Essay Example Women were therefore sexually exploited. Until quite recently, women were relegated to the background in respect of social and economic status, education, politics, health and non - recognition of her unpaid work at home in domestic food production, etc. Until quite recently even in Great Britain, a women's property was considered to belong to her husband. American Women were denied their civil right of suffrage until 1920. In 1960 Women got together to obtain legal equality with men. After the passing of the Civil Rights Act in 1964, women obtained many gains in employment. In 1970, efforts were made by women to change the unfair practices and attitudes towards women in society. In 1970, the U.S. Supreme Court passed a landmark judgment in the case US V Virginia. The Supreme Court decided that Sex Discrimination is unconstitutional unless the state can advance an exceedingly persuasive justification. (Microsoft Corporation, Encarta article Women's Rights, Katrin Schultheiss) The atrocities against women are universal in their prevalence, as attested to by the fact that in the World Human Rights Conference held at Vienna in 1993, special mention was made of these issues.

Thomas Jefferson and Alexander Hamilton 1783-1800 Essay Example for Free

Thomas Jefferson and Alexander Hamilton 1783-1800 Essay The post-revolutionary war period of the Unites States saw the establishment of the first party system and an enlarging gap in viewpoints between the wealthy and the common man. One might argue that a political party develops in response to a series of controversial issues yet to a great extent the contradictory views of Alexander Hamilton and Thomas Jefferson over issues related to views of government, the role of government and social philosophy in foreign and domestic affairs, were primarily responsible for shaping the rise of political parties from 1783-1800. Originally feared by the forefathers, the rise of political parties emerged from intense ideological struggles over views of government between two political leaders important to President Washington’s Cabinet, Alexander Hamilton as Secretary of the Treasury and Thomas Jefferson as Secretary of State. Alexander Hamilton exerted the most influence within the newly emerging Federalist Party. He believed that only an enlightened ruling class could produce a strong, stable and effective federal government. The government therefore needed the support of wealthy men and the promotion of manufacturing interests. Thomas Jefferson and the Republicans defended more the rights of the common man and an agrarian society with limited power from the federal government. His basic principle was grounded in a belief that the people had a more honest and disinterested influence in politics than the wealthy. The Republican Party attracted more of the common people while the Federalist Party drew support from the aristocracy. Although neither side was willing to admit to it, these institutions were known as the first party system. Both parties stance on who should have more power in the government contributed to the largely diverse views of the common man and the wealthy man. Hamilton and Jefferson’s differences in social philosophy over the interpretation of the Constitution and the establishment of a national bank further strengthened the rise of established political parties. Federalists called for the national debt to be funded and hoped to create a large national bank credited by wealthy men. Hamilton defended it in a plan presented to Congress by claiming the general nature of the Constitution allowed for corporations to assist in carrying out by â€Å"all means† necessary that which is required to carry out the duties of government. If permitted, this vein of reasoning presented a broad interpretation of the Constitution, one that relied upon the â€Å"elastic clause† to justif y that which is considered  Ã¢â‚¬Å"necessary and proper†. Jefferson and the Republicans felt the bank was unconstitutional and his opinion on the Constitutionality of a National Bank (1791) required a strict or literal interpretation that drew upon a philosophy of government that stated powers not delegated belonged, or better, are reserved, for the people and the states. This included the incorporation of a bank which is not a delegated power given to government in the Constitution. Hamilton’s rebuttal can be seen in a letter to George Washington that argued for a broad interpretation of the Constitution on the grounds that it gave to the government delegated and implied powers. In essence, all powers deemed â€Å"necessary and proper† for the fulfillment of delegated duties are constitutional, like the incorporation of a bank. This became known as the elastic clause and would be applied in later debates over constitutional interpretation. Both parties reaction to the Constitutionality of a national bank show their contrasting beliefs in how the Constitution was to be interpreted. Proving to be a major point of contention between the developing sides, Federalists also called for an excise tax to be placed on distillers of alcohol. The Whiskey Rebellion was the inevitable consequence of the enactment of this tax. Hamilton argued in his efforts to suppress the Whiskey Boys that the people, in ratifying the Constitution, had given the central governme nt the power to tax for the purpose of paying off debts and providing for the nation’s defense. Since the Constitution had not been amended contrary to those powers Hamilton believed that President Washington had been justified in levying the tax and the Whiskey Rebellion was therefore an unjustified rebellion that needed to be put down by the central government. The Republicans, highly suspicious of taxation as the American colonists had once been, did not believe the excise tax to be constitutional and celebrated the Whiskey Rebellion as an act of protecting rights against an abusive government action. The people had to be the safeguard of the new Republic. The Federalist political cartoon Mad Tom in a Rage portrayed Thomas Jefferson as a liquor soaked anarchist aided by the devil in order to bring the government down. The reactions to the Whiskey Rebellion reflect how the Federalists and Republicans differed in their interpretation of the Constitution. In social philosophy, the two politicians articulated their party’s disagreement over foreign policy concerns regarding the â€Å"revolution† in France. When the French Revolution grew to its most radical peak the Federalists reacted with horror as citizens overthrew the aristocracy. In launching the New Ship of State Hamilton said he did not see the French Revolution as comparable to the American Revolution and doubted if a â€Å"free and good government† was likely to result from the war in France. Thomas Jefferson’s response was to stress the potential outcome of the Revolution, how it would benefit the whole of mankind, meaning the common man, and how this result could only be won with the spilling of blood, thereby justifying the excesses of violence in the name of republicanism. Many Republicans even imitated French Jacobins in dress and in speaking. As tension in Europe grew Federalists favored an alliance with Great Britain while Republicans generally favored a greater alliance to the French. Jay’s Treaty was generally seen as a Hamiltonian move to increase the likelihood of a political relationship with Britain over one with France. The difference between the Federalist and Republican social philosophies regarding foreign relations is most easily seen among Hamilton and Jefferson’s different reactions to the French Revolution. When the Federalists tried to silence the Republican opposition the result was the vastly unpopular Alien and Sedition Acts passed under the Federalist presidency of John Adams. The Alien Act ordered all foreigners considered dangerous to leave the United States. As a result many Republicans found much of its support grew within the nation. The Sedition Act Read That if any person shall write, print, utter, or publish.scandalous and malicious writings against the government of the United St atessuch person shall be punished. The Sedition Act convicted ten men most of whom were Republicans news editors criticizing the Federal government. The Republicans interpreted these laws as an attempt to destroy them and violate the principles of free speech. They fought back with the Virginia and Kentucky Resolutions. The Virginia Resolution pointed out how the Acts violated the rights of free speech protected in the Constitution. Jefferson’s Kentucky Resolution argued the state’s compact (or state’s right) theory that acts by the central government could be nullified by the sovereign states if deemed unconstitutional as the Resolution so deemed the Alien and Sedition Acts. The resolutions nullified the laws and contributed to the rise of Republicanism and the fall of Federalism. The controversial issue contributed largely to the Federalist party’s defeat in  the presidential election of 1800. The differing opinions on how the government in the post-Revolutionary war period should be run ultimately created the first rise in political parties. The Federalist belief in a government run by wealthy men and opposing Republican support for an agrarian society split the nations’ people in support of a government most beneficial to them. Differing reactions to the French Revolution showed the distinct difference in Federalist and Republican over foreign policy. The National Bank an d the excise tax on liquor revealed differing views on how strictly the Constitution should be interpreted and the Alien and Sedition Acts reveal an attempt of one party to dissolve another. The contrasting views of Hamilton’s Federalism and Jefferson’s Republicanism were the ultimate contributors to splitting the nation on views of government and establishing the first political parties.

Project Management Essay example -- Business Research

Project Management Although a development team does most of the work, it is the project manager that is running the development process. All human activity that involves carrying out a project needs a plan. We call this Project Management. But there is a big difference between projects that involve one or two people and projects that involve large numbers of people. There is always a smaller group of individuals behind all larger groups that is planning, directing, and motivating those people. There are three main parts to project management: start date, finish date, and all the tasks that need to be carried out. When the plan starts to involve different things happening at different times, most of which are dependant upon each other, the plan can start to take up an enormous amount of time and space. This is why you must start with a strong plan. Now days there are computer programs that tend to produce answers long after the events have taken place. These project planning and scheduling pr ograms provide real information, risk analysis, time recording, costing, estimating and many other types or project management. But these programs are not at all project management. Project management is control, leadership, teamwork, managing of resources, and a basic knowledge for the project. Project managers are found in every industry, from architects to policeman. There is a demand for more and more people who have the necessary skills it takes to manage a team or a project. The main concerns of a project manager are time, quality, and cost control. These are what drive these managers to be the most efficient as possible. â€Å"The success of a project will depend upon the effort, care and skill you apply in its initi... ...ble components in terms of size and complexity. The major type of graph used is a Work Breakdown Structure (WBS). WBS is very project oriented. Other charts that could be used are Gantt charts and Load charts. As we move into the future there is more and more demand for great leaders no matter the line of work you are in. It seems that less people are able to think for themselves anymore, it is like everyone is becoming robots to technology. I feel that this is creating an enormous door for the people who can lead others into this new frontier. It seems that there are fewer people who have the skills or even who are willing to do this. There are great rewards for the people who recognize this new movement and want to take control of large businesses. So as time moves on we will see how this new technology revolution ends up and who the leaders will be.

Hormones and Dreaming

â€Å"I Dreamed A Dream† We all dream, it is inevitable. You dream about people, places, homework, daily doings, and even things you don’t even recognize as being a part of our life. People may often question the significance of dreaming or why humans do it, but it is an essential part for our brain function as you sleep and live day to day. It allows for our minds to process the input it receives. There have been ample researchers who have studied the brain and its relationship with dreaming.Most people are aware of the influence hormones have on the behavior of a person. However, such hormones have also been linked to the dream process and their content. My goal through this research paper is to identify several hormones, naturally secreted by the body, and the impact they have on the dreaming process for both males and females, with a particular focus on females. The articles provide evidence as to what specific hormones from the body affect dreaming and how the horm ones enable that to occur. Article 1: Sleep, dreams, and memory consolidationIn this article, Payne and Nadel did not perform any actual experiments themselves; they did review the results of a number of different studies pertaining to cortisol and dreams. Researchers focused on the effects of brain neurohormones, specifically cortisol, as it impacts sleep, dreams, and memory. Researchers believed that variations in amounts of cortisol, as well as other neurotransmitters, affect the hippocampal formation and neocortical circuits, two parts essential for fusing memories, a process which occurs during sleep usually through dreams.It is important to understand that cortisol is released by the adrenal cortex in response to stress and low levels of blood glucocorticoid meaning. Researchers of the studies that were reviewed provided background and assumptions for topics concerning sleeping and dreaming such as the sleep stages, the distribution of dreams, and the relationship between drea ms, sleep, and memory consolidation. First, sleep does not merely serve one purpose for humans.Second, content of dreams shows which portions of the brain are active. Third, if cortisol levels affect the hippocampal formation then the stages during sleep in which memory consolidation occurs will be also altered. In the studies looked at by Payne and Nadel, all findings showed that cortisol levels do fluctuate during a night’s sleep based on the sleep stage (REM, NREM, SWS). Some studies also indicated that sleep strengthens communication for the neocortical circuits and hippocampal formation.Many of the same studies continued to point out that the changes in cortisol levels interrupt the hippocampal formation function, which is the processing of episodes, and neocortical interactions. The results therefore alter dream content because the two brain parts are closely linked with dreaming during sleep. This dream interruption comes because the brain is attempting to integrate th e information with pre-existing knowledge and other related concepts.The findings compiled by Payne and Nadel are examples of biological psychology, which displays the relationship between human behavior, the mind, and biological processes in comparison with the influence of neuroscience and chemical/hormonal reactions, specifically cortisol. Cortisol is known to increase with age because of its role as a stress response hormone. Stress increases as age increases, therefore the connection between cortisol and dream interruption is also a part of developmental psychology because it is a change that occurs throughout a lifespan.These findings are also relatable to a cognitive psychological perspective since the studies investigate the mental process of dreams and how the brain sorts through new information and past information; simply stated: it is cognitive psychology because it is the brain working as one sleeps. These articles go into depth about the process of dreaming and how it is affect negatively by cortisol. Payne and Nadel also demonstrate social psychology, which is how our behavior is affected by others, in their review.Cortisol can be released by the body as a response to the stress brought about by others meaning that the behavior produced in our dreams is a result of our interactions with those around us. It would not be necessary to cut off contact with the world to decrease stress levels and attempt to control amounts of cortisol secreted by the body, but it can help people understand their own dream process through the night. Article 2: The Influence of the Hormonal Cycle on Dream Recall in Women In the dissertation by Phyllis Bales, Bales focuses on the impact of womens’ hormonal cycle in relationship to dream intensity, vividness, and content.As demonstrated in the first article, hormones can have a pronounced effect on dreams while sleeping because of hormonal influence on the brain. She hypothesized three things: first, there would b e higher dream activity and recall during the luteal phase, when large amounts of progesterone are emitted; second, dream intensity would be higher during the luteal phase; third, thematic content would co-vary with the hormonal, or menstrual, cycle. Bales performed a study with seven female subjects who were not taking birth control, since birth control is known to alter hormone balances.These participants kept a Dream Analysis Questionnaire and Menstrual Distress Questionnaire throughout the study, to track the content, intensity, and vividness of their own dreams. The findings from her study supported some of her initial hypotheses. The questionnaires showed that there was no difference in dream activity during the pre- and post-ovulatory phases, however, there was a significant increase in dream recall following the post-ovulatory phase, also known as the luteal phase as mentioned previously.Another influence seen in the luteal phase was an increase in maternal dreams along with their duration and intensity concerning maternity. These results proved to be consistent as shown through other studies that even used different methodologies. Bales’ study and dissertation are relatable to individual difference/personality with psychology as the results may vary insignificantly from person to person by extremely small numbers because of interactions with the environment, but will constantly be similar among women as a group, as long as they experience a menstrual cycle and have not entered menopause.An interesting perspective to consider is evolutionary psychology because of its inclusion of behavioral differences among individuals in response to changing physical and social environments. Women may experience such differences in dreams as part of variations between males and females. Through history, females have been the ones to bear children, never men, as told in the bible, but there is the chance that the body may have undergone experiences that have al tered the body in turn altering the mind, including dreams.Article 3: Menstrual hormone changes and instinctual tendencies in dreams In this paper by Judith Baron, Baron investigates whether the female sex hormone, progesterone, contributes to the content of dreams. Her main hypothesis was: the themes of dreams are more likely to contain maternal content when progesterone levels are high in the post-ovulatory or luteal phase. As part of the study included in the paper, seventeen female college students completed dream questionnaires for every dream remembered over two menstrual cycles.Then, scales were created to measure obvious and symbolic dream content. Menstrual cycles were divided into follicular, without progesterone, and luteal, with progesterone, phases for comparison within each subject of dream content. Conclusions taken from this study showed that there were higher obvious and symbolic maternal scores in the luteal phase. It was concluded that hormones do influence matern al instinctual tendencies as expressed in dreams and supported Baron’s beginning hypothesis concerning dream content in relation to progesterone levels.Again, this study backed the hypothesis that hormones do affect dream content. These findings suggest two things: first, hormones do impact the content of dreams; second, specifically progesterone has been linked to increase the maternal content in females’ dreams. This study is relatable to cognitive psychology because it is strongly tied with internal mental processes as the hormones influence the dreams females have and remember, even what they may learn from these dreams.Baron’s results are also representative of a biological perspective since it focuses on the biological foundations in relation with behavior and mental processes, including dreams. Progesterone released by the body affects the behavior that occurs in dreams for women. Conclusion People dream each night because it is our brain’s way of processing new experiences and information for our brain. Dreaming can be fun as it pertains to enjoyable events, like reliving a date or time with a loved one, or it can be terrifying as through nightmares, where our worst fears seem real.I have experienced both ends of the dream content spectrum as I have dreamt about a cute guy or even about death. Looking back at the findings in these articles, I am better able to understand the context in which these dreams happened and rationalize the occurrence I experienced. As a female, this research brings to light the even greater differences that are seen by scientist between men and women. We already have different physical features and behaviors which are linked to the dreams we experience.These physical features and behaviors are typically tied with hormones like testosterone, progesterone, and cortisol, the same hormones that affect dream processing, content, and vividness. With ovulation, the findings of increased maternal dreams in a sleeping pattern can also help women understand the reasoning behind why they are experiencing more dreams about being a mother. Some people may question the importance of such information concerning hormones and their effects on dreams, but it is important to note that many of our bodies’ hormones are released without real control over them.They are a response to outside stimuli or other impacts from our environment. With this research, we are able to answer two rather popular questions as to what our dreams may mean or why we had the dreams we did. Take the time to evaluate the environment around you, whether it is ovulation, stress, or even pregnancy. One thing to consider the next time you dream are the hormones your body may be producing and how they may be affecting your dreams. So next time you recall a dream, just ask â€Å"is a dream really a wish your heart makes? †

Gene Editing in Hematopoietic Progenitor Stem Cells - Free Essay Example

Sample details Pages: 16 Words: 4900 Downloads: 2 Date added: 2019/06/14 Category Biology Essay Level High school Tags: Stem Cell Essay Did you like this example? The genome editing using engineered nuclease has strategically transformed the idea of gene therapy for monogenic diseases including in hematopoietic stem and progenitor cells (HSPCs) (Osborn et al., 2016; Yu et al., 2016). The genome editing technology enables to create a site specific double-strand break (DSB) by the engineered nucleases that programmable triggering the cell’s endogenous repair machinery to edit the genome in a site-specific manner via the non-homology end joining repair (NHEJ) and the homology directed repair (HDR) mechanisms(Branzei and Foiani, 2008). The approach allows the precise alteration of the disease-causing alleles at the specific locus making it a permanent event that maintains the phenotypical gene expression under the control of endogenous regulatory elements.. Don’t waste time! Our writers will create an original "Gene Editing in Hematopoietic Progenitor Stem Cells" essay for you Create order Over the past decade, three major classes of engineered nucleases have been used for genome editing, including zinc-finger nucleases (ZFNs) (Kim et al., 1996; Urnov et al., 2010), transcription activator-like effector nucleases (TALENs) (Li et al., 2011; Miller et al., 2011) and CRISPR–Cas9 (clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) protein 9) (Hsu et al., 2014; Sander and Joung, 2014; Tsai and Joung, 2016; Wiedenheft et al., 2012). ZFNs and TALENs are fusions between arrays of ZF or TALE DNA-binding domains and the dimerization-dependent FokI nuclease domain. The both of ZFN and TELENs nucleases exclusively rely on protein–DNA interactions to mediate site-specific recognition of genomic DNA sequences which requires complex protein engineering for each new targets (Kim and Kim, 2014). By contrast, CRISPR–Cas9 nuclease is a RNA-guided endonuclease. Through the guidance of a 23 nucleotides linked to CRISPR-domain RNA (gRNA), CRISPR-Cas9 finds the complementary protospacer DNA target in a genome where it cuts the double stranded DNA precisely 3 base pairs upstream of a PAM (Protospacer Adjacent Motif). The broken DNA ends generated by those nucleases are repaired either by NHEJ resulting in small insertion/deletions (indels) to disrupt target allele, or by HDR to precisely replace desired nucleotides required with delivery homologous DNA template. Compared to ZFNs and TALEN, the CRISPR/Cas9 system has rapidly become the most promising genome editing tool with demonstrated advantages including simplicity, easy programming, low cost and potential multiplexed editing (Bannikov and Lavrov, 2017; Brunetti et al., 2018; Salsman and Dellaire, 2017; Tsai and Joung, 2016) (Minkenberg et al., 2017). Despite of the genome editing holds tremendous promise for the developing novel gene therapy, the technique has been shown to be more refractory in HSPCs than any other cell types due to their quiescent stat us associated with low activity of the HDR machinery, and prone to DSB induced toxicity. However since first publication of using the ZFNs editing on human CD34+ cell (Genovese et al., 2014), the substantial developments have been made in last few years to circumvent the problems. Optimization of gene editing efficiency in HSPCs In vitro expansion of HSPCs Since all nucleases targeted gene editing occurs through cell cycle progress, the increased stimulation HSPCs ex vivo can make them more permissive to editing components. However, increasing stimulation can also promote cell differentiation. To circumvent this, the compounds that agonist HSPC self-renew while maintain their primitive phenotypes have been discovered and applied in the culture (Boitano et al., 2010; Fares et al., 2014; Goessling et al., 2011). Using the compounds in HSPCs culture, researchers have achieved significantly increased percentage of edited HSPCs in vitro and also increased human cell engraftment in vivo (Charlesworth et al., 2018; Genovese et al., 2014). In a recent published study, Psatha et al. have described 5 days HSPC culture condition, in which StemRegenin 1(SR1) was used with a small molecule Ly2228820 (SL), the p38?MAPK14 inhibitor (Psatha et al., 2017). Using this culture condition, they have  successfully expanded highly engraftable CD34+/CD38?/ CD90+  primitive HSPC cells. They then tested if using SR1 and SL condition can also expand edited HSPCs effectively. For this, they cultured edited HSPCs for additional 5 days after the editing, and found that the edited CD34+/CD38?/CD90+ primitive HSPCs can be effectively expanded in vitro without any loss of editing efficiency. Moreover, the expansion of edited cells gave rise to a more than 2-fold higher engraftment compared to their unexpanded counterparts, showing the same editing rate (Psatha et al., 2018). The study highlights a possible way to obtain sufficient engraftable HSPCs by expanding edited cells effectively ex vivo in presence of SR1 and SL.  However, this study was conducted using the NHEJ directed gene editing strategy for disrupting the genomic locus. It would be important to know if the presence of SR1 and SL in culture can also increase the HDR directed gene editing. And also convincing evidence on long-term in vivo engraftment from significantly expande d HSPCs is needed to ensure no oncogenic burden associated with ex vitro expansion. Delivering the editing components In clinical application setting, the approach for delivering nucleases or other components into HSPCs should be transient to avoid the cytotoxicity engendered by prolonged endonucleases activity and immune responses. Therefore, a â€Å"hit-and-run† approach is used, whereby the nuclease complex is transient expression. The mostly used method for delivering DNA or RNA encoding engineered nucleases is via nuclear transfection. The transfection of plasmid DNA encoding the nucleases to HSPCs has been used with success on editing targeted loci (Holt et al., 2010; Mandal et al., 2014). However the main concern from this approach is its potential random integration into the genome which could lead to cytotoxicity in HSPCs and their progenies. And DNA related cytotoxicity, such as cyclic GMP-AMP synthase induced pathway (Sun et al., 2013), could lead to high toxic to primitive HSPCs. Therefore, the transfection of mRNA encoding nucleases synthesized in vitro has become an optimal alte rnative approach (Liang et al., 2015; Wang et al., 2015). It has emerged from recent studies that the mRNA transfection approach indeed has provided an increased efficiency in genome editing in HSPCs (De Ravin et al., 2016; Kuo et al., 2018; Schiroli et al., 2017). In addition, Cas9 can be delivered as the protein or as the precomplexed ribonucleoproteins (RNPs) by mixing gRNAs with Cas9 protein (Dever et al., 2016; Liang et al., 2015). The approach serves in protecting gRNAs from degradation, and reducing cytotoxicity caused by naked RNA stimulated innate immunity. The improved editing efficiency based on such approach has been achieved in targeting HSPCs shown in recent studies (Bak et al., 2017; Kuo et al., 2018; Schiroli et al., 2017; Vakulskas et al., 2018). Apart from above components, a safe and efficient delivering DNA donor template into edited cells is crucial for achieving HDR process. Several donor template platforms have been used. Single-stranded DNA oligonucleotide (ssODN) donor has been shown as a simple and effective approach in genome editing for correction of single-nucleotide mutation in HSPCs, such as for Sickle  cell disease (SCD) (DeWitt et al., 2016).   Integration defective lentiviral vector (IDLV), that allow incorporating large DNA template, has been used in the ZFN genome editing to target the IL2RG mutations and the  adenosine  deaminase  (ADA) gene (Genovese et al., 2014; Joglekar et al., 2013). However, those early studies showed a very limited gene targeting efficiency in HSPCs, suggesting that IDLV could be more cytotoxicity to HSPCs. The efficiency of IDLV in targeted integration in HSPCs can be significantly improved by using cyclosporine H, which is shown in a very recent study (Petrillo et al., 2018). Certain adenoviral serotypes (Ad5) can transduce human HPSCs and deliver large transgene cassettes (Li et al., 2013) (Saydaminova et al., 2015). However the concern that residual of adenovector particles could be highly immunogenic which may prevent its potential use in clinical application therapy. Recombinant adeno-associated viral vectors (rAAVs) have been shown to naturally mediate HR in mammalian cells without stimulating DSB (Barzel et al., 2015; Mingozzi and High, 2011; Moser and Hirsch, 2016). Hence, rAAV vectors are emerged as ideal delivery approach due to their wide range of tropism, high transduction rate and very low immune response. In particular, the rAAV6 vector has been shown to provide more efficient and robust genome-editing in HSPCs than other delivery vectors shown in recent therapeutic potential application studies (De Ravin et al., 2017; De Ravin et al., 2016; Kuo et al., 2018; Moser and Hirsch, 2016; Schiroli et al., 2017). However, relative small pa ckaging capacity in rAAV6 has limited its use for delivering cassata larger more than 4.5 kb including the both homology arms. To improve the packaging capacity, Bak and Proteus (Bak and Porteus, 2017) have developed a dual-AAV6 donor vector system that enables site-specific integration of large transgene cassette up to 6.5 kb into primary T cells and HSPCs with long-term repopulation capacity. Overall, the conditions for delivery the components used in gene editing should always be optimised for each targeted gene to achieve most efficient targeting and minimum cytotoxicity. A comprehensive detailed protocol using CRISPR/Cas9 with rAAV6 as templet vehicle for HDR-targeted editing in HSPCs has been published by Bak and Daniel recently (Bak et al., 2018), which could be also served as a guide for implement gene editing technique for other nucleases Improve the HDR Unlike NHEJ pathway which occurs throughout the cell cycle, the HDR event is restricted in S/G2 phases of cell cycle which makes the HDR process much less efficient than NHEJ (Gutschner et al., 2016; Heyer et al., 2010). Therefore, inhibiting nuclease activity at G1/M phases and resting cells at S/C2 phases may improve HDR efficiency. The concept has been experimentally tested by Gutschner and colleagues (Gutschner et al., 2016). In which, the hGemCas9 system is generated by incorporating the human geminin domain which allows the nuclease to be ubiquitinated and degraded by APC/Cdh1 complex in G1 and late M phase, therefore leading to increased hGemCas9 activity in S/G2 phases. Using this cell-cycle-tailored hGemCas9 system, Gutschner et al have achieved an increased rate of HDR up to 1.87 fold compared to wild-type Cas9 in cell lines. A further development based on this approach was published recently by Lomova et al. (Lomova et al., 2018). In their study the hGemCas9 was used in c ombination with a cell synchronization compound RO-3306 which functioning in transiently arresting cells at S/G2 phase via inhibiting CDK1(Vassilev et al., 2006). It was shown from Lomova’s study that the ratio of HDR/NHEJ was increased to four-fold on human CD34+ cells compared to the controls in vitro, and a significant improvement of edited HSPCs in immune-deficient mice. The improved HDR has also been achieved by directly inhibiting the NHEJ pathway through targeting DNA ligase IV, a key enzyme in the NHEJ pathway, using the inhibitor Scr7 (Hu et al., 2018; Maruyama et al., 2015). Although high increased efficiency in HDR has been achieved in human cell lines and cancer cells, so far, there has been no published data of using Scr7 on human HSPCs. The assessment off-target sites Although ideal engineered nucleases would have singular genome-wide specificity, unintended off-targets can occur, particularly at loci with homologous to the intended targeting site. Several the off-target detection methods have been used in HSPCs gene editing studies. An early developed assay is based on using the silico prediction off-targets sites that have degree of similarity to the on-targets, and then followed by targeted sequencing (Fine et al., 2014) (Hsu et al., 2013). This initially developed method is still mostly used in the HSPCs editing studies as it is more practicable assay. However the fundamental limitation with this approach is it is not designed to identify off-target sites in an unbiased manner as the sites that not fit the computational criteria will not be discovered, To achieve unbiased off-target detection, the cell based genome-wide assays have been developed. On of such assay used in HSPCs editing studies is Integrase-defective lentiviral vector (IDLV) capture assay, which was designed to capture IDLV into sites of nuclease-induced DSBs. Then clustered sites of integrations are recovered by linear amplification-mediated PCR (LAM-PCR) and mapped using high-throughput sequencing (Gabriel et al., 2011). Although the IDLV capture can directly identify DSBs in living cells, it is relatively insensitive, owing to its low absolute integration efficiencies that require positive selection to overcome (Gabriel et al., 2011). And the assay may have high background due to event of random integration IDLVs into cellular genomes even in the absence of nuclease-induced DSBs (Gabriel et al., 2011). Whole genome sequencing (WGS) has been proposed as an unbiased method for defining engineered nuclease specificity. Although this method is useful for the analysis of single-cell clones (Veres et al., 2014), it lacks sensitivity, particularly for those low frequencies off-target in a population cells (Tsai and Joung, 2014). With existing deep sequencing technology, it is impractical to perform WGS on millions of cellular genomes, and it is inadequate to confirm the off-target sites at Therapeutic potential of HSPC gene editing Non-homologous end joining-based strategy NHEJ DNA repair pathway triggered by engineered nucleases is the active random repair process, leading to the alteration of nucleotide sequencing at the specific site via in-frame deletions, insertions. Sine it is not involved in harnessing the HDR machinery, it has become a viable genome editing option for correcting gene mutations. Two HSPC targeted loci, chemokine coreceptor 5 (CCR5) and BCL11A, have received the most early attention as their potential therapeutic benefits via NHEJ process. The concept of editing CCR5 was intrigued by the report that the transplantation of a donor HSCs with a naturally occurring  CCR5  mutation confers a loss of detectable  HIV-1 RNA and proviral DNA in a HIV patient (Hutter et al., 2009). Holt et al. first published the report of the successful disrupting CCR5 using the ZFNs (Holt et al., 2010). In their study, NSG mice transplanted with ZFN-modified HSPCs underwent rapid selection for CCR5(-/-) cells when challenged with CCR5-tropic HIV-1, showed significantly lower HIV-1 level compared to the controls. Several studies publishes later have also demonstrated the feasibility of CCR5 disruption in HSPCs that lead to resistance to HIV infection in vivo model (DiGiusto et al., 2016; Li et al., 2013; Xu et al., 2017). Among them, DiGiusto et al. conducted a preclinical study to assess efficacy and safety of the ZFN-based CCR5 disruption in HSPCs on the clinical-scale delivering CCR5-specific ZFN-mRNA to normal adult HSPCs. In which, they demonstrated effective biallelic CCR5 disruption of 40-60% in liquid culture cells, and in up to 72.9% of modified colony forming units from edited HSPCs. The edited HSPCs preserved long-term multiple lineage potential  in vivo with no demonstrated potential for tumorigenesis or leukemagenesis (DiGiusto et al., 2016). Based on this, further safety and feasibility studies are ongoing in subjects infected with HIV-1 ([emailprotected]). Targeting HSPCs genomic locus BCL11A via NHEJ gene editing has been developed for potential treatment of the ?-hemoglobinopathies, which are inherited monogenic blood disorders due to the mutations in ?-globin gene causing either Thalassemis (abnormal haemoglobin production) or sickle cell disease (SCD) (abnormal haemoglobin tetramer) (Steinberg, 1999). The observed fact of that the severity of both conditions can be ameliorated by the induction of Fetal haemoglobin (HbF) (Collins et al., 1995) led to discover the BCL11A transcription factor as a repressor for HbF (Bauer and Orkin, 2015), and BCL11A erythroid-specific enhancer, GATAA in association with fetal-to-adult haemoglobin switching (Canver et al., 2015), which could be targeted for inducing HbF in HSPCs for potential treatment of those conditions. To this end, Bjurstom et al. conducted the genome editing strategy to disrupt the BCL11A exon2 in HSPCs using the engineered nucleases ZFNs, TALENs or CRISPR-Cas9 (Bjurstrom et al ., 2016). It was shown in their study that the ZFNs gave rise to more allelic disruption in the  targeted  locus which is associated with increased levels of  HbF  in erythroid cells derived from nuclease-treated CD34+  cells in vitro. However, a low level of disruption in the BCL11A gene in bone marrow (4%) was observed after engraftment into NSG mice. Using the ZFNs approach Chang et al. performed study to compare targeted disruption of the  BCL11A, either within exon 2 or at the GATAA motif (Chang et al., 2017). It was shown from their study that the allelic disruption of GATAA not only give rise to robust  long-term  engraftment  leading to elevated level of  HbF  expression in erythroid  cells, but also prevent the adverse effect of erythroid enucleation seen in the  BCL11A exon2 ablation. Using same strategy, a comprehensive preclinical study has been carried out in HSPCs from adult donors and two patients with ?-Thalassemia Major (Psatha et al., 2018 ). The modification of GATAA motif in mobilized  CD34+  cells  from ?-thalassemia patients resulted in a readily detectable increased ?-globin with a preferential increase in G-gamma, leading to an improved phenotype that likely to give a survival advantage for maturing erythroid  cells. A phase 1/2 clinical trial for correcting the ?-thalassemia phenotype by genome  editing is currently being evaluated by the same group. Homologous recombination based strategy In larger majority genetic blood diseases, the homologous directed repair strategy is required for correcting genotype, with delivering exogenous DNA template. The process is much more challenging than NHEJ-based gene editing due to its low efficiency, particular in targeting primitive HSPCs. However, the promising progress in targeted integration in HSPCs for some PIDs has been made in recent years. Interleukin-2 receptor common gamma-chain (IL2RG) The first attempt using the ZFNs for gene knockin in HSPCs was demonstrated by Genovese et al. (Genovese et al., 2014). In this study, two genomic loci, AAVS1 â€Å"safe harbour† or a mutational hotspot of IL2RG were targeted with a GFP cassette delivered with IDLV vector. Although there was 24-26% indels found in the ZFN target sites, only 5% GFP+ colonies were found in colony-forming cells (CFU) assay. At 8 weeks after transplantation edited CD34+ cells into NSG mice, the frequency of 2% GFP+ cells were found among primitive and committed progenitors in the BM. To improve gene targeting efficiency, Genovese et al. tailored the culture condition by extending cell activation time making them more permissive for the editing molecules, and by adding the compounds into the culture to preserve the stemness in primitive HSPCs (Genovese et al., 2014). The modified protocol indeed gave rise to significantly increased GFP+ cells (?2-fold) in primitive cell population in vitro and also in vivo in long-term engrafted HSPCs. Using improved the ZFNs protocol Genovese et al. performed the IL2RG gene correction in CD34+ cells derived from SCID-X1 patient with delivering IDLV vector consisting of the exons 5-8 IL2RG cDNA and a PGK-GFP cassette flanked by homologous sequences. In which, they found 3% GFP+ cells in primitive HSCs and up to 11% GFP+ in committed progenitors in liquid culture. The CFU assay yield 3 GFP+ colonies out of 100 scored, with a myeloid progeny colony showed reconstituted normal IL2RG protein expression. The data from this study highlighted the problem with targeting primitive HSCs for homologous recombination. A recent development in targeting integration of IL2RG has been demonstrated by same group (Schiroli et al., 2017). In order to establish therapeutic potential of a gene correction strategy for the treatment of SCID-X1, a humanise SCID-X1 mouse model was used to evaluate efficacy and safety of the edited HSPCs in a preclinical setting. To i mprove editing efficiency, they made the modification on the ZFN mRNA by incorporating the base analogs to prevent recognition by cellular sensors that associated with the activation of the interferon-responsive genes by exogenous RNAs. This modification results in a significant reduced cytotoxicity caused by in vitro electroporation of the ZFN mRNA, leading to high HDR (25%) in CD34+ cells derived from a SCID-X1 patient. By changing to use AAV6 as donor DNA vehicle following the ZFN mRNA electroporation, they achieved up to fivefold higher HDR-mediated gene editing in the most primitive CD34+ CD133+ CD90+ cells over the IDLV vehicle approach. It was also demonstrated in this study that optimised clinical relevant protocol is transferable to the clinic scale, showing reproducible editing efficiency even in a large scale 2.5107 HSPCs. More importantly, the edited cells preserved long-term engraftments in NSG mice, showing an average 12% HDR in HSPCs at 23 weeks end point, which excee ded the threshold (10%) of functional HSPCs required for fully reconstitute immune function at a standard transplant dose established in the their study (Schiroli et al., 2017). The off-target assay did not detect significant amounts of modification above the threshold of sensitivity in any of the off-target sites identified previously by genome-wide screening for the ZFN set (Gabriel et al., 2011). Based on these data, it would be interesting to see if the optimised protocol could lead to adequate editing efficiency in HSPCs derived from the SCID-X1 patient, which could paves the way to translation HSPCs gene editing into the therapy. X-linked chronic granulomatous disease (X-CGD) Two recent studies published by De Ravin et al. presented the promising results on the targeted integration of CYBB gene encoding gp91phox for the treatment of X-CGD (De Ravin et al., 2017; De Ravin et al., 2016). Their initial study (De Ravin et al., 2016) was based on the ZFNs targeted integration of transgene into a genomic â€Å"safe habour†AASV1 with the aim to overcome insertional mutagenesis by the viral vector gene therapy, where 3 X-CGD patients underwent the gene therapy developed myelodysplasia due to the integration at MDS-EV11 locus (Stein et al., 2010). De Ravin et al. carried out extensive experiments firstly to explore the optimised conditions in clinical relevant approaches for delivery of the ZFNs, and AAV6 delivery of donor construct containing promoter-less Venus marker cDNA into the intron 1of the PPP1R12C gene at AAVS1 locus. The results from their study showed up to 58% Venus-positive HSCs in vitro and 6–16% human cell marking were observed follow ing engraftment into NSG mice. Using their optimised approach, they then targeted HSPCs derived from X-CGD/gp91phox patients with donor constructs containing either a promoter less gp91phox (2A-2A-gp91), or gp91phox driven by a synthetic MND promoter (MND-91). Although the both approaches showed a similar targeted integration efficiencies (~15% gp91phox expression), a robust functional correction through MND promoter, rather than the endogenous PPP1R12C promoter was obtained with significant high MFI of gp91expression and DHR oxidase activity in edited HSPCs in vitro. At 8 weeks following transplantation of edited HSPCs into NSG mice, the MND-91 and 2A-2A-gp91 corrected HSPCs grafted average 3.7 ±4.2% and 10.7 ±4.2% of human CD45+ cells respectively from bone marrow gp91expressing cells. Since the gene therapy corrected cells in X-CGD patients do not entail a selective advantage, the question is if the level of reconstituted gp91expressing cells achieved in this study would be sufficient for the disease phenotype correction. Nerveless, the data presented in the study has provided the first promising alternative approach in correction of X-CGD. However, long-term efficiency in vivo still remain to be established, and the safety issue of disrupting PPP1R12C gene encoding for a phosphatase in stem cells also need to be determined. In a later study led by the same group (De Ravin et al., 2017), De Ravin et al. have achieved the targeted correction of the point mutation C676T X-CGD using CRISPR/Cas9 and delivering single strand oligo nucleotide (ssODN). The C676T mutation, accounted for 6% of X-CGD patients, occurs at the exon 7 of CYBB gene resulting in a premature stop codon and an inactive gp91phox protein. Following experiments to optimise the targeting CYBB 676 locus in normal CD34+ cells, they achieved level of HDR editing efficiency even within primitive (CD34+CD133+CD90+) HSPCs at ~30%, which is high than any previously reported. In CD34+ cells derived from CYBB 676 patient, they achieved targeted repair of 20% of HSPCs and restored gp91expression to 31% in myeloid cells differentiated from edited HSPCs, which resulted in restoration of the function of NADPH oxidase activity and superoxide radical production. Analysing of transplantation of gene-repaired X-CGD HSPCs into NSG mice at 8 and 20 weeks, they demonstrated not only improved stable human engraftment and corrected CYBB alleles, but also the production of functional mature human myeloid and lymphoid cells for up to 20 weeks. The off-target sequencing analysis on computationally predicted off- target sites in edited CD34+ cells from the patient revealed one single indel (3 bp) at the RP11-454H19.2 gene at a high read depth 1,200,000x, but not at 10,000 read depth. However, one single indel observed in the uncorrected healthy control CD34+ HSPCs, indicating that this could be due to amplification/sequencing errors at high level of coverage. Whole-exome sequencing at 800Ãâ€" coverage of corrected patient CD34+ HSPCs also failed to detect any off-targets. Using same approach, De Ravin et al. have tried to correct a second X-CGD patient with CYBB 676 mutation (De Ravin et al., 2017). Although the gene repair efficiency was achieved in a similar level to the patient 1 in vitro, a less than 50% of the gene repair rate was observ ed after transplantation into NSG mice. This has highlighted the necessity of careful validation of editing condition at every level to achieve a consistent outcome. Nerveless, this study presented a viable approach in correction of a missense mutation in HSPCs by targeted integration that restore gene function under the control of the genes endogenous promoter. X-linked hyper-IgM syndrome (XHIM) XHIM is a primary immunodeficiency due to mutations in CD40 ligand gene (CD40L) expressed on the activated T cells. The mutated CD40L fail to bind CD40 on B cells which affect immunoglobulin class switch recombination that represented by the absence of IgG, IgA, IgE with normal to elevated IgM. XHIM patients are susceptible to bacterial infection, with development of autoimmunity and malignancies in some X-HIM individuals (Hayward et al., 1997; Levy et al., 1997). XHIM can be treated by allogenic HSCT, but has been associated with some sever site effects. Although the experimental gene therapy using viral vector in XHIM mouse model showed the correction of immune defect, the mice developed abnormal lymphoproliferation due to unregulated expression of the gene from ectopic genomic loci (Brown et al., 1998; Sacco et al., 2000). Therefore, using gene editing tools in targeted integration of XHIM gene under control of its endogenous promoter has become an optimal alternative approach for treating the disease. Using the TALEN as targeted gene editing approach Hubbard et al. have first demonstrated the feasibility in restoration of normal expression of CD40L and rescued IgG class switching in XHIM  patient  T cells (Hubbard et al., 2016). A later study by Kuo et al. developed the both TALEN and CRISPR/Cas9 platforms to achieve site-specific editing of a human CD40L cDNA, at the 5’UTR of the gene allowing bypassing all known disease-causing mutations in XHIM (Kuo et al., 2018). The both approaches were tested in T cells derived from XHIM patient. Although the TALEN approach resulted in CD40L expression at the baseline in unstimulated cells, an up-regulated CD40L expression to 20% was detected upon anti-hCD3/anti-hCD28 immune stimulation which is comparable to stimulated T cells from healthy donors. The corrected XHIM T cells demonstrated a normal receptor-binding activity to recombinant chimeric CD40-muIg. The data highlighted that a proportionally small n umber of gene-corrected T cells in XHIM may be sufficient to allow enough class-switching to ameliorate the disease. In CRISPR/Cas9 treated XHIM T cells, high rates of targeted gene integration was attained with restore physiologically-regulated CD40L expression and function. In targeting CD34+ cells from healthy donor, Kuo et al. have shown that both platforms gave rise to a similar level of allelic disruption rate in samples from 8 biological replicate, 4 PBSC donors (29.1  ± 7.8% with TALEN, average 33% with CRISP/Cas9). A relative high targeted gene integration rate was observed in CRISP/Cas9 treated cells, particular when gRNA and Cas9 protein delivered as RNP (to 20.8  ± 6.6%). By adding the adenovirus helper protein that co-introduced as mRNA during electroporation with TALENs or CRISPRs, a 2-fold enhanced gene modification was achieved. However, this augment effect was not observed in engrafted NSG mice in vivo. Following transplantation of edited cells into NSG mice at 12-20 weeks, the targeted gene integration was detected in the bone marrow from 80% of mice, with integration rates ranged from 0.3% to 22%, a mean of 4.4% across all treatment groups. The analysing of thymus from engrafted mice showed 60% mice had thymic reconstitution, With frequency of engraftment trending higher in those analysed at 5 months compared to 3 months post-transplant. The off-target activity was not detected based on silico predicted off-target sites for both TALENs and CRISPR in K562 edited cells. However, using IDLV capture approach in TALENs edited K562 cell, three off-target loci (OT1, OT2 and OT3) were observed. High-throughput sequencing of off-target sites in HSPCs and K562 cell treated with TALENs mRNA demonstrated statistically significant gene disruption at OT1 in HSPCs, and OT2 in both cells. However, there was no off-target site identified in CRISPR treaded cells using another cell based assay GUIDE-seq, which was designed recently with a high sensitivity for detecting the off-target sites mutagenized by Cas9-gRNA (Tsai et al., 2015). Taking together, CRISPR approach showed some advantages over TALENs in targeting integration of XHIM gene. Overall, this study paves an important step toward to developing a curative therapy for XHIM through site-specific gene correction. The major hurdles in HSPCs gene editing Despite the genome editing holds tremendous promise for the developing novel gene therapy, HSPCs targeted editing is still in its infancy, and many issues regarding this new technology are remained to be addressed before translating it into safe clinical application. One major hurdle facing in HSPCs targeted editing is low efficiency, particularly in vivo following transplantation of edited cells, where the engrafted cells and frequency of edited cells decline significantly within 8 to 12 weeks and continuously decline in prolonged period. This suggests the â€Å"real† long-term HSPCs either have failed to undergo genome editing due to their quiescence and more resistance to homologous recombination, or they have been damage by DSBs due to exposure to nuclease and lost their self-renew property underwent apoptosis.