Foundation and Empire 4. The Emperor

CLEON II commonly called â€Å"The Great.† The last strong Emperor of the First Empire, he is important for the political and artistic renaissance that took place during his long reign. He is best known to romance, however, for his connection with Bel Riose, and to the common man, he is simply â€Å"Riose's Emperor.† It is important not to allow events of the last year of his reign to overshadow forty years of†¦ Encyclopedia Galactica Cleon II was Lord of the Universe. Cleon II also suffered from a painful and undiagnosed ailment. By the queer twists of human affairs, the two statements are not mutually exclusive, nor even particularly incongruous. There have been a wearisomely large number of precedents in history. But Cleon II cared nothing for such precedents. To meditate upon a long list of similar cases would not ameliorate personal suffering an electron's worth. It soothed him as little to think that where his great-grandfather had been the pirate ruler of a dust-speck planet, he himself slept in the pleasure palace of Ammenetik the Great, as heir of a line of Galactic rulers stretching backward into a tenuous past. It was at present no source of comfort to him that the efforts of his father had cleansed the realm of its leprous patches of rebellion and restored it to the peace and unity it had enjoyed under Stanel VI; that, as a consequence, in the twenty-five years of his reign, not one cloud of revolt had misted his burnished glory. The Emperor of the Galaxy and the Lord of All whimpered as he lolled his head backward into the invigorating plane of force about his pillows. It yielded in a softness that did not touch, and at the pleasant tingle, Cleon relaxed a bit. He sat up with difficulty and stared morosely at the distant walls of the grand chamber. It was a bad room to be alone in. It was too big. All the rooms were too big. But better to be alone during these crippling bouts than to endure the prinking of the courtiers, their lavish sympathy, their soft, condescending dullness. Better to be alone than to watch those insipid masks behind which spun the tortuous speculations on the chances of death and the fortunes of the succession. His thoughts hurried him. There were his three sons; three straight-backed youths full of promise and virtue. Where did they disappear on these bad days? Waiting, no doubt. Each watching the other; and all watching him. He stirred uneasily. And now Brodrig craved audience. The low-born, faithful Brodrig; faithful because he was hated with a unanimous and cordial hatred that was the only point of agreement between the dozen cliques that divided his court. Brodrig – the faithful favorite, who had to be faithful, since unless he owned the fastest speed-ship in the Galaxy and took to it the day of the Emperor's death, it would be the radiation-chamber the day after. Cleon II touched the smooth knob on the arm of his great divan, and the huge door at the end of the room dissolved to transparency. Brodrig advanced along the crimson carpet, and knelt to kiss the Emperor's limp hand. â€Å"Your health, sire?† asked the Privy Secretary in a low tone of becoming anxiety. â€Å"I live,† snapped the Emperor with exasperation, â€Å"if you can call it life where every scoundrel who can read a book of medicine uses me as a blank and receptive field for his feeble experiments. If there is a conceivable remedy, chemical, physical, or nuclear, which has not yet been tried, why then, some learned babbler from the far comers of the realm will arrive tomorrow to try it. And still another newly-discovered book, or forgery morelike, will be used as authority. â€Å"By my father's memory,† he rumbled savagely, â€Å"it seems there is not a biped extant who can study a disease before his eyes with those same eyes. There is not one who can count a pulse-beat without a book of the ancients before him. I'm sick and they call it ‘unknown.' The fools! If in the course of millennia, human bodies learn new methods of falling askew, it remains uncovered by the studies of the ancients and uncurable forevermore. The ancients should be alive now, or I then.† The Emperor ran down to a low-breathed curse while Brodrig waited dutifully. Cleon II said peevishly, â€Å"How many are waiting outside?† He jerked his head in the direction of the door. Brodrig said patiently, â€Å"The Great Hall holds the usual number.† â€Å"Well, let them wait. State matters occupy me. Have the Captain of the Guard announce it. Or wait, forget the state matters. Just have it announced I hold no audience, and let the Captain of the Guard look doleful. The jackals among them may betray themselves.† The Emperor sneered nastily. â€Å"There is a rumor, sire,† said Brodrig, smoothly, â€Å"that it is your heart that troubles you.† The Emperor's smile was little removed from the previous sneer. â€Å"It will hurt others more than myself if any act prematurely on that rumor. But what is it you want. Let's have this over.† Brodrig rose from his kneeling posture at a gesture of permission and said, â€Å"It concerns General Bel Riose, the Military Governor of Siwenna.† â€Å"Riose?† Cleon II frowned heavily. â€Å"I don't place him. Wait, is he the one who sent that quixotic message some months back? Yes, I remember. He panted for permission to enter a career of conquest for the glory of the Empire and Emperor.† â€Å"Exactly, sire.† The Emperor laughed shortly. â€Å"Did you think I had such generals left me, Brodrig? He seems to be a curious atavism. What was the answer? I believe you took care of it.† â€Å"I did, sire. He was instructed to forward additional information and to take no steps involving naval action without further orders from the Imperium.† â€Å"Hmp. Safe enough. Who is this Riose? Was he ever at court?† Brodrig nodded and his mouth twisted ever so little. â€Å"He began his career as a cadet in the Guards ten years back. He had part in that affair off the Lemul Cluster.† â€Å"The Lemul Cluster? You know, my memory isn't quite – Was that the time a young soldier saved two ships of the line from a head-on collision by†¦ uh†¦ something or other?† He waved a hand impatiently. â€Å"I don't remember the details. It was something heroic.† â€Å"Riose was that soldier. He received a promotion for it,† Brodrig said dryly, â€Å"and an appointment to field duty as captain of a ship.† â€Å"And now Military Governor of a border system and still young. Capable man, Brodrig!† â€Å"Unsafe, sire. He lives in the past. He is a dreamer of ancient times, or rather, of the myths of what ancient times used to be. Such men are harmless in themselves, but their queer lack of realism makes them fools for others.† He added, â€Å"His men, I understand, are completely under his control. He is one of your popular generals.† â€Å"Is he?† the Emperor mused. â€Å"Well, come, Brodrig, I would not wish to be served entirely by incompetents. They certainly set no enviable standard for faithfulness themselves.† â€Å"An incompetent traitor is no danger. It is rather the capable men who must be watched.† â€Å"You among them, Brodrig?† Cleon II laughed and then grimaced with pain. â€Å"Well, then, you may forget the lecture for the while. What new development is there in the matter of this young conqueror? I hope you haven't come merely to reminisce.† â€Å"Another message, sire, has been received from General Riose.† â€Å"Oh? And to what effect?† â€Å"He has spied out the land of these barbarians and advocates an expedition in force. His arguments are long and fairly tedious. It is not worth annoying Your Imperial Majesty with it at present, during your indisposition. Particularly since it will be discussed at length during the session of the Council of Lords.† He glanced sidewise at the Emperor. Cleon II frowned. â€Å"The Lords? Is it a question for them, Brodrig? It will mean further demands for a broader interpretation of the Charter. It always comes to that.† â€Å"It can't be avoided, sire. It might have been better if your august father could have beaten down the last rebellion without granting the Charter. But since it is here, we must endure it for the while.† â€Å"You're right, I suppose. Then the Lords it must be. But why all this solemnity, man? It is, after all, a minor point. Success on a remote border with limited troops is scarcely a state affair.† Brodrig smiled narrowly. He said coolly, â€Å"It is an affair of a romantic idiot; but even a romantic idiot can be a deadly weapon when an unromantic rebel uses him as a tool. Sire, the man was popular here and is popular there. He is young. If he annexes a vagrant barbarian planet or two, he will become a conqueror. Now a young conqueror who has proven his ability to rouse the enthusiasm of pilots, miners, tradesmen and suchlike rabble is dangerous at any time. Even if he lacked the desire to do to you as your august father did to the usurper, Ricker, then one of our loyal Lords of the Domain may decide to use him as his weapon.† Cleon II moved an arm hastily and stiffened with pain. Slowly he relaxed, but his smile was weak, and his voice a whisper. â€Å"You are a valuable subject, Brodrig. You always suspect far more than is necessary, and I have but to take half your suggested precautions to be utterly safe. We'll put it up to the Lords. We shall see what they say and take our measure accordingly. The young man, I suppose, has made no hostile moves yet.† â€Å"He report none. But already he asks for reinforcements.† â€Å"Reinforcements!† The Emperor's eyes narrowed with wonder. â€Å"What force has he?† â€Å"Ten ships of the line, sire, with a full complement of auxiliary vessels. Two of the ships are equipped with motors salvaged from the old Grand Fleet, and one has a battery of power artillery from the same source. The other ships are new ones of the last fifty years, but are serviceable, nevertheless.† â€Å"Ten ships would seem adequate for any reasonable undertaking. Why, with less than ten ships my father won his first victories against the usurper. Who are these barbarians he's fighting?† The Privy Secretary raised a pair of supercilious eyebrows. â€Å"He refers to them as ‘the Foundation.'† â€Å"The Foundation? What is it?† â€Å"There is no record of it, sire. I have searched the archives carefully. The area of the Galaxy indicated falls within the ancient province of Anacreon, which two centuries since gave itself up to brigandage, barbarism, and anarchy. There is no planet known as Foundation in the province, however. There was a vague reference to a group of scientists sent to that province just before its separation from our protection. They were to prepare an Encyclopedia.† He smiled thinly. â€Å"I believe they called it the Encyclopedia Foundation.† â€Å"Well,† the Emperor considered it somberly, â€Å"that seems a tenuous connection to advance.† â€Å"I'm not advancing it, sire. No word was ever received from that expedition after the growth of anarchy in that region. If their descendants still live and retain their name, then they have reverted to barbarism most certainly.† â€Å"And so he wants reinforcements.† The Emperor bent a fierce glance at his secretary. â€Å"This is most peculiar; to propose to fight savages with ten ships and to ask for more before a blow is struck. And yet I begin to remember this Riose; he was a handsome boy of loyal family. Brodrig, there are complications in this that I don't penetrate. There may be more importance in it than would seem.† His fingers played idly with the gleaming sheet that covered his stiffened legs. He said, â€Å"I need a man out there; one with eyes, brains and loyalty. Brodrig-â€Å" The secretary bent a submissive head. â€Å"And the ships, sire?† â€Å"Not yet!† The Emperor moaned softly as he shifted his position in gentle stages. He pointed a feeble finger, â€Å"Not till we know more. Convene the Council of Lords for this day week. It will be a good opportunity for the new appropriation as well. I'll put that through or lives will end.† He leaned his aching head into the soothing tingle of the force-field pillow, â€Å"Go now, Brodrig, and send in the doctor. He's the worst bumbler of the lot.†

Unit 3 Assignment

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Tour Operations Essay Aim and purpose The aim of this unit is to develop learners’ understanding of the dynamic and challenging world of tour operations and for them to appreciate the variety of tour operators’ products and services. Learners will gain knowledge of how tour operators plan, sell and administer a package holiday programme and will also develop practical skills to plan and cost a package holiday. Unit introduction Every year millions of people turn to tour operators to provide them with holidays to all corners of the world. In this unit learners will explore how tour operators link with different types of travel and tourism organisations to provide a wide range of holiday experiences. They will see that tour operators must respond to legislation and external influences, and also face many challenges in the constantly changing travel and tourism sector. Learners will investigate these challenges and the ways in which tour operators respond to them. Tour operators are at the forefront of the travel and tourism sector, constantly seeking out new destinations and holiday experiences to satisfy the ever-demanding and ever-changing needs of today’s holidaymakers. Different types of tour operators will be identified and learners will examine how they develop an extensive portfolio of products and services to meet differing customer needs. Whatever their size, tour operators must work through the same processes when planning, developing, selling and operating their holiday programmes. These different functions will be examined and time scales identified. Learners will find that tour operators compete in a commercially sensitive environment and they will identify how commercial considerations inform many of the business practices. Practical skills will be developed in the planning and costing of a tour operator’s package holiday, allowing learners to appreciate some of the commercial decisions to be made in this competitive industry. Learning outcomes On completion of this unit a learner should: Understand the tour operations environment Know the range of products and services offered by tour operators for different target markets Know how tour operators plan, sell, administer and operate a package holiday programme Be able to plan and cost a package holiday. Unit content 1 Understand the tour operations environment Links with other component industries: travel agents; transport providers; accommodation providers; providers of ancillary products and services eg insurance, car hire; horizontal and vertical integration Links with trade and regulatory bodies: The Travel Association (ABTA); Federation of Tour Operators (FTO); Association of Independent Tour Operators (AITO); UKInbound; Civil Aviation Authority (CAA) Legal framework: EU Package Travel Regulations; consumer protection eg Trades Description Act, Consumer Protection Act, Disability Discrimination Act; contract law; licensing eg Air Transport Operators Licence (ATOL) External influences: environmental eg hurricanes, floods; political eg terrorism, strikes. taxes; economic eg currency fluctuations, price of oil; social eg UK demographics, exploitation in host country; technological eg internet, computerised reservation systems Challenges: eg dynamic packaging, distribution channels, integration, budget airlines, maintaining market share, trend towards independent travel, responsible tourism 2 Know the range of products and services offered by tour operators for different target markets Tour operator categories: outbound; inbound; domestic; specialist; mass market Products and services: components of standard package; tailor made; range of destinations; accommodation choices; transport options; ancillary products and services Target market: eg families, couples, solo travellers, specific age groups, special interests, people with specific needs 3 Know how tour operators plan, sell, administer and operate a package holiday programme Planning: research; forecasting; product development; methods of contracting; costing the package; data input; timescales Sell: brochure production; pricing strategies; distribution eg travel agents, internet, direct sell; promotions eg advertising, sales promotions, sponsorship; reservations; commission; late sales Administer: confirmations; rooming lists; passenger manifests; errata; cancellations; amendments; travel itineraries; ticketing Operations: consolidations; load factors; over-bookings; transport operations; duty office; UK and overseas resort liaison; health and safety; emergency situations; crisis management; quality control; customer service (pre-, during and post-holiday); excursion sales Commercial considerations: maximising profitability; links to different planning, selling, administrative and operational functions 4 Be able to plan and cost a package holiday Plan: destination; transport; accommodation; excursions (included, optional); activities; additional services Cost a package holiday: using load factors; mark-up or profit margin; currency conversions; fixed costs; variable costs Assessment and grading criteria In order to pass this unit, the evidence that the learner presents for assessment needs to demonstrate that they can meet all the learning outcomes for the unit. The assessment criteria for a pass grade describe the level of achievement required to pass this unit. Assessment and grading criteria To achieve a pass grade the evidence must show that the learner is able to: To achieve a merit grade the evidence must show that, in addition to the pass criteria, the learner is able to: M1 discuss the impact of challenges facing tour operators To achieve a distinction grade the evidence must show that, in addition to the pass and merit criteria, the learner is able to: D1 evaluate the effectiveness of tour operators in responding to challenges facing the sector recommend, with justification, how a selected tour operator could expand its range of products and services for its current target market or adapt its range of products and services to appeal to a new market. P1 explain the tour operations environment and the challenges it faces P2 describe the products and M2 analyse how a selected services provided by different tour operator’s portfolio categories of tour operator of products and services for different target markets meets the needs of its target market(s) D2 P3 outline how tour operators plan, sell, administer and operate a package holiday programme, identifying commercial considerations plan and cost a package holiday for inclusion in a tour operator’s programme [CT 1, CT 2, CT 3, CT 4, CT 5, CT 6]. M3 explain ways of maximising profitability during the different stages of planning, selling, administering and operating a package holiday. P4 PLTS: This summary references where applicable, in the square brackets, the elements of the personal, learning and thinking skills applicable in the pass criteria. It identifies opportunities for learners to demonstrate effective application of the referenced elements of the skills. Key IE – independent enquirers CT – creative thinkers RL – reflective learners TW – team workers SM – self-managers EP – effective participators Essential guidance for tutors Delivery It is likely that learners will have already identified the role of tour operators when examining the structure of the UK travel and tourism sector in Unit 1: Investigating the Travel and Tourism Sector. A simple recap would be useful and this could be achieved by asking learners to produce their own definition of tour operators and a summary of their role within the sector, perhaps producing a diagram that highlights their position within the  structure. Holiday brochures will help learners to identify how tour operators link with other component industries when providing and selling holiday packages. Links with trade and regulatory bodies and the legal framework could be researched in small groups, culminating in short, informal presentations. Vertical and horizontal integration can be a difficult concept for some learners and they will benefit from being given simple definitions, followed by practical tasks using the internet and holiday brochures to research one of the large in tegrated organisations. Findings could be presented in the form of a diagram and could then be compared with one of the integration charts that are produced from time to time by the trade press. Tutors will need to explain how the travel and tourism sector is constantly changing (which is why textbook models of integration are likely to be out of date). Learners will need to read the trade press regularly in order to keep abreast of changes of ownership and takeovers. Tutors could initiate a debate or discussion on the impact of integration to determine whether integration is a good or bad force within the sector, and about the challenges integration creates. Research activities could be developed to examine external influences including environmental, political, economic, social and technological influences. Hurricanes, the credit crunch, unemployment and terrorist activities are just a few occurrences that can present significant challenges for tour operators. A noticeboard could be created in the classroom to display any topical events or issues. Learners need to appreciate that there are hundreds of different tour operators, falling broadly into the categories of outbound, inbound, domestic, mass market and specialist. Learners, in pairs or small groups, could research to identify tour operators within each of the categories, and the range of products and services they offer. The internet is an excellent source of information, as are holiday brochures; however, tutors should discourage indiscriminate collection of holiday brochures. Learners will find that most tour operators have products and services that target different market segments and this will be reflected in some of the accommodation, travel, destination and ancillary services choices provided. Learners need to understand that all tour operators, whether large or small, carry out the same functions when planning, selling, administering and operating the holiday package. Larger tour operators may  have separate departments to carry out a particular function whereas a very small tour operator might have just one person responsible for a range of functions. A practical task could involve learners organising a college trip and relating the activities they carry out to the functions of tour operating. A visit to a large- or mediumsized tour operator would be very beneficial so that learners can see how tour operators work and how the different functions are carried out. Additional tutor input on planning, selling, administration and operations will be required. Activities using case studies can reinforce understanding of aspects such as different methods of contracting, currency considerations and pricing strategies. It is essential that learners develop a sound understanding of all functional areas. Discussions are to be encouraged to help learners appreciate commercial considerations, the difficulties tour operators have in making a profit and to identify ways in which profit can be maximised within the planning, selling, administrative and operational functions. In preparation for assessment, learners will need to practise designing and planning a package. Working in groups to a specific brief, they could practise by planning a college trip. As part of the planning, they would need to consider transport options, type of accommodation and board basis, excursions and activities. Each group could present their proposals to the class and vote on the most interesting proposals. Tutors should explain the terms ‘load factor’, ‘mark up’, ‘profit margin’, ‘fixed costs’ and ‘variable costs’ and then work through simple costing exercises to show how these terms are used. When learners have understood the process for costing a package, exercises should be designed to put this into practice. Tutors may need to devise additional exercises before learners become confident in working with these calculations.

Tumour Supressor Genes and Retinoblastoma

Tumour Supressor Genes and Retinoblastoma Throughout our life time growth is constant. Barring a few cells, most cells continue to grow, divide and replace themselves. Such processes require a strict regulation and this is brought about by cell cycle processes. These processes are carried out by proteins which control the growth and development. Proteins are coded by the genes and when the genetic information is altered or is mutated, it leads to a protein which is dysfunctional and the cell might lose its restraint on growth processes. This in turn leads to an uncontrolled growth of the cells which then causes cancer. Cancer is a disease of the genes. At a molecular level, there are two major reasons which have been attributed for cancer induction. The first one is the gain of function in genes and the other one is loss of function of genes. The genes which gain function, that is, get activated after certain specific events are known as proto-oncogenes. They are typically activated in cancer cells conferring new properties, such as hyperactive growth and division, protection against programmed cell death, loss of contact inhibition between cells, and the ability to become established in diverse and adverse environments. Those genes which lose their functions due to specific events are termed tumor suppressor genes (Eeles et al 2004). Tumor suppressor genes are inactivated in cancer cells, resulting in loss of normal functions, such as accurate DNA replication, cell cycle control, adhesion within tissues. Tumor suppressor genes are named such because when they are expressed in a normal cell they maintain the cell in a differentiated state and do not allow unchecked proliferation of cells. Therefore, at least one functional copy is required to prevent tumor initiation. That there are tumor suppressor genes was proposed when it was experimentally found by Harris et al. (1969) in cell fusion experiments wherein a fusion between a normal and a tumor cell rendered the cell non-cancerous and therefore, it was proposed there must be tumor suppressor genes which suppress cell growth in a dominant fashion (Skapek et al, 1997). As long as the normal copy is functional, the protein expressed maintains normal functioning of the cells. Many tumor suppressors have been identified and extensively characterized. TP53, WT1, NF1, BRCA, VHL, APC, MEN1 are a few examples of tumor suppressor genes. Tumor suppressor genes are divided into three categories- the gatekeepers, the caretakers and the landscapers. Gatekeepers are genes that directly regulate the growth of tumors by inhibiting their growth or by promoting apoptosis. In contrast, inactivation of caretakers does not directly promote growth of tumors. Rather, inactivation of caretakers leads to genetic instability that only indirectly promotes growth by causing an increased mutation rate. Landscaper genes do not directly affect cancer cell growth but contribute to an abnormal stromal environment that contributes to neoplastic transformation of the overlying epithelium. This project deals with one gatekeeper gene, known as retinoblastoma susceptibility gene (RB1). RB1 is the first tumor suppressor gene to be identified and cloned (Lee at al., Eeles et al, 2004; Andrade et al, 2006). It is the gene which when mutated predisposes a person to a common malignancy of the eye, retinoblastoma. Retinoblastoma is the most common intraocular cancer in children. It generally manifests in children before the age of five years with a majority of the tumors occurring by the age of 2 years (Lee et al., Eeles et al, 2004). Clinical features of retinoblastoma: As the name implies, retinoblastoma is one of the rare embryonic neoplasms originating in the retina. It is the most common intraocular tumor in children (Valverde et al, 2005). It was first described as a specific entity by James Wardrop. In majority of cases, the first sign at presentation is the characteristic cats eye reflex, which is usually noted by direct visualization. This white, pink-white, or yellow-white pupillary reflex, termed leukocoria, results from replacement of vitreous by the tumor or by a tumor growing in the macula. Another common symptom, strabismus or squint (exotropia or esotropia) can occur alone when small macular tumors interfere with the vision, or can be associated with leukocoria. Uncommon presenting signs for retinoblastoma are red, painful eye with secondary glaucoma, orbital cellulitis (infection of the soft tissues of the eyelids), unilateral mydriasis (excessive dilation of the pupil due to disease or due to trauma), and heterochromia (the iris of the two eyes show different color). In rare cases, presenting symptoms include hypopyon (pus in the anterior chamber of eye), hyphema (blood in the anterior eye chamber), keratitis, and vitreous hemorrhage (Vogelstein and Kinzler, 2002). A complete evaluation for retinoblastoma includes ophthalmologic examination, radiographic evaluation (skull X-ray, CT scan, MRI), and more recently, genetic testing. Fundus examination of first degree relatives is also done to look for the presence of retinoma or a regressed tumor which may indicate a hereditary component of the disease. Retinoblastoma can be exophytic or endophytic. It is exophytic when tumor occurs between the choroid and the retina and it is endophytic when it extends from retina towards the vitreous chamber. Therapy depends on the stage at which it is discovered. Based on that, treatment is given which includes enucleation, external beam radiotherapy, cryotherapy, episcleral plaques, xenon and argon laser photocoagulation, and chemotherapy. The choice of treatment depends on the factors such as: Multifocal or unifocal disease, Site and dimensions of the tumor, Diffused or focal vitreous seeding, Age of the individual, Histopathological finding. Therefore, staging and grouping of the disease is very important. Retinoblastoma can manifest in one of the eyes, both eyes and / or pineal body of the brain. When it is observed in one eye, it is referred to as unilateral retinoblastoma. When it is present in both the eyes, it is referred to as bilateral retinoblastoma. It is called trilateral retinoblastoma when the pineal gland is also involved. Why should retinoblastoma occur in one eye in some individuals and both the eyes in others? One more observation was that most of the individuals who came with retinoblastoma in both the eyes were diagnosed at an age earlier than those who presented with unilateral retinoblastoma. What is different in the genotypes of these two types of individuals that warrant a delayed onset of disease in the unilateral retinoblastoma cases? This was explained by Knudson in his study. Genetics in retinoblastoma: Retinoblastoma occurs with a frequency of 1 in 13,500 (Mateu et al., 1997) to1 in 20,000 (Di Commo et al., 2000). It is seen in both hereditary and nonhereditary forms (Knudson, Lee et al.) and shows no significant variation between races, countries, or level of industrialization (Mateu et al., 1997). However, contradictory views have been expressed by Mastrangelo as he questions the credibility of the data. Previous studies indicated that a gene predisposing to retinoblastoma manifests in young children was localized to chromosome 13. The gene was probably at band q14, since several retinoblastoma patients had shown to carry constitutional deletions of this region of chromosome 13. Retinoblastoma can be hereditary as well as sporadic. Those who have a mutation at one of the alleles of RB1 in germline cells are said to be predisposed to the disease. Such cases are categorized under hereditary retinoblastoma. Both hereditary as well as non-hereditary forms of retinoblastoma may show tumors in one or both the eyes. In the hereditary form of retinoblastoma, a germline mutation is transmitted as high penetrance (90%) autosomal dominant trait (Martinez et al). Most reported cases are sporadic (Knudson, 1971; Mateu et al, 1997). Retinoblastoma is caused by two mutational events at the retinoblastoma (RB1) locus (Knudson, 1971). That is, biallelic inactivation of RB1 due to mutations is a crucial event in the development of retinoblastoma (Andrade et al, 2006). Knudsons hypothesis: Alfred Knudson realized the implications of the fact that individuals with hereditary bilateral retinoblastoma were diagnosed at a younger age than those children with non-heritable disease, mostly unilateral retinoblastoma. The mean age of individuals on diagnosis was found to be 19 months in unilateral retinoblastoma cases whereas it was found to be 5 months in bilateral retinoblastoma cases. Also, in most cases of familial retinoblastoma, tumor develops in both the eyes. To explain these two important phenomena, age of onset and tumor development (unifocal or multifocal) in one or both eyes, Knudson proposed the two hit hypothesis. The hypothesis seeks to explain the occurrence of hereditary and nonhereditary retinoblastoma and its correlation with the age of onset of the disease. According to Knudson, the first mutational hit can be inherited through the germline or can be somatically acquired, whereas the second occurs somatically in both cases and leads to tumor in cells that is double defective at the RB1 locus (Knudson, 1971; Mateu et al., 1997). Thus in case of hereditary retinoblastoma, the individual must have inherited the mutation through the germline and hence, during the course of development may show the second mutational hit leading to tumorigenesis. As this individual already has a mutation in germline, it shows the second hit early in the life time. Statistical analyses indicated that as few as two mutational hits were rate limiting for the development of retinoblastoma tumors. The occurrence of the first mutation (M1) in the germline and all developing retinal cells gives retinoblastoma tumor a head start in hereditary cases (only M2 must arise in a retinal cell), compared to non-hereditary tumors where both M1 and M2 must arise in a single retinal cell. On the other hand, in unilateral retinoblastoma cases, the individual has not inherited a germline mutation at the RB1 locus. During the course of development, the cells of such patients gather both the mutations in somatic cells with some exceptions. Thus these tumors arise later than the hereditary forms of retinoblastoma. Knudson performed a statistical analysis of some patients presenting with retinoblastoma. The number of tumors in each eye was calculated and he devised a distribution keeping number of tumors in one eye, m= 3. Each tumor which is seen originates from a single cell. Thus, a mutation rate can be roughly calculated. If the total number retinal cells are n, m/n is the probability of a cell undergoing mutation at one of the alleles. Now, retinoblastoma is derived from the inner and outer neuroblastic layer. The order of magnitude of retinoblasts is reflected by the magnitude of the number of ganglion cells which are derived from the early differentiated inner nuclear layer of the retina. The estimated number of ganglion cells has been put at 2 x 106 per retina. Thus, using this as an approximation for the total number of cells, the probability that a cell will inherit one mutation is 0.75 x 10-6. Since a majority of hereditary cases occur in the first two years of life, the probability expressed per year at either member of the autosomal gene pair would be one fourth of this value, or approximately 2x 10-7 per year. This estimates the rate of second mutation in mutated cells (Knudson, 1971). It is seen that the rate at which the second mutation occurs is relatively lower than the first mutational hit. Retinoblastoma in hereditary cases which present themselves as bilateral retinoblastoma show high penetrance. In such cases, the vast majority of high penetrance mutations are null alleles where the mutations abrogates which destabilizes RB mRNA, presumably due to pre mature truncation of translation, so that no pRb is detected. However, some mutations show low penetrance. The low penetrance phenotype can result from several different types of RB alleles. Germline deletion of the whole RB gene often results in unilateral retinoblastoma, presumably because an unknown adjacent critical gene is also deleted, without which the RB-/- cell cannot survive. Only cells in which M2 is a different intragenic RB mutation on an allele with the adjacent critical gene still intact can survive to form retinoblastoma. Some mutations reduce expression of wild type pRB by targeting the promoter or splice sites. In-frame mutations result in a stable pRB with some aberrant functions. THE RB1 GENE: The RB gene family includes at least three members- RB1, RBL1, and p130. The RBL1 and p130 also show similar protein binding characteristics as RB1 and therefore they come under one gene family (Mulligan and Jacks, 1998). All three genes code for pocket proteins because their main sequence similarity resides in the pocket domain, which mediates interactions with the cellular and viral proteins to exert biological functions of this family (Pogoriler et al., 2006). The RB1 gene has been localized on chromosome 13 of humans on the long arm with locus 14.2 (Cavenee et al, 1971). The RB1 gene codes for a protein which is 928 amino acids long. There are 27 exons in RB1 and occupies nearly 200 kb of the genome. The gene transcribes a 4.7 kb mRNA. The exon size varies across the gene. The largest is exon 27 which is 1892bp long while exon 24 has only 30bp in its exonic region (NCBI database: www.ncbi.nlm.nih.gov/). Comings et al. suggested that RB1 is a tumor suppressor gene which is recessive at cellular level (Comings, 1971; Di Commo et al., 2000). The RB1 promoter present upstream of the exons does not show the typical TATA box binding domain. The promoter sequence of RB1 reveals that the sequence between -300 and +400 is GC rich (Hong et al, 1989). As the promoter lacks a TATA element, it might explain the presence of three transcriptional initiation sites. Deletion analysis of the promoter by Hong et al demonstrated that the sequence stretching from +13 to +83 suffices the promoter activity. Another characteristic of the promoter region is that the G+C rich region shows similarity with many housekeeping genes (Hong et al, 1989). This outlines the fact that the RB1 gene is expressed constitutively in almost all tissues of our body. The Leiden Open source Variation Database (LOVD) maintains the reported mutations in the RB1 gene. Almost 940 mutations and polymorphisms have been reported in RB1 by many scientists (www.rb1-lsdb.d-lohmann.de/). Single base pair mutations are the most frequent M1 mutations and account for nearly 40% of the confirmed mutations, followed by short and large mutations. The second hit might be associated with loss of heterozygosity (LOH) mutations, promoter hypermethylation, or even a second independent base substitution (Andrade et al, 2006; Lohmann et al., 1996). The most common point mutation found in the studies is the change from C>T at the CGA sites which codes for amino acid arginine. This change leads to premature termination of the protein (Lohmann et al., 1996). Expression of Rb protein: Initially, RB gene was considered to be expressed ubiquitously in all tissues of the body considering its role in maintaining cell differentiation (Karantza et al, 1993). However, later studies revealed differential expression of Rb protein. In situ Hybridization studies done with Rb expression during embryogenesis show, that the Rb family of proteins is differentially expressed in only certain specific cell lineages. According to studies, Rb1 mRNA transcripts were detected not only during in the ganglionic cell layer of retina but also during neurogenesis, hematopoiesis, myogenesis, lens development prior to and during differentiation. In the liver and the CNS, RB1 is co-expressed along with p107 protein. Consequently, RB-/-, p107-/- cells undergo cell apoptosis. RB1 transcripts were also detected throughout myogenesis. pRB has also been found to be expressed during spermatogenesis (Yan et al, 2001). Since RB1 mutations specifically arise in the human eye, analysis has been performed for the developing eye. The results suggested that RB1 transcripts were detected in the ganglion cell layer of the developing retina from embryonic day 14 through 18 (Jiang et al, 1997). Preliminary studies had indicated that Rb expression in developing retina initiates as the cells commit to differentiation, but pRb has been detected only in certain subsets of retinal cells (Di Commo et al, 2000). In conclusion, pRb expression is important for terminal mitosis in peripheral nervous system, keratinocytes, and skeletal muscles (Di Commo et al, 2000). THE RETINOBLASTOMA SUSCEPTIBILITY PROTEIN: The RB1 gene transcribes a 4.7 kb mRNA which encodes a phosphoprotein which is 928 amino acids long. It is an example of a pocket protein as there are sites or pockets which interact with other proteins. The protein is a negative regulator of the cell cycle. The pRb migrates in SDS PAGE as a multiple, closely spaced bands with molecular weights between 110 and 114 kDa (Skapek et al, 1997). The pRb can be divided into three domains protease resistant, protease soluble and structural domains comprising of the N terminal, R motif, and A/B pocket (Di Commo et al, 2000). The N Terminal: The N terminal region extends from amino acid 1-379. Although the N terminal is well conserved among Rb orthologs and paralogs, it has been studied far less. However, a significant number of mutations in this region occur in retinoblastomas, strongly implicating it in tumor suppression. Another study by Goodrich et al, 2003, suggested that integrity of the domain is necessary for rescue from both developmental defects as well as tumor susceptibility. The crystal structure of the domain reveals a globular entity formed by two rigidly connected cyclin folds similar to the pocket domains which suggests that Rb evolved through domain duplication. A coherent conformation of the Rb holoprotein has been suggested in which the N terminal domain and the pocket domains interact directly (Hassler et al). The A/B domain: The pocket domain consists of two non consecutive stretches of amino acids, A (amino acids 380-577) and B (amino acids 645-785) (Xiao et al, 2003). It is coded by the exons 12 through 22 of the RB1 gene (Brichard et al, 2006). This region has been shown to interact with many proteins. This domain has been shown to be critical for many interactions of pRb including interaction with a variety of cellular proteins like E2F transcription factor (extensively characterized), tethering of pRb to nuclear structures (Skapek et al., 1997), phosphorylation during the G1 phase of cell cycle. Between the A and B domain is a small stretch of 75 amino acids, the spacer region. A small deletion within the spacer region or replacement of the spacer region with a random sequence has no effect on the function of pRb. However, deletion of entire spacer affects the physical interaction between the two domains. There is another pocket referred to as the C pocket domain in the large A/B domain of the pRb protein. This C pocket lies within the minimal functional domain of RB (Rb amino acids 395 to 876) (Whitaker et al, 1998). The C terminal: The C terminal stretches from amino acid 786 to 928. Of the sixteen sites for phosphorylation by cdks identified, six lie in the C terminal. It has been demonstrated that phosphorylation of S788 and S795 destabilizes the E2F complex interaction directly while phosphorylation of T821 and T826 induces an intramolecular interaction with Rb pocket that destabilizes the remaining interactions indirectly (Rubin et al.). The C terminal also contains a Nuclear Localization Signal (NLS) as well as cyclin binding motif [R/K]XL that are important for Rb phosphorylation (Di Commo et al, 2000). RB AND CELL CYCLE: pRB is a negative regulator of the cell cycle. The cell cycle consists of DNA synthesis (S phase) and mitosis (M phase) separated by two gap intervals, G1 and G2. When they are not cycling, cells are in a quiescent phase, G0, and extra- and intracellular signals are required to re-enter the cell cycle. Serum-starved cells in G0 will enter G1upon growth factor stimulation, and will return to G0 if mitogens are removed prior to a point in late G1. Beyond this restriction point (R) cells traverse through S, G2 and M, and will not stop even if serum is removed. There are two checkpoint controls which ensure proper cell cycle progression. The first one is referred to as the G1S checkpoint that ensures that there are proper environmental conditions for cell division. Importantly, many of the extracellular and intracellular signals that regulate passage through R point converge on the pRB pathway (Di Commo et al.) The second one is called as the G2M checkpoint which ensures that all the req uirements for cell division are fulfilled. Fig: Schematic diagram showing RB phosphorylation pathway. (1) E2F activity repressed in G0 phase imparting cell cycle inhibition. (2) Mitogens trigger a signaling pathway leading to activation of cdk 4/6- cyclin D, cdk 2-cyclin E complexes which in turn phosphorylate RB sequentially rendering it inactive. (3) E2F mediated gene expression allows progression through S phase. (4) During transition to mitosis, the action of mitosis reactivates RB to hypophosphorylated form. The regulation of pRB is by phosphorylation. Hypophosphorylated pRb is in its active form whereas on phosphorylation it loses its activity. The protein contains 16 CDK recognition motifs (S/TP) for phosphorylation, six of which are located in the C-terminus (Rubin et al, 2005). Hypophosphorylated pRB binds target proteins and arrests cells in G1. This block is relieved by a crescendo of CDK-mediated phosphorylation that begins as cells in G1 approach R, and is abruptly reversed at the end of M phase. The major targets for hypophosphorylated pRB are E2F and co repressors such as Histone Deacetylases (HDACs). E2F belongs to a family of transcription factors who have evolutionarily conserved domains including the one for DNA binding and a dimerization domain. E2F is found as a heterodimer with another class of proteins- Differentiation Regulated Transcription Factors (DRTF-b). E2F-pRB co repressor complexes maintain the gene repression (Lees et al, 1993) that is required for progression through R, such as cyclin E. To pass this checkpoint, these repressor complexes are disrupted in two stages by the sequential action of cyclin D and cyclin E activated CDKs. As cells exit G0, cyclin D levels rise, causing activation of CDK4/6 and phosphorylation of multiple C-terminal sites on pRB (Gorges et al, 2008). The C-terminal region of pRB contains a series of (R/K)XL cyclin docking motifs. Ser 795 is the first site to be phosphorylated, and is critical for inactivating growth suppression by pRB. Following D-CDK4/6 phosphorylation, the increase in negative charge promotes an intramolecular interaction between the C-terminus and a series of positively charged lysine residues (the lysine patch) that surround the LXCXE binding groove in the B domain of the pocket. Associated LXCXE proteins, such as HDACs, are also dislodged. However, E2F which does not use LXCXE motif to interact with the pRB does not dislodge. Removing HDACs is thought to relieve active repression of certain target genes such as cyclin E. The genes which are required for DNA replication like gene for thymidine kinase, DNA polymerase and dihydrofolate synthase are also activated as a result of phosphorylation of RB1 and subsequent loss of interaction with E2F protein which now recruits other transcription factors. The cell thus enters the S phase. In the S phase of cell cycle, DNA gets replicated and synthesized. Histone synthesis also occurs during the S phase. Once DNA replication is complete, the cell enters another gap, G2 ÂÂ ­where the cell continues to grow till the cell enters the M phase or mitosis phase. Significant protein synthesis takes place during the G2 phase. Proteins like microtubules involved in mitosis stage are synthesized. At the end of the G2 is the G2/M checkpoint. Once it overcomes the second checkpoint, the cell enters actual cell division- mitosis. RB1 PROTEIN INTERACTIONS IN CELL: Cell cycle control at the G1 S checkpoint and growth suppression as well as differentiation into a particular subset of cell is considered the major function of RB1 protein. Transcription regulation is a control mechanism that is critical for fundamental processes such as cell growth and differentiation. Proteins involved in transcription regulation either bind to DNA sequences or act as co-activators or co-repressors. pRb is one such transcription regulator. In accordance with its role as a tumor suppressor, introduction of Rb into Rb-/- cells diminishes their capacity for malignant transformation which underlines the fact that pRb plays a critical role in DNA replication, cellular senescence, differentiation, and apoptosis, placing pRb at the center of cellular proliferation and tumorigenesis through its interaction with various proteins. At least three distinct protein binding activities have been identified and extensively studied: the large A/B pocket binds E2F (Benevolenskaya et al, 2005), the A/B pocket binds the LXCXE peptide motif, and the C pocket binds the nuclear c-Abl tyrosine kinase (Whitaker et al, 1998). Also, the protein also stabilizes the heterochromatin to maintain the overall chromatin structure. The C pocket is distinct from the A/B pocket domain as pRb can simultaneously bind to c-Abl as well as E2F (Whitaker et al, 1998). The A/B domains are sufficient for E2F subunit binding to Rb. However, the E2F-DP1 heterodimer requires the presence of C terminal. The retinoblastoma protein inhibits E2F mediated transcription via two distinct mechanisms- 1.) pRb binds to E2F transactivation membrane and inhibits E2Fs ability to promote transcriptional activation of E2F dependent genes. 2.) pRb actively represses expression of certain genes by recruiting HDACs and other chromatin remodeling factors (Gorges et al, 2008). The C terminal has also been shown to bind to MDM2. MDM2 interaction with the extreme C terminal region has therefore been shown to contribute towards regulation of apoptosis (Janicke et al., 1996; Sdek et al, 2004). MDM 2 has been known to stimulate E2F transactivation activity and promote S phase entry of cells, independent of p53 (Sdek et al., 2004). The retinoblastoma tumor suppressor protein has been known to bind directly and inhibit a transcriptionally important amino terminal kinase domain of TATA- binding protein associated factor TAFII250 (Siegert et al., 2000). TAF II250 is the largest of approximately 10 TAF subunits of Pol II specific human TFIID. It directly binds to TBP and is believed to be a central scaffold for assembly of TAFs and TBP into a stable TFIID complex (Siegert et al., 2000). The retinoblastoma protein interacts even with transcription factors ATF2. ATF2 enhances the activity of TGF ÃŽÂ ² promoter. The retinoblastoma protein also enhances the stimulatory effects of ATF 2. The site on Rb required for its effect alone and in combination with ATFs has been mapped mainly to A/B products and the C pocket (Li and Wicks, 2001). It has been also reported that the amino terminal of BRCA 1 can efficiently bind to the ABC region (from amino acids 379-928) of the Rb protein. It has been shown that growth suppressor activity of BRCA1 takes place only in presence of a functional Rb protein (Aprelikova et al., 1999). pRb has been known to interact with proto-oncogene c-jun. One of the transcriptional modulator target sites of pRB is the AP-1 binding site within the c-jun and collagenase promoters. c-Jun also physical interacts with pRb where the C terminal site of leucine zipper interacts with pRb (Nishitani et al., 1998). pRb also represses the expression of c-Fos gene the gene product of which , Fos, is one component of the heterodimeric transcription factor, AP-1. Thus, pRb can be functionally linked to c-jun for transcriptional regulation. pRB when recruited to DNA via E2F is a potent transcriptional repressor due to its ability to recruit HDACs (Kennedy et al., 2001) and histone methylases. Again, one pRB binding protein, EID1 is a potent inhibitor of histone acetylases, p300 and CBP and blocks differentiation (Benevolenskaya et al.). HDACs interact directly with pRB by means of a LXCXE motif (Kennedy et al., 2001; Gorges et al., 2008). p53 controls phosphorylation of pRB in a cell indirectly. On DNA damage induces the transcription of its target gene p21WAF1/CIP1. The p21 protein thus formed binds to two different proteins. First, it inhibits the activity of CDKs in cell which in turn keeps pRB in active state. Thus, p53 helps in negative regulationof cell cycle. Second, the p21 protein interacts with the PCNA which then leads to inhibition of cell cycle (Hsieh et al, 1999). Androgen receptors show a unique interaction with pRb at the N terminal. Over expression of pRb leads to increased transcription activity of androgen receptor, AR. pRb also potentiates the activity of glucocorticoid recptors, GR. However, loss of pRb activity inhibits AR but not GR activity (Lu and Danielsen, 1998). MUTATIONS IN RB GENE: After RB1 gene was first cloned by Friend et al in 1986, mutations have been identified in the gene ranging from single base pair deletions, to small length insertions and deletions (Lohmann et al. 1996, Andrade et al. 2006). The mutations do not show any hotspots and they are widely distributed over the 27 exons of RB1 as well as the promoter region (Dalamon et al. 2003). The most common mutation found to result in predisposition to retinoblastoma is the point mutation from C>T. At times the mutation at this point changes the codon from CGA to TGA, from Arginine to stop codon. This premature truncation of protein leads to abrogated expression of pRb in cells. Hypermethylation of RB1 promoter has been also observed as a common epigenetic event in certain tumors (Gonzalez- Gomez et al., 2003). Retinoblastoma Gene Mutation database (RBGMdb) maintains a comprehensive list of all mutations in the RB1 gene. Till now, 932 mutations have been reported in the RBGMdb. Most of the mutations are nonsense mutations (42%). However, if recurrent nonsense mutations are not considered, the percentage comes down to 18%. RB1 mutations are scattered all along the genomic sequence. However, there are a few hotspots which show high recurrence. Most of the recurrences correspond to C>T changes in the sequence. Out of 351 nonsense mutations 271 (79%) are C>T transitions in eleven CGA (arginine) codons, in exon 8, 10, 11, 14, 17, 18, and 23. No mutations have been found in the three other CGA codons in exon 1 and 27. In four of the mutated CGA codons, R251and R255 in exon 8, R451 and R455 of exon 14, a high frequency of constitutive hypermethylation has been demonstrated. In addition to hot spots, frameshift and point mutations leading to translational changes or splice site mutations are scattered along the retinoblastoma coding region and non-coding adjacent splicing sites. With the exception of exons 5, 14, 15, 24, 25 and the non-mutated exons 26 and 27, frameshift mutations are randomly distributed through the RB1 coding sequence. Splicing mutations are also evenly distributed, but show preference for intronic sequences adjacent to exons 6, 12, 16, 17, 19 and 24. It is worth to mention that most missense substitutions (60 %) are located in cyclin box B, underlined by exons 19 to 21.

Critical Debate On Nuclear Family Sociology Essay

Critical Debate On Nuclear Family Sociology Essay There is a great deal of work within many disciplines, such as history, psychology and anthropology, on family studies, available to researchers. This undoubtedly serves to inform our awareness of the interdisciplinary, varied, and at times controversial, nature and lack of stability around the idea of family. Much of this research highlights a number of major perceived problematics: the related characteristic political discourses, social policies and cultural narratives, which differ dramatically from contemporary family relationships and formations of the 21st century. In view of this, this essay critically explores the concept of the nuclear family. It discusses the political contexts and social discourse in which understanding of family has been set. It explores how and why understandings of what make family have changed, paying attention to how it is lived within contemporary society. It reflects on the practices that equate to family. Section 1 Critical debate on nuclear family Many early functionalist sociologists perspectives on the family (Murdock, 1949; Talcott Parsons, 1960) focus heavily on the idea of the nuclear family, which consists of a married couple (male and female) and their biological offspring. There are many issues with the functionalist nuclear family model. For example, it assumes the family to be composed of a heterosexual couple, and that specific structures and practices exist which define this type of family (Widner Jallinoja, 2008). Further to this, the nuclear family model makes assumptions about gender roles within these specific structures (OINONEN, 2008). It is heterosexist (Stacey Davenport, 2002; Pothan, 1992), based on traditional historic ideas of what family should be (Richardson, 2001). For example, the man is the provider and the woman is the nurturer. It promotes hierarchies within the family, with the man situated at the top in relation to the woman, but also as adults in relation to the children (Taylor, 1998). This model can also be seen as western, and assumes a universal model rather than thinking through the historical and cultural specificity of family formations. As a functionalist construct, some researchers (Weeks, Heaphy Donovan, 2001) highlight the heterosexual functions and practices that families have assumed, such as the socialisation of children, where children and young people learn social roles and morals, what is right or wrong: the norms. Donavan (2013) notes this as the heterosexual assumption; similarly, Rich (2007) discusses this in terms of compulsory heterosexuality, assuming this is how gendered roles are transmitted and important for the development of sexualities. The functionalist nuclear family model makes the assumption that specific family formation is not neutral, often with a privileging of heterosexuality (Donavan. 2013). This, however, is a certain form of heterosexuality, as not all heterosexuals are privileged in the same way, for example, if they live outside of the normative ways of living associated with the nuclear family model, such as single or gay parents. Therefore, it could be argued that the nuclear family model is heterosexualised, classed and racialised against these none-normative ways of living (single and gay parents) and their forms of inappropriate heterosexuality. It could be claimed that the functionalist nuclear family model suggests that there is a particular form of living within a heterosexual way that becomes the pinnacle of how we should live, look up to and aspire to do or be. That is not just in terms of how we live with our families, but also the practices within and outside of society: the public and private, for example how we believe authentic love happens. To conclude, many early functionalist sociologists perspectives on the nuclear family (Murdock, 1949; Talcott Parsons, 1960) are now heavily criticised and outdated. However, what we do have are cultural, political and ideological discourses that equate the family to being a specific shape, structure and set of roles. Section 2 Political and social contexts Before discussing and evaluating the new terms and theories within and around family, it is important to reflect on the political contexts and social discourse in which understandings of family and specifically the nuclear family have been set. The late 80s and early 90s were noted as the start of a neo-liberalist society, yet ideologically this era also promoted a particular way of living: a neo-conservative family life. After reading up on some of the literature around government policy and practices from this period, I can see a real contradiction as to whether the state had any involvement in personal / private family lives or not. It tended to step away, detach and disengage in one sense, yet normalise, regulate and control in another. For example, Thatchers views on family and what family was were simple: traditional Victorian family values and the nuclear family. Thatcher and the Conservative government argued that the 60s had started to tear apart this ideal of the family and promote inappropriate promiscuity and sexual freedom. Thatchers also disliked the fact that there were many social movements developing, such as the Hippy Movement, Civil Rights Movement and Peace Movement, and in the late 70s and early 80s, the conservative government felt like their ideal of the family was under attack (Holborn Steel, 2012). Thatcher argued that this was potentially the end of society and the nuclear family and that she will fight hard to regain the traditional family values. It could be claimed that her neo-conservative intentions were to reinforce traditional Victorian family values in society, and re-establish the importance of the traditional heterosexual nuclear family. There was a great deal of legislation created on the basis of Thatcherism, a new hegemonic politics in which the Left was increasingly marginalized. For example, Section 28 (also known as Claus 28) of the local government act 1988 was a controversial amendment to the UKs local government act 1986. Enacted on the 24th May 1998, the amendment stated that local education authorities shall not intentionally promote homosexuality or publish material with the intention of promoting homosexuality or promote the teaching in any maintained school of the acceptability of homosexuality as a pretended family relationship. After Section 28 was passed, there was a lot of debate as to whether it actually applied in schools or whether it applied only to local education authorities. Most teachers acted extra cautious due to not knowing what they were actually permitted to do. Some sociologists (Weeks, 2007) believed that Section 28 enlisted teachers to stigmatise part of our society; and this then caused schools to fail to engage in basic social justices. In relation to these concerns; and a call for further explanation by numerous professionals working in the pedagogic environment, the National Union of Teachers published a statement, remarking that: whilst section 28 applies to local authorities and not to schools, many teachers believe, albeit wrongly, that it imposes constraints in respect of the advice and counselling they give to pupils. Professional judgement is therefore influenced by the perceived prospect of prosecution. Similarly, the Department for Education and Science (1988) made the following statement regarding Section 28: Section 28 does not affect the activities of the school governors, nor the teachers. It will not prevent the objective discussion of homosexuality in the classroom, nor the counselling of pupils concerned about their sexuality Many Conservative backbenchers disagreed with the above statements, and supporters such as Baroness Knight of Collingtree (then Conservative MP Jill Knight) who introduced Section 28, and wanted to back up her initial justification for the act, discussed the history behind initially setting up Section 28. She was the chairman of her local Child and Family Protection Group, and was contacted by numerous concerned parents who strongly objected to the fact that their children were being taught about homosexuality through specific literature that was being used to teach their 5 and 6 year olds. For example, a book called The Playbook for Kids about Sex, in which brightly coloured stick men showed all about homosexuality, and how it was done. Another book called The Milkmans on his Way explicitly described homosexual intercourse. In retrospect, the above statements seem to suggest something of an internal problem: a problem with the literature that was being produced for the pedagogic environments. This was also brought to light in 1983, when the Daily Mail reported that a copy of a book entitled Jenny lives with Eric and Martin, portraying a little girl who lives with her father and his gay partner, was provided in a school library run by a London Education Authority. There was a large political response towards Clause 28; and this served to galvanise the disparate British gay rights movement into action; and the resulting protests saw the rise of now famous groups like Stonewall, started by, amongst other people, Ian McKellen and OutRage!, subsequently led by Peter Tatchell, who is still now an iconic gay activist (Tatchell, 1993; LGF, 2008). Although Section 28 has been repealed on the 18th November 2003 by section (122) of the local government act 2003, there are still a number of complex issues to be tackled with regards to the teaching of homosexuality, gay marriage and contemporary family life. Faith school are a major problem (LGF, 2008), and as Waller (2009) suggests religious views need to be addressed more. More debate is needed on love, respect and diversity within and outside of contemporary family life for faith schools, as this would then avoid the so called promotion of homosexuality and pretend family relationships, and focus more on the diversity of sexuality and family life. Gay rights activists, such as Tatchel (2001), discuss their concern for the lack of progress within this area, and mentioned that there is going to be more of a battle to beat the last acceptable prejudice within our education system (LGF, 2008). In contrast, Waller (2009) suggested that as sex education in England and Wales has been regulated solely by the Secretary of State for Education since the Learning and Skills Act (2000) and the Education Act (1996), it could be argued that Section 28, before its repeal, was already largely redundant. Local education authorities, such as Manchester, continued to deliver training to their staff on how to deliver their services without discrimination against lesbians and gay men; and these pioneering works were never once challenged by the act (Waller, 2009). There is, however, one case of Section 28 being used to bring a case to the courts against a council. In May, 2000, the Christian Institute unsuccessfully took Glasgow City Council to court for funding an AIDS support charity which the Institute alleged promoted homosexuality and disrespectful family relationships. It could be suggested that in order to create change, we must consider the psychology (Hanley, 1993): mapping the information against the general certificate of secondary education (GCSE) curriculum, and making it accessible to the children. Training the teachers so that they are confident in delivering it correctly, as at present, many teachers are not equipped to discuss the complexities of the human sexuality and contemporary family life. Cookson et al, (2009) suggests that this personal and professional development should be a priority for any local education authority. Schools should be encouraged to expressively forbid discrimination on the grounds of sexual orientation within their codes of conduct, whether the school has a religious character or not (Cookson et al, 2009). Then, at an appropriate stage of the national curriculum, students should be encouraged to examine the variety of views on human sexuality and family life, and as Waller (2009) suggests, this will then allow them to develop their own position within their understanding of and within these complex areas. However, despite the controversy around Section 28, it should be noted that Thatcher supported legalising homosexuality in the 1960s, and in the face of severe opposition from Tory traditionalists, in 1967, she voted in favour of the decriminalisation of homosexuality in England and Wales. The Conservative government still however caused much uproar, as although the hegemonic legislation was in force, to ostracise; to an extent it did the opposite. It made people fight. Fight for their right to have equality, to be a family, or at least have that choice. Although many gay communities had been decimated by the AIDS epidemic, something extraordinary happened. People joined together, from within and outside of their communities, as a family, setting up support groups, lobbying parliament, fighting for their right as a community, and as a family. Not blood-related though, but as families of choice (Donavan, 2012; Weeks, 2001). They had connectedness, cared for each other, and were loyal: and not the drug-taking, promiscuous loons as described by one Tory MP at the time (Briggs, 1987). Over the following years, many of the HIV positive men died, and during this period further inequalities became stark. Partners, who had supported, cared for and loved their partner for many years were not recognised legally, for example, during the sale of a house. Blood family members of the deceased or dying would deny same sex partners access to their dying partners bedside or attendance at the funeral. These harsh inequalities highlighted through these challenging times, but also politicised a generation (Donavan, 2013). Weeks (2007: 2) support this notion of politicisation, and suggests that the longer term perspective tells us something different as despite the setbacks, pain and loss of the 1980s and early 1990s we can now see that under the surface of events, dramatic changes in sexual and intimate life were taking place, a sort of grass roots revolution, that have transformed the possibilities of LGBTQ lives In view of Weeks (2007) quote, it should therefore be argued that the battle for legislative reform is about a formalisation of a right to exist in the public sphere, and a public declaration of, for example, love, marriage, equal opportunities and family. Weeks (2007) supports this critique and proposes that this shake up also started to deconstruct the idea of a family unit, and so destabilise specific social norms and boundaries, which existed between the public and the private. This political and social shift is important, as when public and private start to collide, the old school family unit that is ideologically engrained within society and culture is challenged (Richardson, 2000). This is a powerful, and much needed shake up, which has had considerable consequences further down the line, and has attacked many discriminative social forces and factors underpinned within many forms of discrimination. It is also important to acknowledge the processes and changes underpinned within the wider political, economic and cultural realities, and how these may have been challenged. In de constructing the idea of the family, we can then start to challenge the tradition behind it, which takes away its power, its right to dominance, govern and lead. This idea of tradition is still however problematic, as Weeks (2007) notes, due to the fact that the evidence is limited when looking at tradition beyond specific recent time frames and histories, and that due to this lack of empiricability, can we be certain people always follow tradition, and by tradition I mean as how we see it. It could be argued that this was not the case, and tradition, as we see it, has shifted over time, context and reality. What we see now as tradition may have at specific points in history been its opposite, with the normal of our tradition shifting to the abnormal of our non-traditional realities. Therefore, it could be argued that tradition and its underpinnings are by no means monochrome, in any historical, political and / or cultural reality. Williams (2004) conceptualises this well and terms this re-traditionalisation, yet Weeks (2007) still argues for more of a de-traditionalisation. Whatever the term used, it could be argued that either or suggest that back in the 80s during the birth of Stonewall and other political and social equality movements, and also now, as we were (and still are) searching for an individualism, or a framework that supports this. It could be maintained that if people were allowed to manage their own lives, their own way of living, without fear or discrimination, different forms of community and / or individual arrangements would develop, assisting life in its creative, problem-solving, innovatory way. This process of social restructuring (or as Williams (2004) terms re-traditionalisation and Weeks (2007) terms de-tradionalisation) is important to consider with my research when thinking about my research, and the participants (also my own) political, cultural and social histories and contexts, and how these have been changed, adapted and developed within and outside of tradition as we see it now in this specific context and reality, during their specific coming-out process. Section 3 Why / how family has changed and how it is now lived + reflections on family practices. These previously discussed political and social developments highlight the fact that ways of living have changed, causing major variations in the compositions and practices of families and intimate relationships. At the core of the debate sociologists such as Finch (2007), Smart (2007), Donavan (2013) and Stacey (2004) emphasise that the old concepts no longer capture the realities of contemporary family living and that new definitions, concepts, ideas, ideologies, terms and legislation are needed. Smart (2007: 84), a feminist sociologist and academic, defines the family as: a set of personal relationships that are forged together to create dynamic and multidimensional connections held together through shared histories and memories. Smarts (2007) quote suggests that individuals live in a diverse array of living conditions and relationship formations, within and throughout a major social institution and a locus of much of an individuals social activity. It also highlights the importance of shared histories and memories, not just blood ties or relations. Smarts (2007) definition recognises that this new conceptualisation of family highlights the significance of dependencies, interdependencies, connectedness and relationalism as central features within social grouping identified as family. All the above suggests there are many factors that shape the experience of family life, for example, social class, race, sexuality (lesbian or heterosexual couples) and family structure, for example, nuclear family, extended family and single-parent families. This adds a new dimension to the study of family as it links family experiences to other influences in society, signifying that the family is not an isolated entity but rather an integral part of the wider social system with society. Calvin (2011), on the other hand, disagrees with much of Smart (2007) observations and defines the family as: a social unit created by blood, marriage, or adoption, which can be described as nuclear (parents and children) or extended (encompassing other relatives). There remains many obvious problematics within the Calvin (2011) definition. For example, extended family may not be relatives, but could be friends, neighbours, work colleagues, and / or ex or current partners. The nuclear family concept has also been critiqued by many (Finch, 2007, Smart, 2007 and Donavan, 2013) (also see section 1) and holds many perceived problematics: westernised, heterosexist, gendered, and assuming a universal model which alludes to the historical and cultural specificity of contemporary family formations. It could be argued that in contemporary society, many individuals now live in households that are single-parent, gay, lesbian, interfaith, international, interracial, intergenerational, and increasingly single-person, not to mention families of long-term companions, adopted children, or half-siblings. Calvins (2011) definition does not seem to take this specificity and multidimensionality into consideration. Fields, Jason and Casper (2001:67) support my critique of Calvins (2011) definition, and suggest that it is generally assumed today that the modern family has undergone significant transformations in its structure, and that societal changes have contributed to a harsh reduction in the percentage of classical typical families, predominantly nuclear families. Replacing these are childless families, one parent families, other family formations, and quasi-family units based on non-marital cohabitation (Fields, Jason and Casper, 2001:69), which includes (and will include more so after the recent legalisation of gay marriage in the UK) gay parents and families. Sociologists such as Finch (2007) and Smart (2007) have clearly highlighted the many diverse arrays of living as a family, and how this must be recognised within the literature. However, there are also many terms that underpin these theories, for example, families of choice (Weeks, Donavan, and Heaphy), postmodern families, and families of origin (Morgan (2007). There has been much debate as to whether these sit alongside the idea of the nuclear family or in opposition. There has also been much debate around a shifting postmodern nuclear family. This section of this essay will therefore discuss and evaluate some of these terms, critiquing the literature. Donavan et al (2001) incorporated the term families of choice (also known as families we choose coined by Kath Western, 1998) which means literally asking the participants for names of people they see as family. For example, if I decided to use this term within my research and one of my participants stated that 2 of his friends, his step brother and his second aunt were the people he recognised as family this would be fine. Similarly, if another participant involved no blood relatives this would also be fine. Families of choice literally mean people choose their families. Donavan (2001) does however express some concerns with this method and notes that within her 2001 study with Weeks and Heaply, two well-known social constructionists, as many of the heterosexual participants named blood family when ask to discuss family; whereas many of the non-heterosexual participants named mainly friends and (ex) lovers as family. Although this does not suggest an obvious issue, it does suggest a lack of closeness, or connectness with the LGBT participants and their blood family compared to that of their heterosexual counterparts. Although this term sits well for my research, the same issue could occur. A way around this could be to break the question down further. For example, ask the participants to name 5 people who they feel are most important to them in their life. And once a list has been put together, ask them to decide who they see as family. This 2 staged question may be a way of getting around this issue around participants misunderstanding the term family. Not including the term family would be helpful until I understood who they classed as family. On the other hand, by using the term families of choice, I am giving the participants a choice to choose whoever as their family members, and this open-ended approach is enabling them to decide. Therefore, would it really be an issue if they did not include any blood relatives, or included all blood relative? Modern policy (Children and Adoption Act, 2006; Equal Marriage Bill, 2013; Human Fertilisation and Embryology Act, 2008) has noted a shift to two parents of any gender (but still a demonization of single parent families due to an underlying stigmatization mainly but not exclusively enhanced by stereotypical negative Media perceptions). The question is could we call the 2 parent family of the same gender a nuclear family and would we want too? Donavan (2013) suggests it is not, although structurally it looks the same, i.e. two parents, 2 children, a household, but if you look at the social roles within it, it is very different. For example, there may be no men or no women involved, and usually there is at least one parent who has no biological relation to the child. It could therefore be argued that the term postmodern family sits better here (and also potentially within my research). This term suggests it can be what it is, in this specific moment in time, through the specific structures and practices it has/uses. This concept also recognises that what you describe as your family now may not be family in 5 years time for example. Although it could be argued that the term postmodern family is doing nothing apart from saying meaning of family can change historically. On the other hand, terms that help to destabilise gendered and heterosexist terms like that nuclear family model are a welcome addition. There are many different ways of theorizing family and the practices within it, but in reality, when it comes to gay youth and my intended area of study, many of these individuals will come from heterosexual family set ups and have been exposed unconditionally to heterosexual family practices. Therefore, using the a term like families of origin (Morgan, 2007) could be beneficial as it describes the setup of your life at that point in time, whether it be step families, friends, blood mother or adopted father. This again gives the participant flexibility in their choices. The term origin however may be confusing as origin suggests where you have come from, which then suggests blood or adopted family, with the exclusion of friends, (ex) partners, and work colleagues. It could also be beneficial to ask my participants about their understanding of families i.e. where they see their families being, or who is classed as their family, as during Weeks, Heaply and Donavans (2001) study, many of their LGBT participants failed to recognise blood family as family members. This would suggest that they may have disconnected from their families of origin and that it did not occur to them to speak or include them into their LGBT sphere, or private world. However, this study is now 12 years old, and many changes have occurred since then, potentially highlighting a shift in generational understandings and acceptance of how, who and why we consider certain people to be classed as our family. In view of the above, Finch (2007: 71) notes that the way in which we consider our family is qualitatively orientated. By this she means decided by a number of internal and external factors including, location, relationships, love, employment, religion, sexuality and friendship. In view of Finchs (2007) consideration, it could be argued that this process of qualitative orientation demands considerable creativity when initiating the design, composition and practices of the family, and how these intimate networks are constructed, perceived and maintained (Stacey, 2004: 359). It could also be argued that as Stacey (2004) has identified this as a process, this then suggests a considerable shift from the previous definition of family and the nuclear family, through the household or through kinship: set and defined, to a more holistic way of thinking, friendly and accepting to the diversity and variation of modern family formations. Gabb (2008: 22), who is an interdisciplinary sociologist, terms this the extended family. Her research consists of a combination of autobiographical, anecdotal and empirical methods and methodologies, which re-situate emotions at the centre of family studies. She suggests that the process of family selection mentioned by Stacy (2004) requires an extended approach; a wide angle research lens that can record the evolving matrix of intimacy (Gabb, 2008:17). I agree with Gabbs (2008) comments on the matrix or intimacy and argue that this idea places much emphasis on relationship formation, which in turn constitutes and creates family life. Contemporary psycho-sociologists Mcload and Thomson (2009) support this critique, and suggest that Gabbs (2008) idea of the extended family places increasing importance on the way in which relationships are built, with ideas of social change at the forefront of this process. The contemporary research above highlights the importance of recognises fluidity within the composition of the family unit and also highlights briefly how we select family; however, it is also important to discuss how contemporary family life is defined more by doing family things rather than being a family. For example, Morgan (1996) is one of the most influential sociologist who initially highlighted the importance to shift sociological analysis away from family as a structure to which individuals in some sense belong, towards understanding families as sets of activities which take on a particular meaning, associated with family, at any a given point in time (Finch, 2007:66). Morgan (1996) defines these family practices as: a set of practices which deal in some way with ideas of parenting, kinship and marriage and the expectedness and obligation which are associated with these practices. The key features of the practices approach in general are as follows: à ¢Ã¢â€š ¬Ã‚ ¢ An attempt to link the perspectives of the observers and the social actors; à ¢Ã¢â€š ¬Ã‚ ¢ An emphasis on the active or doing; à ¢Ã¢â€š ¬Ã‚ ¢ A sense of the everyday; à ¢Ã¢â€š ¬Ã‚ ¢ A sense of the regular; à ¢Ã¢â€š ¬Ã‚ ¢ A sense of fluidity or fuzziness; à ¢Ã¢â€š ¬Ã‚ ¢ A linking of history and biography. Morgan (2011) uses the term family practices as an illustration of wider currents of thought in sociology engaged with understanding how social relations are enacted and represented as symbols, combining a number of key concepts that other scholars have used to analyse contemporary families. These include fluidity, diversity, and multi-facetedness, by rooting our understanding of doing family in the everyday and the routine. These everyday routines are where individuals constitute certain actions and activities as family practices, as family (defined by Morgan and Finch) is a facet of social life, not a social institution; it represents a quality not a thing. A good example of this routine that constitutes family practices was in Finch (2007) where she discusses 2 examples of her own family practices: the weekly phone call which she makes to her sister; and her care in assuring that a step child gets Christmas presents as valuable as those she gives to her own children. These are actions that allow her to regard these people as part of her family. Finch (2007:55) also quotes from my perspective these are family practices. When discussing these practices, Morgan (1996: 190) recognises that these practices are often little fragments of daily life which are part of the normal taken for granted existence of practitioners. Their significance derives from their location in a wider system of meaning. Finch (2007:66) supports Morgan (1996) quote and suggest that the emphasis is on social actors creatively constituting their own social world. It could therefore be argued that an individuals understanding of family is subject to change over time and locations, deeply rooted in individual biographies and realities. This is something I need to