Customer Value Propositions in Business Markets

Customer Value Propositions in Business Markets by JAMES C. ANDERSON, JAMES A. NARUS, AND WOUTER VAN ROSSUM Under pressure to keep costs down, customers may only look at price and not listen to your sales pitch. Help them understand – and believe in – the superior value of your offerings. â€Å"CUSTOMER VALUE PROPOSITION† has become one of the most widely used terms in business markets in recent years. Yet our management-practice research reveals that there is no agreement as to what constitutes a customer value proposition – or what makes one persuasive. Moreover, we ? d that most value propositions make claims of savings and bene? ts to the customer without backing them up. An offering may actually provide superior value – but if the supplier doesn’t demonstrate and document that claim, a customer manager will likely dismiss it as marketing puffery. Customer managers, increasingly held accountable for reducing costs, don’t have the l uxury of simply believing suppliers’ assertions. PETER HOEY march 2006 91 C u s t o m e r Va l u e P ro p o s i t i o n s i n B u s i n e s s M a r ke t s Take the case of a company that makes integrated circuits (ICs).It hoped to supply 5 million units to an electronic device manufacturer for its next-generation product. In the course of negotiations, the supplier’s salesperson learned that he was competing against a company whose price was 10 cents lower per unit. The customer asked each salesperson why his company’s offering was superior. This salesperson based his value proposition on the service that he, personally, would provide. Unbeknownst to the salesperson, the customer had built a customer value model, which found that the company’s offering, though 10 cents higher in price per IC, was actually worth 15. cents more. The electronics engineer who was leading the development project had recommended that the purchasing manager buy those ICs, even a t the higher price. The service was, indeed, worth something in the model–but just 0. 2 cents! Unfortunately, the salesperson had overlooked the two elements of his company’s IC offering that were most valuable to the customer, evidently unaware how much they were worth to that customer and, objectively, how superior they made his company’s offering to that of the competitor. Not surprisingly,We conducted management-practice research over the past two years in Europe and the United States to understand what constitutes a customer value proposition and what makes one persuasive to customers. One striking discovery is that it is exceptionally dif? cult to ? nd examples of value propositions that resonate with customers. Here, drawing on the best practices of a handful of suppliers in business markets, we present a systematic approach for developing value propositions that are meaningful to target customers and that focus suppliers’ efforts on creating super ior value.Three Kinds of Value Propositions We have classi? ed the ways that suppliers use the term â€Å"value proposition†into three types: all bene? ts, favorable points of difference, and resonating focus. (See the exhibit â€Å"Which Alternative Conveys Value to Customers? †) All bene? ts. Our research indicates that most managers, when asked to construct a customer value proposition, simply list all the bene? ts they believe that their Customer managers, increasingly held accountable for reducing costs, don’t have the luxury of simply believing suppliers’ assertions. hen push came to shove, perhaps suspecting that his service was not worth the difference in price, the salesperson offered a 10-cent price concession to win the business – consequently leaving at least a half million dollars on the table. Some managers view the customer value proposition as a form of spin their marketing departments develop for advertising and promotional copy. T his shortsighted view neglects the very real contribution of value propositions to superior business performance. Properly constructed, they force companies to rigorously focus on what their offerings are really worth to their customers.Once companies become disciplined about understanding customers, they can make smarter choices about where to allocate scarce company resources in developing new offerings. offering might deliver to target customers. The more they can think of, the better. This approach requires the least knowledge about customers and competitors and, thus, the least amount of work to construct. However, its relative simplicity has a major potential drawback: bene? t assertion. Managers may claim advantages for features that actually provide no bene? to target customers. Such was the case with a company that sold highperformance gas chromatographs to R&D laboratories in large companies, universities, and government agencies in the Benelux countries. One feature of a particular chromatograph allowed R&D lab customers to maintain a high degree of sample integrity. Seeking growth, the company began to market the most basic model of this chromatograph to a new segment: commercial laboratories. In initial meetings with prospective customers, the ? rm’s James C. Anderson is the William L.Ford Distinguished Professor of Marketing and Wholesale Distribution at Northwestern’s Kellogg School of Management in Evanston, Illinois; the Irwin Gross Distinguished ISBM Research Fellow at the Institute for the Study of Business Markets in University Park, Pennsylvania; and a visiting research professor at the School of Business, Public Administration, and Technology at the University of Twente, the Netherlands. James A. Narus is a professor of business marketing at the Babcock Graduate School of Management at Wake Forest University in Charlotte, North Carolina.Wouter van Rossum is a professor of commercial and strategic management at the School of Business, Public Administration, and Technology at the University of Twente. 92 harvard business review C u s t o m e r Va l u e P ro p o s i t i o n s i n B u s i n e s s M a r ke t s Which Alternative Conveys Value to Customers? Suppliers use the term â€Å"value proposition† three different ways. Most managers simply list all the bene? ts they believe that their offering might deliver to target customers. The more they can think of, the better.Some managers do recognize that the customer has an alternative, but they often make the mistake of assuming that favorable points of difference must be valuable for the customer. Best-practice suppliers base their value proposition on the few elements that matter most to target customers, demonstrate the value of this superior performance, and communicate it in a way that conveys a sophisticated understanding of the customer’s business priorities. VALUE PROPOSITION: ALL BENEFITS FAVORABLE POINTS OF DIFFERENCE All favorable po ints of difference a market offering has relative to the next best alternativeRESONATING FOCUS Consists of: All bene? ts customers receive from a market offering The one or two points of difference (and, perhaps, a point of parity) whose improvement will deliver the greatest value to the customer for the foreseeable future Answers the customer question: â€Å"Why should our ? rm purchase your offering? † â€Å"Why should our ? rm purchase your offering instead of your competitor’s? † â€Å"What is most worthwhile for our ? rm to keep in mind about your offering? † Requires: Knowledge of own market offering Knowledge of own market offering and next best alternativeKnowledge of how own market offering delivers superior value to customers, compared with next best alternative Has the potential pitfall: Bene? t assertion Value presumption Requires customer value research salespeople touted the bene? ts of maintaining sample integrity. Their prospects scoffed a t this bene? t assertion, stating that they routinely tested soil and water samples, for which maintaining sample integrity was not a concern. The supplier was taken aback and forced to rethink its value proposition. Another pitfall of the all bene? ts value proposition is that many, even most, of the bene? s may be points of parity with those of the next best alternative, diluting the effect of the few genuine points of difference. Managers need to clearly identify in their customer value propositions which elements are points of parity and which are points of difference. (See the exhibit â€Å"The Building Blocks of a Successful Customer Value Proposition. †) For example, an international engineering consultancy was march 2006 bidding for a light-rail project. The last chart of the company’s presentation listed ten reasons why the municipality should award the roject to the ? rm. But the chart had little persuasive power because the other two ? nalists could make mos t of the same claims. Put yourself, for a moment, in the place of the prospective client. Suppose each ? rm, at the end of its presentation, gives ten reasons why you ought to award it the project, and the lists from all the ? rms are almost the same. If each ? rm is saying essentially the same thing, how do you make a choice? You ask each of the ? rms to give a ? nal, best price, and then you award the project to the ? rm that gives the largest price concession.Any distinctions that do exist have been overshadowed by the ? rms’ greater sameness. 93 C u s t o m e r Va l u e P ro p o s i t i o n s i n B u s i n e s s M a r ke t s Favorable points of difference. The second type of value proposition explicitly recognizes that the customer has an alternative. The recent experience of a leading industrial gas supplier illustrates this perspective. A customer sent the company a request for proposal stating that the two or three suppliers that could demonstrate the most persuasive v alue propositions would be invited to visit the customer to discuss and re? e their proposals. After this meeting, the customer would select a sole supplier for this business. As this example shows, â€Å"Why should our ? rm purchase your offering instead of your competitor’s? † is a more pertinent question than â€Å"Why should our ? rm purchase your offering? † The ? rst question focuses suppliers on differentiating their offerings from the next best alternative, a process that requires detailed knowledge of that alternative, whether it be buying a competitor’s offering or solving the customer’s problem in a different way.Knowing that an element of an offering is a point of difference relative to the next best alternative does not, however, convey the value of this difference to target customers. Furthermore, a product or service may have several points of difference, complicating the supplier’s understanding of which ones deliver the grea test value. Without a detailed understanding of the customer’s requirements and preferences, and what it is worth to ful? ll them, suppliers may stress points of difference that deliver relatively little value to the target customer. Each of these can lead to the pitfall of value presumption: assuming that favorable points f difference must be valuable for the customer. Our opening anecdote about the IC supplier that unnecessarily discounted its price exempli? es this pitfall. Resonating focus. Although the favorable points of difference value proposition is preferable to an all bene? ts proposition for companies crafting a consumer value proposition, the resonating focus value proposition should be the gold standard. This approach acknowledges that the managers who make purchase decisions have major, ever-increasing levels of responsibility and often are pressed for time.They want to do business with suppliers that fully grasp critical issues in their business and deliver a customer value proposition that’s simple yet powerfully captivating. Suppliers can provide such a customer value proposition by making their offerings superior on the few elements that matter most to target customers, demonstrating and documenting the value of this superior performance, and communicating it in a way that conveys a sophisticated understanding of the customer’s business priorities. This type of proposition differs from favorable points of difference in two signi? cant respects.First, more is not better. Although a supplier’s offering may possess several favorable points of difference, the resonating focus proposition steadfastly concentrates on the one or two points 94 of difference that deliver, and whose improvement will continue to deliver, the greatest value to target customers. To better leverage limited resources, a supplier might even cede to the next best alternative the favorable points of difference that customers value least, so that th e supplier can concentrate its resources on improving the one or two points of difference customers value most.Second, the resonating focus proposition may contain a point of parity. This occurs either when the point of parity is required for target customers even to consider the supplier’s offering or when a supplier wants to counter customers’ mistaken perceptions that a particular value element is a point of difference in favor of a competitor’s offering. This latter case arises when customers believe that the competitor’s offering is superior but the supplier believes its offerings are comparable–customer value research provides empirical support for the supplier’s assertion.To give practical meaning to resonating focus, consider the following example. Sonoco, a global packaging supplier headquartered in Hartsville, South Carolina, approached a large European customer, a maker of consumer packaged goods, about redesigning the packaging T he Building Blocks of a Successful Customer Value Proposition A supplier’s offering may have many technical, economic, service, or social bene? ts that deliver value to customers – but in all probability, so do competitors’ offerings. Thus, the essential question is, â€Å"How do these value elements compare with those of the next best alternative? We’ve found that it’s useful to sort value elements into three types. Points of parity are elements with essentially the same performance or functionality as those of the next best alternative. Points of difference are elements that make the supplier’s offering either superior or inferior to the next best alternative. Points of contention are elements about which the supplier and its customers disagree regarding how their performance or functionality compares with those of the next best alternative.Either the supplier regards a value element as a point of difference in its favor, while the custom er regards that element as a point of parity with the next best alternative, or the supplier regards a value element as a point of parity, while the customer regards it as a point of difference in favor of the next best alternative. harvard business review C u s t o m e r Va l u e P ro p o s i t i o n s i n B u s i n e s s M a r ke t s for one of its product lines. Sonoco believed that the customer would pro? from updated packaging, and, by proposing the initiative itself, Sonoco reinforced its reputation as an innovator. Although the redesigned packaging provided six favorable points of difference relative to the next best alternative, Sonoco chose to emphasize one point of parity and two points of difference in what it called its distinctive value proposition (DVP). The value proposition was that the redesigned packaging would deliver signi? cantly greater manufacturing ef? ciency in the customer’s ? l lines, through higher-speed closing, and provide a distinctive look that consumers would ? nd more appealing – all for the same price as the present packaging. Sonoco chose to include a point of parity in its value proposition because, in this case, the customer would not even consider a packaging redesign if the price went up. The ? rst point of difference in the value proposition (increased ef? ciency) delivered cost savings to the customer, allowing it to move from a seven-day, three-shift production schedule during peak times to a ? e-day, two-shift operation. The second point of difference delivered an advantage at the consumer level, helping the customer to grow its revenues and pro? ts incrementally. In persuading the customer to change to the redesigned packaging, Sonoco did not neglect to mention the other favorable points of difference. Rather, it chose to place much greater emphasis on the two points of difference and the one point of parity that mattered most to the customer, thereby delivering a value proposition with resonating focu s.Stressing as a point of parity what customers may mistakenly presume to be a point of difference favoring a competitor’s offering can be one of the most important parts of constructing an effective value proposition. Take the case of Intergraph, an Alabama-based provider of engineering software to engineering, procurement, and construction ? rms. One software product that Intergraph offers, SmartPlant P&ID, enables customers to de? ne ? ow processes for valves, pumps, and piping within plants they are designing and generate piping and instrumentation diagrams (P&ID).Some prospective customers wrongly presume that SmartPlant’s drafting performance would not be as good as that of the next best alternative, because the alternative is built on computer-aided design (CAD), a better-known drafting tool than the relational database platform on which SmartPlant is built. So Intergraph tackled the perception head on, gathering data from reference customers to substantiate tha t this point of contention was actually a point of parity. march 2006 Here’s how the company played it.Intergraph’s resonating focus value proposition for this software consisted of one point of parity (which the customer initially thought was a point of contention), followed by three points of difference: Point of parity: Using this software, customers can create P&ID graphics (either drawings or reports) as fast, if not faster, as they can using CAD, the next best alternative. Point of difference: This software checks all of the customer’s upstream and downstream data related to plant assets and procedures, using universally accepted engineering practices, company-speci? c rules, and project- or process-speci? rules at each stage of the design process, so that the customer avoids costly mistakes such as missing design change interdependencies or, worse, ordering the wrong equipment. Point of difference: This software is integrated with upstream and downstream tasks, such as process simulation and instrumentation design, thus requiring no reentry of data (and reducing the margin for error). Point of difference: With this software, the customer is able to link remote of? ces to execute the project and then merge the pieces into a single deliverable database to hand to its customer, the facility owner.Resonating focus value propositions are very effective, but they’re not easy to craft: Suppliers must undertake 95 C u s t o m e r Va l u e P ro p o s i t i o n s i n B u s i n e s s M a r ke t s customer value research to gain the insights to construct them. Despite all of the talk about customer value, few suppliers have actually done customer value research, which requires time, effort, persistence, and some creativity. But as the best practices we studied highlight, thinking through a resonating focus value proposition disciplines a company to research its customers’ businesses enough to help solve their problems.As the exper ience of a leading resins supplier amply illustrates, doing customer value research pays off. (See the sidebar â€Å"Case in Point: Transforming a Weak Value Proposition. †) savings from reduced power usage that a customer would gain by using a Rockwell Automation motor solution instead of a competitor’s comparable offering: Power Reduction = [kW spent number of operating hours per Cost Savings year $ per kW hour number of years system solution in operation] Competitor Solution ? [kW spent number of operating hours per year $ per kW hour number of years system solution in operation] Rockwell Automation SolutionSubstantiate Customer Value Propositions In a series of business roundtable discussions we conducted in Europe and the United States, customer managers reported that â€Å"We can save you money! † has become almost a generic value proposition from prospective suppliers. But, as one participant in Rotterdam wryly observed, most of the suppliers were telling â€Å"fairy tales. † After he heard a pitch from a prospective supplier, he would follow up with a series of questions to determine whether the supplier had the people, processes, tools, and experience to actually save his ? m money. As often as not, they could not really back up the claims. Simply put, to make customer value propositions persuasive, suppliers must be able to demonstrate and document them. Value word equations enable a supplier to show points of difference and points of contention relative to the next best alternative, so that customer managers can easily grasp them and ? nd them persuasive. A value word This value word equation uses industry-speci? c terminology that suppliers and customers in business markets rely on to communicate precisely and ef? iently about functionality and performance. Demonstrate Customer Value in Advance Prospective customers must see convincingly the cost savings or added value they can expect from using the supplier’s off ering instead of the next best alternative. Best-practice suppliers, such as Rockwell Automation and precision-engineering and manufacturing ? rm Nijdra Groep in the Netherlands, use value case histories to demonstrate this. Value case histories document the cost savings or added value that reference customers have actually received from their use of the supplier’s market offering.Another way that best-practice ? rms, such as Pennsylvania-based GE Infrastructure Water & Process Technologies (GEIW&PT) and SKF USA, show the value of their offerings to prospective customers in advance is Some best-practice suppliers are even willing to guarantee a certain amount of savings before a customer signs on. equation expresses in words and simple mathematical operators (for example, + and ? ) how to assess the differences in functionality or performance between a supplier’s offering and the next best alternative and how to convert those differences into dollars.Best-practice ? rm s like Intergraph and, in Milwaukee, Rockwell Automation use value word equations to make it clear to customers how their offerings will lower costs or add value relative to the next best alternatives. The data needed to provide the value estimates are most often collected from the customer’s business operations by supplier and customer managers working together, but, at times, data may come from outside sources, such as industry association studies.Consider a value word equation that Rockwell Automation used to calculate the cost 96 through value calculators. These customer value assessment tools typically are spreadsheet software applications that salespeople or value specialists use on laptops as part of a consultative selling approach to demonstrate the value that customers likely would receive from the suppliers’ offerings. When necessary, best-practice suppliers go to extraordinary lengths to demonstrate the value of their offerings relative to the next best alte rnatives.The polymer chemicals unit of Akzo Nobel in Chicago recently conducted an on-site two-week pilot on a production reactor at a prospective customer’s facility to gather data ? rsthand on the performance of its high-purity metal organics offering relative to the next best alternative in producing compound semiconductor wafers. Akzo Nobel paid this harvard business review C u s t o m e r Va l u e P ro p o s i t i o n s i n B u s i n e s s M a r ke t s prospective customer for these two weeks, in which each day was a trial because of daily considerations such as output and maintenance.Akzo Nobel now has data from an actual production machine to substantiate assertions about its product and anticipated cost savings, and evidence that the compound semiconductor wafers produced are as good as or better than those the customer currently grows using the next best alternative. To let its prospective clients’ customers verify this for themselves, Akzo Nobel brought them sample wafers it had produced for testing. Akzo Nobel combines this point of parity with two points of difference: signi? cantly lower energy costs for conversion and signi? antly lower maintenance costs. Document Customer Value Demonstrating superior value is necessary, but this is no longer enough for a ? rm to be considered a best-practice company. Suppliers also must document the cost savings and incremental pro? ts (from additional revenue gener- ated) their offerings deliver to the companies that have purchased them. Thus, suppliers work with their customers to de? ne how cost savings or incremental pro? ts will be tracked and then, after a suitable period of time, work with customer managers to document the results.They use value documenters to further re? ne their customer value models, create value case histories, enable customer managers to get credit for the cost savings and incremental pro? ts produced, and (because customer managers know that the supplier is willing to return later to document the value received) enhance the credibility of the offering’s value. A pioneer in substantiating value propositions over the past decade, GEIW&PT documents the results provided to customers through its value generation planning (VGP) process and tools, which enable its ? ld personnel to understand customers’ businesses and to plan, execute, and document projects that have the highest value impact for its customers. An online tracking tool allows GEIW&PT and customer managers to easily monitor the Case in Point: Transforming a Weak Value Proposition A leading supplier of specialty resins used in architectural coatings – such as paint for buildings – recognized that its customers were coming under pressure to comply with increasingly strict environmental regulations. At the same time, the supplier reasoned, no coating manufacturer would want to sacri? e performance. So the resins supplier developed a new type of highperformance resi ns that would enable its customers to comply with stricter environmental standards – albeit at a higher price but with no reduction in performance. In its initial discussions with customers who were using the product on a trial basis, the resins supplier was surprised by the tepid reaction it received, particularly from commercial managers. They were not enthusiastic about the sales prospects for higher-priced coatings with commercial painting contractors, the primary target market.They would not, they said, move to the new resin until regulation mandated it. Taken aback, the resins supplier decided to conduct customer value research to better understand the requirements and preferences of its customers’ customers and how the performance of the new resin would affect their total cost of doing business. The resins supplier went so far as to study the requirements and preferences of the commercial painting contractors’ customers – building owners. The suppl ier conducted a series of focus groups and ? eld tests with painting contractors to gather data.The performance on primary customer requirements – such as coverage, dry time, and durability – was studied, and customers were asked to make performance trade-offs and indicate their willingness to pay for coatings that delivered enhanced performance. The resins supplier also joined a commercial painting contractor industry association, enrolled managers in courses on how contractors are taught to estimate jobs, and trained the staff to work with the job-estimation software used by painting contractors. Several insights emerged from this customer value research.Most notable was the realization that only 15% of a painting contractor’s costs are the coatings; labor is by far the largest cost component. If a coating could provide greater productivity – for example, a faster drying time that allowed two coats to be applied during a single eight-hour shift – contractors would likely accept a higher price. The resins supplier retooled its value proposition from a single dimension, environmental regulation compliance, to a resonating focus value proposition where environmental compliance played a signi? cant but minor part.The new value proposition was â€Å"The new resin enables coatings producers to make architectural coatings with higher ? lm build and gives the painting contractors the ability to put on two coats within a single shift, thus increasing painter productivity while also being environmentally compliant. † Coatings customers enthusiastically accepted this value proposition, and the resins supplier was able to get a 40% price premium for its new offering over the traditional resin product. march 2006 97 C u s t o m e r Va l u e P ro p o s i t i o n s i n B u s i n e s s M a r ke t s xecution and documented results of each project the company undertakes. Since it began using VGP in 1992, GEIW&PT has documented more th an 1,000 case histories, accounting for $1. 3 billion in customer cost savings, 24 billion gallons of water conserved, 5. 5 million tons of waste eliminated, and 4. 8 million tons of air emissions removed. As suppliers gain experience documenting the value provided to customers, they become knowledgeable about how their offerings deliver superior value to customers and even how the value delivered varies across ation can submit NPI requests whenever they have an inventive idea for a customer solution that they believe would have a large value impact but that GEIW&PT presently does not offer. Industry marketing managers, who have extensive industry expertise, then perform scoping studies to understand the potential of the proposed products to deliver signi? cant value to segment customers. They create business cases for the proposed product, which are â€Å"racked and stacked† for review. The senior management team of GEIW&PT sort through aBest-practice suppliers make sure the ir people know how to identify what the next value propositions ought to be. kinds of customers. Because of this extensive and detailed knowledge, they become con? dent in predicting the cost savings and added value that prospective customers likely will receive. Some best-practice suppliers are even willing to guarantee a certain amount of savings before a customer signs on. A global automotive engine manufacturer turned to Quaker Chemical, a Pennsylvania-based specialty chemical and management services ? m, for help in signi? cantly reducing its operating costs. Quaker’s team of chemical, mechanical, and environmental engineers, which has been meticulously documenting cost savings to customers for years, identi? ed potential savings for this customer through process and productivity improvements. Then Quaker implemented its proposed solution – with a guarantee that savings would be ? ve times more than what the engine manufacturer spent annually just to purchase cool ant. In real numbers, that meant savings of $1. 4 million a year.What customer wouldn’t ? nd such a guarantee persuasive? large number of potential initiatives competing for limited resources. The team approved Panichella’s initiative, which led to the development of a new offering that provided re? nery customers with documented cost savings amounting to ? ve to ten times the price they paid for the offering, thus realizing a compelling value proposition. Sonoco, at the corporate level, has made customer value propositions fundamental to its business strategy. Since 2003, its CEO, Harris DeLoach, Jr. and the executive committee have set an ambitious growth goal for the ? rm: sustainable, double-digit, pro? table growth every year. They believe that distinctive value propositions are crucial to support the growth initiative. At Sonoco, each value proposition must be: †¢ Distinctive. It must be superior to those of Sonoco’s competition. †¢ Measurable. A ll value propositions should be based on tangible points of difference that can be quanti? ed in monetary terms. †¢ Sustainable. Sonoco must be able to execute this value proposition for a signi? ant period of time. Unit managers know how critical DVPs are to business unit performance because they are one of the ten key metrics on the managers’ performance scorecard. In senior management reviews, each unit manager presents proposed value propositions for each target market segment or key customer, or both. The managers then receive summary feedback on the value proposition metric (as well as on each of the nine other performance metrics) in terms of whether their proposals can lead to pro? table growth.In addition, Sonoco senior management tracks the relationship between business unit value propositions and business unit performance – and, year after year, has concluded that the emphasis on DVPs has made a signi? cant contribution toward sustainable, double-digit, profitable growth. harvard business review Superior Business Performance We contend that customer value propositions, properly constructed and delivered, make a signi? cant contribution to business strategy and performance. GE Infrastructure Water & Process Technologies’ recent development of a new service offering to re? ery customers illustrates how general manager John Panichella allocates limited resources to initiatives that will generate the greatest incremental value for his company and its customers. For example, a few years ago, a ? eld rep had a creative idea for a new product, based on his comprehensive understanding of re? nery processes and how re? neries make money. The ? eld rep submitted a new product introduction (NPI) request to the hydrocarbon industry marketing manager for further study. Field reps or anyone else in the organi98 C u s t o m e r Va l u e P ro p o s i t i o n s i n B u s i n e s s M a r ke t sBest-practice suppliers recognize that construct ing and substantiating resonating focus value propositions is not a onetime undertaking, so they make sure their people know how to identify what the next value propositions ought to be. Quaker Chemical, for example, conducts a value-proposition training program each year for its chemical program managers, who work on-site with customers and have responsibility for formulating and executing customer value propositions. These managers ? rst review case studies from a variety of industries Quaker serves, where their peers have executed savings projects and quanti? d the monetary savings produced. Competing in teams, the managers then participate in a simulation where they interview â€Å"customer managers† to gather information needed to devise a proposal for a customer value proposition. The team that is judged to have the best proposal earns â€Å"bragging rights,† which are highly valued in Quaker’s competitive culture. The training program, Quaker believes, he lps sharpen the skills of chemical program managers to identify savings projects when they return to the customers they are serving. As the ? al part of the training program, Quaker stages an annual real-world contest where the chemical program managers have 90 days to submit a proposal for a savings project that they plan to present to their customers. The director of chemical management judges these proposals and provides feedback. If he deems a proposed project to be viable, he awards the manager with a gift certi? cate. Implementing these projects goes toward ful? lling Quaker’s guaranteed annual savings commitments of, on average, $5 million to $6 million a year per customer.Each of these businesses has made customer value propositions a fundamental part of its business strategy. Drawing on best practices, we have presented an approach to customer value propositions that businesses can implement to communicate, with resonating focus, the superior value their offerings pr ovide to target market segments and customers. Customer value propositions can be a guiding beacon as well as the cornerstone for superior business performance. Thus, it is the responsibility of senior management and general management, not just marketing management, to ensure that their customer value propositions are just that.Reprint R0603F; HBR OnPoint 3544 To order, see page 151. P VEY . C. â€Å"What we need are some fresh new ideas. You know, like we had last year. † march 2006 99 Harvard Business Review Notice of Use Restrictions, May 2009 Harvard Business Review and Harvard Business Publishing Newsletter content on EBSCOhost is licensed for the private individual use of authorized EBSCOhost users. It is not intended for use as assigned course material in academic institutions nor as corporate learning or training materials in businesses.Academic licensees may not use this content in electronic reserves, electronic course packs, persistent linking from syllabi or by a ny other means of incorporating the content into course resources. Business licensees may not host this content on learning management systems or use persistent linking or other means to incorporate the content into learning management systems. Harvard Business Publishing will be pleased to grant permission to make this content available through such means. For rates and permission, contact [email  protected] org.

Home School vs. Public School Essay

I prefer home schooling over public schooling; which one do you prefer? There are both pros and cons for both Home Schooling and Public Schooling. I am going to explain this all to you in my essay. I personally was home schooled for a few years during middle and high school. All of elementary school and part of middle school I went to a regular school. My reasoning for choosing to be home schooled is I have Agoraphobia which is an anxiety disorder caused by situations where people perceive the environment as being difficult to escape or get help. As soon as I would walk into a class room I would have a panic attack. One thing I liked about public school was being able to play volleyball. I loved playing it for the little bit of time that I was in middle school. Even though I wasn’t really all that great, So I didn’t play very much. That is one con of being home schooled. You cannot play sports affiliated with any school. A pro for public schooling is you have a group environment to learn in with others to help you. On the other hand with home schooling you are on your own. In home schooling you have less choices of curriculum as you would if you were going to public school. You also have more diversity in public school. When going to public school you have a higher student to teacher ratio, now with home schooling there is a small teacher to student ratio. In home schooling you are free to choose your schedule, as in public school your schedule is strict and chosen for you. Public school chooses the curriculum for you. Unlike in home schooling you can choose your own. There are now roughly millions of children being home schooled. Being home schooled teaches students to be independent in their learning choices. Sometimes home schooling can be more expensive than going to public school. Teachers are not always qualified to teach all subjects, and colleges sometimes have stricter admission policies concerning home schooled students. It is also harder to provide social interaction when being home schooled. Like I had stated before I prefer home schooling but everyone has their own opinions. This is the reason why I have enrolled myself into the University of Phoenix online. So that I can have the flexibility of my classes, this way I can work around my everyday life and not miss out when it comes to spending time with my boys. I hope that the information in my essay was helpful to you.

John Donne and Reformation

John Donne was born in Bread Street, London in 1572 to a prosperous Roman Catholic family – a precarious thing at a time when anti-Catholic sentiment was rife in England. His father, John Donne, was a well-to-do ironmonger and citizen of London. Donne's father died suddenly in 1576, and left the three children to be raised by their mother, Elizabeth, who was the daughter of epigrammatist and playwright John Heywood and a relative of Sir Thomas More. [Family tree. ] Donne's first teachers were Jesuits. At the age of 11, Donne and his younger brother Henry were entered at Hart Hall, University of Oxford, where Donne studied for three years. He spent the next three years at the University of Cambridge, but took no degree at either university because he would not take the Oath of Supremacy required at graduation. He was admitted to study law as a member of Thavies Inn (1591) and Lincoln's Inn (1592), and it seemed natural that Donne should embark upon a legal or diplomatic career. In 1593, Donne's brother Henry died of a fever in prison after being arrested for giving sanctuary to a proscribed Catholic priest. This made Donne begin to question his faith. His first book of poems, Satires, written during this period of residence in London, is considered one of Donne's most important literary efforts. Although not immediately published, the volume had a fairly wide readership through private circulation of the manuscript. Same was the case with his love poems, Songs and Sonnets, assumed to be written at about the same time as the Satires. Having inherited a considerable fortune, young â€Å"Jack Donne† spent his money on womanizing, on books, at the theatre, and on travels. He had also befriended Christopher Brooke, a poet and his roommate at Lincoln's Inn, and Ben Jonson who was part of Brooke's circle. In 1596, Donne joined the naval expedition that Robert Devereux, 2nd Earl of Essex, led against Cadiz, Spain. In 1597, Donne joined an expedition to the Azores, where he wrote â€Å"The Calm†. Upon his return to England in 1598, Donne was appointed private secretary to Sir Thomas Egerton, Lord Keeper of the Great Seal, afterward Lord Ellesmere. Donne was beginning a promising career. In 1601, Donne became MP for Brackley, and sat in Queen Elizabeth's last Parliament. But in the same year, he secretly married Lady Egerton's niece, seventeen-year-old Anne More, daughter of Sir George More, Lieutenant of the Tower, and effectively committed career suicide. Donne wrote to the livid father, saying: â€Å"Sir, I acknowledge my fault to be so great as I dare scarce offer any other prayer to you in mine own behalf than this, to believe that I neither had dishonest end nor means. But for her whom I tender much more than my fortunes or life (else I would, I might neither joy in this life nor enjoy the next) I humbly beg of you that she may not, to her danger, feel the terror of your sudden anger. 1 Sir George had Donne thrown in Fleet Prison for some weeks, along with his cohorts Samuel and Christopher Brooke who had aided the couple's clandestine affair. Donne was dismissed from his post, and for the next decade had to struggle near poverty to support his growing family. Donne later summed up the experience: â€Å"John Donne, Anne Donne, Undone. † Anne's cousin offered the couple refuge in Pyrford, Surrey, and the couple was helped by friends like Lady Magdalen Herbert, George Herbert's mother, and Lucy, Countess of Bedford, women who also played a prominent role in Donne's literary life. Though Donne still had friends left, these were bitter years for a man who knew himself to be the intellectual superior of most, knew he could have risen to the highest posts, and yet found no preferment. It was not until 1609 that a reconciliation was effected between Donne and his father-in-law, and Sir George More was finally induced to pay his daughter's dowry. In the intervening years, Donne practised law, but they were lean years for the Donnes. Donne was employed by the religious pamphleteer Thomas Morton, later Bishop of Durham. It is possible that Donne co-wrote or ghost-wrote some of Morton's pamphlets (1604-1607). To this period, before reconciliation with his inlaws, belong Donne's Divine Poems (1607) and Biathanatos (pub. 1644), a radical piece for its time, in which Donne argues that suicide is not a sin in itself. As Donne approached forty, he published two anti-Catholic polemics Pseudo-Martyr (1610) and Ignatius his Conclave (1611). They were final public testimony of Donne's renunciation of the Catholic faith. Pseudo-Martyr, which held that English Catholics could pledge an oath of allegiance to James I, King of England, without compromising their religious loyalty to the Pope, won Donne the favor of the King. In return for patronage from Sir Robert Drury of Hawstead, he wrote A Funerall Elegie (1610), on the death of Sir Robert's 15-year-old daughter Elizabeth. At this time, the Donnes took residence on Drury Lane. The two Anniversaries— An Anatomy of the World (1611) and Of the Progress of the Soul (1612) continued the patronage. Sir Robert encouraged the publication of the poems: The First Anniversary was published with the original elegy in 1611, and both were reissued with The Second Anniversary in 1612. Donne had refused to take Anglican orders in 1607, but King James persisted, finally announcing that Donne would receive no post or preferment from the King, unless in the church. In 1615, Donne reluctantly entered the ministry and was appointed a Royal Chaplain later that year. In 1616, he was appointed Reader in Divinity at Lincoln's Inn (Cambridge had conferred the degree of Doctor of Divinity on him two years earlier). Donne's style, full of elaborate metaphors and religious symbolism, his flair for drama, his wide learning and his quick wit soon established him as one of the greatest preachers of the era. Just as Donne's fortunes seemed to be improving, Anne Donne died, on 15 August, 1617, aged thirty-three, after giving birth to their twelfth child, a stillborn. Seven of their children survived their mother's death. Struck by grief, Donne wrote the seventeenth Holy Sonnet, â€Å"Since she whom I lov'd hath paid her last debt. According to Donne's friend and biographer, Izaak Walton, Donne was thereafter ‘crucified to the world'. Donne continued to write poetry, notably his Holy Sonnets (1618), but the time for love songs was over. In 1618, Donne went as chaplain with Viscount Doncaster in his embassy to the German princes. His Hymn to Christ at the Author's Last Going into Germany, written before the journey, is laden with apprehension of death. Donne returned to London in 1620, and was ap pointed Dean of Saint Paul's in 1621, a post he held until his death. Donne excelled at his post, and was at last financially secure. In 1623, Donne's eldest daughter, Constance, married the actor Edward Alleyn, then 58. Donne's private meditations, Devotions upon Emergent Occasions, written while he was convalescing from a serious illness, were published in 1624. The most famous of these is undoubtedly Meditation 17, which includes the immortal lines â€Å"No man is an island† and â€Å"never send to know for whom the bell tolls; It tolls for thee. † In 1624, Donne was made vicar of St Dunstan's-in-the-West. On March 27, 1625, James I died, and Donne preached his first sermon for Charles I. But for his ailing health, (he had mouth sores and had experienced significant weight loss) Donne almost certainly would have become a bishop in 1630. Obsessed with the idea of death, Donne posed in a shroud – the painting was completed a few weeks before his death, and later used to create an effigy. He also preached what was called his own funeral sermon, Death's Duel, just a few weeks before he died in London on March 31, 1631. The last thing Donne wrote just before his death was Hymne to God, my God, In my Sicknesse. Donne's monument, in his shroud, survived the Great Fire of London and can still be seen today at St. Paul's.

Sociology - Ubran Sociology & Crime and Criminology Research Proposal

Sociology - Ubran Sociology & Crime and Criminology - Research Proposal Example As part of examining the possible impact of implementing a diet program for police officers, the health benefits, identified positive work improvements, and social benefits of this program will be tackled in details. In relation to the implementation of a strict diet program for local police officers, the proposed research study is important in terms of improving the health and work performance of the local police officers. Because of the nature of work, the U.S. police officers live roughly 15 years less as compared to the average Americans (Tracy, 1993). This is possible due to the fact that approximately 50% of the local police officers are likely to develop a form of heart disease during their retirement age (Vonk, 2007). The problem with being overweight is highly associated with the risk of developing a long list of health problems including: (1) high blood pressure; (2) Type 2 diabetes or non-insulin dependent diabetes mellitus (NIDDM); (3) high blood pressure; (4) atherosclerosis; (5) high cholesterol levels; (6) gallbladder disease; (7) atherosclerosis; (8) cerebral hemorrhage; (9) coronary heart diseases; (10) osteoarthritis; (11) sleep apnea; and (12) certain types of cancer. (Alberti et al., 2007; Nazario, 2007; Nanchahal et al., 2005; WHO, 2005; Ballington, 2002; American Psychiatric Association, 2000; Lau et al., 2000; Yuan et al., 1998) On top of the health consequences of being overweight, it also contributes to the slow physical movements can endanger the lives of the local police officers. The proposed research design includes the use of qualitative and quantitative research survey questionnaire which will be distributed to a group of police officers. To determine the best diet program which can be designed for the specific nutritional needs of the police officers, a one-on-one interview will be conducted with a qualified nutritionist. After requesting

Critique on Movie The Last King of Scotland Review

Critique on The Last King of Scotland - Movie Review Example For most, the journey is hopeless; there is no where to hide or destination to run to in Uganda. It is through characterization, plot, and themes that viewers are lead and eventually dragged violently into the deprived paranoid world of General Idi Amin. There are three profound characters: General Idi Amin, Nicholas Garrigan, and Kay Amin. Forest Whitaker's betrayal of Idi Amin starts to build the psychological drama with the introduction of General Idi Amin. Whitaker the actor is a presence at 6 feet, and, in his portrayal of the dictator, closely resembled him. He has a film history of playing powerful big men. As an actor Whitaker has charisma on screen. The film viewers want to trust and feel safe with him. This adds to the believability of the character, because General Idi Amin is also very charismatic. The magnetic connection that Nicholas Garrigan has to General Idi Amin is compelling. The actor James McAvoy is a compliment to Whitaker's character. He has the power to evoke curiosity, frailty, strength, and manliness in his characters. He showed this same talent when portraying Mr. Tumnus in the screen version of the Chronicles of Narnia: The Lion, the Witch, and the Wardrobe. The combination of the larger than life Whitake r and the frail but manly McAvoy opens the movie with undeniable and effective chemistry.The young Scottish doctor although accomplished academically is very idealist and care free. He shows little forward knowledge of the consequences of his actions. This is a sharp contrast to General Idi Amin who examines, judges, and harshly punishes the action of everyone around him. Nicholas Garrigan came to Uganda to escape from what he views as a boring life. He has the same outlook as young men joining the Army with the promise of adventures and the opportunity to seek a new land vastly different from their home. Like General Idi Amin, he insensitively toys with others. He is womanizer. Nicholas Garrison is enthralled and seductively enticed by the benefits of being in General Idi Amin's inner circle. He has no idea of the consequences or power being a personal physician to a dictator brings. The relationship in the beginning is one of infatuation between General Idi Amin and Nicholas Garrison. General Idi Amin admires the young doctor, because he is Scottish and decisive. He is bold enough without permission to use General Idi Amin's gun to shoot a cow. Again Nicholas Garrigan shows his blindness from consequences of his actions. It is through the plot of the movie that both characters of General Idi Amin and Nicholas Garrigan evolve to where the General's character is fully revealed to Garrigan. He wakes up one day to realize that he loves a monster and has been part of his ghoulish dealings. Garrigan finally realizes that consequences can be deadly. Kay Amin's role is the anchor in the plot. She forces Garrigan to acknowledge the horror that he has created in Uganda, and his role in it. Her relationship, death, and wrongly stitched together body put on public display shocks Garrison. It forces him to conspire with the British. Kay Amin, portrayed by Kerry Washington, catalyst Nicholas Garrigan's epiphany. Without her death, Nicholas could not have understood and felt the full horror or General Idi Amin. Although General

Ousmane Sembene's cinema Essay Example | Topics and Well Written Essays - 2750 words

Ousmane Sembene's cinema - Essay Example In films such as Ceddo and Xala he pointed an irate, often ironic finger at the failures and extremes of contemporary African governments. (Scott, 2007) ''''''Sembene believed that most of the African post-colonial states had failed to meet the expectations that their populace initially related with autonomy from colonial rule. For many African people the official end of colonial rule did not generate an end to social injustice and radical economic imbalance. Sembene's work was dominated by a desire to spell out what he thought was going wrong with his society. He made a critical examination of post-colonial African society neither beautifying nor discrediting them, but simply depicting a reality in which the intercession of the critic comes as an effort to objectively consider problems that are of critical import to contemporary African nations. In a dialogue with Francoise Pfaff (1984), Sembene said that "I have never tried to please my audience through the embellishment of reality . I am a participant and an observer of my society" ''''''Cinema has been divided into three groups commonly known as first, second and third cinema. This terminology was established at the Bandung Conference of 1955(the first conference of the Non-Aligned Movement). China promulgated the premise of the three distinctive economic worlds. The first world inclusive of the superior capitalist countries like Western Europe, North America and Australasia; the second world comprising of the prior socialist countries of the Soviet Union and Eastern Europe. The left over countries were accordingly the third world, to which China confirmed its commitment. (Chanan, 1997)' ''''''First Cinema refers the form recognized as the Hollywood movie, where cinema is pure entertainment. The primary aim of first cinema is to maximize profits. All types of films appear under this classification; feature, short and educational films, even scientific documentary is inclined to the aspirations capitalism. Second Cinema is also known as parallel cinema. Parallel cinema has its own structure, pattern of distribution and exhibition, and its own ideology. Nowadays parallel cinema is made by and for limited social groups. It articulates the desires and ideology of the middle layers or the petty bourgeoisie and as a result is often radical but pessimist and at times mystical. Similar to first cinema all types of films may be found in this group. Third cinema ''''''There is a deliberate imprecision in the term 'Third Cinema' which requires clarification. The term 'Third Cinema' is derived from the correlation with the term 'third world'. The third world consists of the underdeveloped nations of Asia, Africa and South America. In the developing countries, third cinema is concerned with the problems of de-colonisation, propagates national liberation. Third cinema tries to debunk old myths, eradicate racism and dissolve economic hierarchies. ''''''Originally typical third cinema included radical political views that were usually hostile to the regime and signification of the concerned images. Militant cinema in which the camera is often equated to the gun was also a form of third cinema. Militant cinema required the film crew to operate with a drastic and original notion not

The effects of entertainment on culture Research Paper

The effects of entertainment on culture - Research Paper Example Today’s entertainment target particular groups of people basing on modalities such as gender, age, occupation, social standards and even physical abilities. Sadly, today’s fast growing entertainment industry has not come without its share of blame, particularly with regard to culture erosion. Here, culture is taken as the collective belief, customs, and social behaviors of a particular people in a given geographical region. Such is the case that culture function as a tool to identify a group of people simply put as â€Å" totality of a people socially transmitted pattern of thought, manifested in the way they live, worship, relate with each other and perceive humanity† (Macionis & Linda 53). Entertainment is an important part of every culture, a factor that makes it part of both the past and today and even future generations. Such is the case that as the world changes so doe’s entertainment with its effect which is usually reflected on culture, sometimes i n harmful ways. This works details Entertainment impact on culture which is often depicted by audience thought of the people involved, the communication style used, and content of the entertainment, place and time of the entertainment. Generally, audiences are influenced through entertainment into taking new patterns of socializing, thinking and response to inter-cultural communication. Entertainment results to culture clash, an effect that is experience across the globe, particularly following the internet era. Here, cultural interactions in the name of intertainment have resulted to a wide range of outcome, some good and others bad. For instance, Pop culture, widely associated with American entertainment industry is a trend that attracted large audience across America and other regions of the world. This culture that is associated with particular consumer clothing,

Brick and Mortar vs Based Businessess Term Paper

Brick and Mortar vs Based Businessess - Term Paper Example On the other hand, online business does not cost physical labor, though a businessman might have to spend some money initially purchasing licenses or getting his business registered as per the official requirements of trade. One needs to know and satisfy the legal ramifications of one’s online business before starting it (Elizabeth, 2010). Still, online business can be started immediately because it usually does not take long for initial online formalities to be met, whereas the traditional business costs much in terms of time, labor and money in the start. In traditional business, the staff required to do the work costs a businessman a lot. In addition to that, the businessman has to face overheads as office and serviceability charges, logistics, food and traveling expenses. On the other hand, an online business provides a businessman with the leverage that he can work from home. Although the businessman still might have to hire staff for organizing the work online, yet the overhead charges are significantly reduced. There are no traveling expenses, no utility bills except for internet or electricity bill and no food charges. It is indeed, irrational to count electricity charges here because computers and internet are also frequently made use of in traditional businesses. Brick and mortar businesses are far more expensive than online businesses because of overhead charges, insurance, taxes and other property charges (Kayne, 2010). Online business ensures effective communication. Communication and timely conveyance of instructions are vital for the success of a business. The electronic mail delivers instructions to the concerned immediately, and the sender does not have to incur any additional cost unlike traditional businessmen, who have to incur huge telephone bills and yet, the communication is hardly ever effective or meaningful. This drawback

Linux and Mac File Systems Article Example | Topics and Well Written Essays - 250 words

Linux and Mac File Systems - Article Example lso highly scalable and support Access Control lists as compared to Ext3fs which support a basic form of ACL or HFS+ which moved NTFS style of ACL recently. Moreover, NTFS is more robust than Ext3fs in that Ext3fs is based on Ext2fs and hence carries some of the problem from the older file system. Also, Ext3fs has an impact on performance due to its journaling features. An inode (index node) is data structure in the file system that stores all the information about a file except its name. The information includes access permissions, the owner of the file, file type and size of the file. The Linux file system (ext3fs) employs this approach for indexing small files. For larger files, Linux allows the use of indirect blocks. The indirect blocks extend the file size that can be stored to slightly more than 4 MB. On the other hand, NTFS has entries in the master file table (MFT) instead of inodes. The MFT contains the information required to retrieve a file from NTFS. The MFT have a unique identifier, i.e., FILE_RECORD_SEGMENT_HEADER which is a file header used to identify a file from other files. HFS+ also does not have inodes, but it emulate its behavior. In Mac OS, the equivalent of the inode in Linux is referred to as indirect node file. The indirect node file is stored in the metadata directory, which exist in the root directory. The indirect node file stores file’s content properties like the owner ID and the group ID. Though, Mac OS is UNIX based, its file system does not implement inode like Linux but a similar indexing is implemented. In contrast, the inode is a file system feature found in UNIX based operating system like Linux but not found in Window Operating system. The MFT, indirect node file, and inode are similar in that they store file’s properties and allow easy retrieval of the files. The NTFS and Mac OS inode structure are more superior to the Linux one, and thus they improve performance and efficiency. Linux adoption both by desktop users and

International Sales of Goods by Sea Essay Example | Topics and Well Written Essays - 4500 words

International Sales of Goods by Sea - Essay Example This is to ensure that no material losses occur to the goods during transit. The liability of the seller under CIF is larger than under FOB, in that, the responsibility of the goods, vests with the seller until it is loaded onboard the ship. In other words, the liability is not restricted until it is entrusted to the carrier, but remains intact until the shipments are aboard the ship. Any losses that occur during the intervening period would fall upon the seller, and not anybody else. Thus, the Academy could initiate action against Llodd’s in respect of the books having missing pages. Under Section 14 (2) (a) of Sale of Goods Act, it is seen that â€Å"where a seller sells goods in the course of a business, there is an implied term that the goods supplied under the contract are of satisfactory quality. It provides that goods are of satisfactory quality if they meet the standard that a reasonable person would regard as satisfactory, taking account of any description of the goods, the price (if relevant) and all the other relevant circumstances. Again, under Section 13 of the Sale of Goods Act, sale of goods by description, it is incumbent on the part of the seller to ensure that the goods match the description; otherwise the buyer is at liberty to repudiate the treaty, and /or claim damages for compensatory damages. (Sale of Goods Act 1979). Again under the provisions of Section 11 of the Sale of Goods Act 1979, it is seen that when a contract of sale is incumbent upon certain conditionality to be fulfilled by the seller, especially in a CIF contract, the buyer has the options either to excuse the conditions or may elect to treat the breach of condition, as a breach of warranty, which may not be cause for action of cancelling the contract. There may be certain aspects surrounding the case that could suggest whether the requirement could be treated as a condition precedent, in which case the buyer could elect to cancel the contract or, in cases,

Information accessible Essay Example for Free

Information accessible Essay In the late twentieth century, when world was introduced to internet, it all began from there. Everyone wanted a presence on the global repository, a network of information accessible by anybody in the world with the help of WWW (World Wide Web). The importance of data was very significant and the interoperability of data among different websites was a necessity. This gave a boost to web and programming. Many languages have emerged in front of a Web Developer. It is difficult for a developer to decide which one to choose and also to comprehend the maximum advantages rendered by each. At this stage, the web developer is interested to find which language would be less complex but more powerful. Although there are languages like JAVA, C++, Visual Basic, VC++, etc. that allow one to create applications that can be taken as web pages, for viewing these applications the web browser has to interpret them into HTML (Hyper Text Markup Language). This gave the boost to the Markup Language specified by the web consortium as the default language understood by all the web browsers. Abstractly, marking-up text is a methodology for encoding data with information about it itself. Examples of markups (encoded data) are universal in the real world. For example, when we were in school, we probably used to use a bright yellow highlighter pen to highlight sentences in our schoolbooks. We did so because we thought that the highlighted sentences would be useful to review around exam time and we also wanted a quick way to skim through the important points. Just like us, thousands of students around the world did exactly the same thing for the exact same reason. By highlighting certain bit of text, we were effectively Marking-Up† the data. Essentially, we specified that certain sentences were important by marking them in yellow. These sentences became encoded with the fact that they were important. Because everyone followed the same standard of marking up, we could easily pick up a used text book and get a good idea about the core points of the book from the highlighted sections. Similarly, a standard must be in place to define what a valid markup is. Markup involves adding of characters to a piece of information such that these characters can be used to process that information in a particular way. A Markup language is not a formatting language. A formatting language focuses on describing the final display of a document without describing the document content. The best example of formatting language is RTF (Rich Text Format). RTF was created specifically to describe the final format of a document, using codes embedded in a document. These codes are readable through a wide variety of applications, from word processors to page layout programs, but they are generally invisible to a document developer. A Markup language is not a programming language because a programming language creates a set of instructions that are interpreted or compiled into a program or application. The best example of a programming language is Java and a markup language is XML. A markup language does not worry about how the content it describes is formatted, but is instead, concerned about accurately describing its contents.

Physician one day Essay Example for Free

Physician one day Essay Hope began playing a major role in my life when my father was diagnosed with stage IV pancreatic cancer. I remember the exact day my family and I found out, the terrible feeling in my stomach and my utter disbelief. From that day on it had only grown worse. The doctor bluntly told us that my father had only about three to six months to live. The only thing I had left was hope. It was the hope that he would miraculously get better, but as his illness progressed, I simply hoped to have him with me just a little longer. Nine months later my father died. To this day I still cannot fully fathom the fact that he has passed away. However, the painful journey that led to his demise is the motivational experience that empowers me to strive for excellence. Having to see the person I love endure painful chemotherapy sessions and watching him slowly deteriorate was the hardest experience I have had to bear thus far. In a way, I was able to benefit from it. When he was diagnosed, I spent all the time I could with my father, trying to ameliorate his pain and mine. I would give him his medications, cater to his every need, and even accompany him to his chemotherapy appointments. Ultimately, I became his personal nurse. On several occasions, my father could not withstand the pain caused not only by the cancer, but also by the chemotherapy. In these moments, I was distraught because I felt incompetent; I could not help him in any way. With desperation in his voice, he would tell me, â€Å"Be a doctor one day, so you can cure people like me. † His words determined the career path I would take. The few times I could ameliorate my father’s pain were the times when I felt a satisfaction like no other. Helping others in any way became my passion because it reminds me of the instances I helped my father. My father’s words inspired me to help others who suffer due to illness. His death gave me hope and the drive to become a physician. My father’s battle with cancer was a life changing experience. I am now able to say that it has made me the strong individual I consider myself to be. Hope led me to survive the loss of my father and it is hope that guides me every day. Hope allows me to continue in times of despair, as well as to strive for the best in school. Whenever I am in any predicament, I remember my father and everything we went through together; I immediately gain the courage to overcome the issue.

Effects of Physiological Reproductive Events on Ovary

Effects of Physiological Reproductive Events on Ovary Chapter one Introduction Background The two majors function of the ovary is the differentiation and release of female gametes (oocyte), which can then be successfully fertilised and ensure the survival of species. The ovary is also an endocrine organ that produces steroid hormones that allow the development of female secondary sexual characteristics and supports pregnancy. The mammalian ovary is covered by a single layer of epithelial cells (surface epithelium), which vary in type from simple squamous to cuboidal to low pseudostratified columnar (Anderson et al. 1976). Directly underneath the surface epithelium there is a layer of dense connective tissue known as the tunica albuginea. The mammalian ovary is a heterogeneous organ containing follicles and corpora lutea at various stages of development. The ovarian follicle is the fundamental unit of the ovary, each follicle consists of an oocyte, surrounded by granulosa cells and outer layer of theca cells ( 1.2 Folliculogenesis During embryogenesis, primordial germ cells (PGCS) migrate from the yolk sac through the dorsal mesentery of the hindgut, to the genital ridge. The germ cells then undergo extensive proliferation, and lose their motile characteristics, in addition, somatic cells derived from the mesenchyme of the genital ridge, proliferate as well (Hirshfield 1991). The germ cells cease mitotic division and form association with small numbers of pre-granulosa cells to form primordial follicle (Telfer et al. 1988). The germ cells undergo the first meiotic division and are now called primary oocytes. The oocytes then become arrested in the diplotene stage of prophase I of meiosis until the primordial follicles start to grow and finally reach the ovulatory stage. In the diplotene stage, the oocyte may prepare itself for rapid mitosis and implantation, by producing large amounts of mRNA and ribosomes (Picton et al. 1998). Primordial follicles may be observed from week 22 in the human (Faddy and Gosden 19 95) and week 13 in the cow (van den Hurk and Zhao 2005). The pool of primordial follicles develops during fetal life in some species (e.g primates, ruminants), but in others it develops during the early neonatal period (e.g rodents, rabbits) (Marion et al. 1971). The number of primordial follicles present at birth represents the total population of germ cells available to mammalian females during their entire reproductive life (Kezele et al. 2002), and is believed to serve as the source of developing follicles and oocytes (Eppig 2001). Although recent studies have suggested that postnatal oogenesis may also occur in female mammals (Johnson et al. 2004), they suggested that germline stem cells can repopulate the postnatal ovary and renew the primordial follicle pool. This group subsequently went on to suggest that these cells were derived from bone marrow (Johnson et al. 2005). This has attracted a great deal of attention as well as criticism (Gosden 2004; Byskov et al. 2005; Telfer et al. 2005). This is an ongoing debate but the balance of evidence suggests that renewal is not a major factor in ovarian development (Eggan et al. 2006). In mammals, the number of primordial follicles in the ovaries at birth varies enormously between species, ranging from tens of thousands in mice to millions in humans and domestic species (Gosden and Telfer 1987). These follicles must develop through primordial, primary and secondary stages before reaching the preovulatory stage, and subsequent ovulation (Figure 1.1). Proper follicle development involves maturation of the oocyte, which is surrounded by variable layers of granulosa cells, enveloped by theca cells (Drummond 2005). Granulosa cells provide physical support of the oocyte and mediate signals between the oocyte, outer theca cells and endocrine hormones. Once the pool of primordial follicles has been established, follicles gradually and continually leave the resting pool to begin growth. However, less than 1% of primordi al follicles present at the time of birth of an animal will ever proceed to ovulation (Erickson 1966), with the majority of follicles degenerating by atresia. 1.3 Regulation of early folliculogenesis A critical process in ovarian biology is the transition of the developmentally arrested primordial follicle to the developing primary follicle. Follicular growth may begin at any time during the females life. The primordial follicle contains an oocyte arrested in meiosis I surrounded by flattened somatic cells termed the pregranulosa (Kezele et al. 2002). During onset of primordial follicle growth, flattened pregranulosa cells become cuboidal and begin to proliferate. The enclosed oocyte begins to grow at the same time (Anderson et al. 2000; Clark and Eddy 1975). The growths of both the primordial follicles with oocytes characterize the initiation of the growing phase. The oocytes within the primordial follicles remain quiescent for months to years until they receive the appropriate signals to initiate folliculogenesis and primordial to primary follicle transition. So far, little is known about the molecular mechanisms and extracellular signalling factors that regulate this process. These processes directly affect the number of oocytes available to a female throughout her reproductive life. Once the pool of primordial follicles is depleted, ovarian steroidogenesis ends and the series of physiological changes called menopause begins (Richardson et al. 1987). It is unclear whether the signals originate from the oocyte, or/and from surrounding somatic cells, or from outside the ovary. It is also unknown if it is an inhibitory factor preventing resting primordial follicles from leaving the stock or a stimulus acting on the resting primordial follicles store that stimulates some follicle to leave it (Gougeon and Busso 2000). A multitude of factors may act locally to regulate early folliculogenesis by promoting growth (Bennett et al. 1996) or by inhibiting growth (Bukovsky et al. 1995). The initial growth signal appears to be independent of the pitui tary gonadotropins (Peters et al. 1975) (Figure 1.3). Primordial follicles do not possess receptors for FSH hormone (Oktay et al. 1997). Despite some studies suggesting that gonadotropins are involved in the initiation of follicular growth in immature rodents (Lintern-Moore 1977; Neal and Baker 1973), nevertheless, during natural hypopituitary conditions in both animal species and humans, the initiation process is not completely abolished (Howe et al. 1978; Halpin et al. 1986). Although follicles at early stages of development have been shown to express follicle stimulating hormone receptors (FSH-R) (Bao et al. 1998), in the absence of gonadotropins during the early stages of follicle growth, follicles can still develop to the early antral stage (Awotwi et al. 1984; Gong et al. 1996). Knockout mice who are null mutants for either FSH receptor or LH receptor are able to undergo the primordial to primary follicle transition (Zhang et al. 2001; Abel et al. 2000). Several local factors have been found that can regulate the primordial to primary follicle transition. Bone morphogenetic protein-7 (BMP-7) has been shown to promote the primordial to primary follicle transition and to increase granulosa cell proliferation (Lee et al. 2001). Leukemia inhibitory factor (LIF) has also been shown to promote the primordial to primary follicle transition and to up-regulate granulosa cell expression of kit ligand (KL) (Nilsson et al. 2002). Bone morphogenic protein-15 (BMP-15) is a growth factor expressed in the oocytes of developing follicles that plays a role in early follicle progression (Dube et al. 1998) and stimulates granulosa cell proliferation (Otsuka et al. 2000). Growth differentiation factor-9 (GDF-9) has been localized inthe oocytes of mouse (Dong et al. 1996) rat (Jaatinen et al. 1999) and human (Aaltonen et al. 1999) primary follicles. Nilsson and Skinner (2002) have shown that GDF-9 promotesthe development of primary follicles in neonatal r at ovaries,but it has no effect on the growth of primordial follicles (Nilsson and Skinner 2002).Studies by Wang and Roy (2004) have provided the first evidence that GDF-9 can promote the formation of primordialfollicles and their subsequent growth in neonatal hamster ovaries (Wang and Roy 2004) . Anti-Mullerian hormone (AMH) is a member of the transforming growth factor- ÃŽ ² (TGF-ÃŽ ²) is considered as a negative regulator of the early stages of follicular development. AMH is produced by the granulosa cells of developing preantral and small antral follicles which inhibits the primordial to primary follicle transition (Durlinger et al. 1999). AMH is never found in primordial follicles, theca cells or oocytes (Ueno et al. 1989; Hirobe et al. 1994; Baarends et al. 1995). Examination of ovarian follicles in AMH-deficient female mice revealed lower numbers of primordial follicles and more growing follicles compared with wild-type mice, these findings revealed that, in the absence of AMH, ovaries are depleted of their primordial follicles earlier than they are in control mice and these observations led to the propsal that AMH inhibits primordial follicle recruitment (Durlinger et al. 1999). Results were obtained from another in vitro experiments on the bovine ovarian cortex sugges ted that, at least in nonhuman species, the presence of AMH acts as a brake on the activation of primordial follicles and the growth of preantral follicles (Gigli et al. 2005). It has been demonstrated that oocytes from early preantral, late preantral and preovulatory follicles up-regulate AMH mRNA levels in granulosa cells, in a fashion that is dependent upon the developmental stage of the oocyte (Salmon et al. 2004). These findings suggest that oocyte regulation of AMH expression may play a role in intra- and interfollicular coordination of follicle development. ; kit ligand (KL) and basic fibroblast growth factor (bFGF) secreted by pre-granulosa cells and oocyte respectively, have mutual stimulatory effects on oocytes and granulosa cells; they also promote recruitment of theca cells from the surrounding stromal/interstitial cell population. Stromal/interstitial cells and theca cells secrete BMP-4 and BMP-7, which promote follicle activation and survival. GDF-9 and/or BMP-15 secreted by the oocyte of the activated follicle promote granulosa cell proliferation, KL expression and theca formation. Granulosa cells of growing follicles secrete AMH that appears to act as a ‘brake on primordial follicle recruitment (Knight and Glister 2006). Foxo3a (FKHRL1), a member of the FOXO subfamily of forkhead transcription factors, has been implicated in the regulation of follicle activation. It has been indicated that Foxo3a functions at the earliest stages of follicular growth as a suppressor of follicular activation (Castrillon et al. 2003). It was suggested that Foxo3a serves an essential role by suppressing the growth of primordial follicles, thereby preserving them until later in life (John et al. 2007). It was shown that Foxo3a -/-ovaries contained markedly elevated numbers of early growing follicles, and this extensive of follicular growth in Foxo3a -/- females resulted in the progression of increased numbers of follicles to more advanced stages of follicular development and this misregulation of this process can lead to premature ovarian failure (Castrillon et al. 2003). Kit ligand (KL) is produced by the granulosa cells of developing ovaries (Manova et al. 1993; Ismail et al. 1996) and KL receptors (c-kit) are present on oocytes and theca cells (Manova et al. 1990). C-kit is expressed at the surface of mammalian oocytes at all stages of follicular development in postnatal ovaries of the mouse, the rat and humans (Driancourt et al. 2000; Horie et al. 1991; Manova et al. 1990; Orr-Urtreger et al. 1990) and its only known ligand, Kit-ligand (KL), which is also referred to as stem cell factor (SCF). KL acts to recruit theca cells from surrounding ovarian stroma during folliculogenesis (Parrott and Skinner 2000). Therfore, KL is thought to act as a signal from the granulosa cells around primordial follicles to the oocyte and surrounding stroma to promote the events of the primordial to primary follicle transition (Parrott and Skinner 1999). In this study (Parrott and Skinner 1999), treatment of in vitro cultured follicles from postnatal ovaries from 4 da y old rats, with KL dramatically induced the development of primordial follicles, but was completely blocked by the Kit antibody ACK2. 1.4 Follicle development Follicular development is regulated by both endocrine and intraovarin mechanisms which co-ordinate the processes of somatic cell proliferation and differentiation (Moley and Schreiber 1995). The basic functional unit in the ovary is the ovarian follicle that is composed of somatic cells and developing oocyte. The two primary somatic cell types are the theca cells and granulosa cells. These two somatic cell types are the site of action and synthesis of a number of hormone that promote a complex regulation of follicular development. The prolifetation of these two cell types is in part responsible for the development of the antral ovarian follicle. At the same time, the oocyte is undergoing developmental changes necessary to allow the resumption of meiosis after the preovulatory surge of gonadotrophins (Montgomery et al. 2001). This regulation occurs according to endocrine principles, involving hormones such as pituitary gonadotropins , ovarian steroids and locally produced factors that act either on the cell that produces them (autocrine) or on neighbouring cells (paracrine) (Salha et al. 1998). Ovarian follicular development is a long process which can take around 6 months from the initiation of growth of primordial follicles until development of a preovulatory follicle in humans, cattle and sheep (Lussier et al. 1987; Cahill and Mauleon 1980) and around 4 months in pigs (Morbeck et al. 1992). The majority of this time is spent in the pre-antral stages of development. Already at this stage, a considerable proportion of growing follicles fail to survive and they degenerate through a process termed follicular atresia. Observations in humans and in animals suggest that apoptosis is the mechanism of follicular atresia (Tilly 1996; Kaipia and Hsueh 1997). In women, the dominant follicle orginates from primordial follicle that was recruited to grow almost 1 year earlier Folliculogenesis can be divided into two stages: the gonadotropin-independent (preantral) and gonadotropin-dependent (antral or Graafian) periods (Erickson and Shimasaki 2000). Locally produced growth factors are critically involved in controlling preantral follicle development during the gonadotropin-independent period. After antraum formation, the follicle becomes dependent on FSH stimulation for continued growth and development. Interestingly, it was discovered that the process of folliculogenesis is controled by growth factors secreted by the oocyte (Matzuk 2000). Five growth factors have been identified in mamalian oocytes: growth differentiation factor-9 (GDF-9) (McGrath et al. 1995), bone morphogenetic protein -15 (BMP-15) (Dube et al. 1998; Laitinen et al. 1998), bone morphogenetic protein -6 (BMP-6) (Knight and Glister 2006), transforming growth factor -ÃŽ ²2 ( TGF-ÃŽ ²2) (Schmid et al. 1994), and fibroblast growth factor-8 (FGF-8) (Valve et al. 1997). Experiments with knockout mice have demonstrated that in the absence of GDF-9, folliculogenesis is blocked at the primary to preantral stage (Dong et al. 1996). Consequently, there are no Graafian follicles, no ovulations, and no pregnancies. 1.4.1 Follicular cell types and follicle classification The two primary somatic cell types in the ovarian follicle are the theca cells and granulosa cells. These two somatic cell types are the site of action and synthesis of a number of hormones that are involved in the complete regulation of follicular development. 1.4.1.1 Granulosa cells Granulosa cells are the primary somatic cell type in the ovary that provides a physical support of the oocyte and mediated signals between the oocyte, outer theca cells and endocrine hormone. Regulation of granulosa cell differentiation during folliculogenesis requires the actions of a number of hormones and growth factors. Specific receptors have been demonstrated on granulosa cells for gonadotropins follicle stimulating hormone (FSH) and luteinizing hormone (LH) (Richards and Midgley, Jr. 1976). In addition, receptors have been found for factors such as insulin-like growth factor (IGF) (Adashi 1998) epidermal growth factor (EGF) (Vlodavsky et al. 1978) and anti-Mullerian hormone (AMH) (Josso et al. 2001). Actions of these hormones and growth factors on granulosa cells vary with the stage of differentiation. Follicular growth and steroidogenesis are dependent on the coordinated actions of FSH and LH with their receptors on granulosa cells and thecal cells of ovarian follicles. Both granulosal and thecal cells are involved in production of estradiol-17ÃŽ ² (two cell/two gonadotropin model which is well accepted for many species). 1.4.1.2 Theca cells Another important cell type in the ovary is the ovarian theca cell. These are differentiated stromal cells that surround the follicle and have also been termed theca interstitial cells (Erickson and Case 1983). The thecal cells can be distinguished as two distinct layers, the inner layer of cells, the theca interna has a basement membrane separating it from the outmost layer of granulosa cells. The theca interna is a highly vascular layer. One of the major functions of theca cells in species such as the cow, human and rodent is the secretion of androgens (Fortune and Armstrong 1977). At the primordial stage, no theca cells are present; however during the transition to the primary stage, theca cells at this stage of development are gonadotropin and steroid independent and non-steroidogenic (Braw-Tal and Roth 2005). Theca externa which is less vascularized layer and merges into the stromal tissue without clear boundaries. The ‘two-gonadotrophin, two-cell model of follicular estradiol biosynthesis According to the two-cell-two-gonadotrophin theory, the ovary has two cellular compartments that are driven independently by LH and FSH to produce ovarian steroids. Androgen production by theca cells is a function of LH, whereas aromatization of these androgens to oestradiol by granulosa cells is controlled by FSH (Gougeon 1996) (Figure 1.5). Androgen synthesis occurs in the theca interna regulated by LH, by expressing P450c17, the rate-limiting steroidogenic enzyme in androgen synthesis (Sasano et al. 1989). Theca interna are capable of synthesizing all the steroids from cholesterol to testosterone and are the major source of follicular androstenedione. In contrast, granulosa cells are the major source of follicular estradiol. Granulosa cells are intrafollicular sites of androgen metabolism (Ghersevich et al. 1994) and express aromatase P450arom (Whitelaw et al. 1992) this enzyme converts androgens to estrogens. FSH also induces granulosa cell LH receptors that are functionally coup led to aromatase. Thus, uniquely in the preovulatory follicle, both the synthesis of androgen (in theca cells) and its aromatization to estradiol (in granulosa cells) are directly regulated by LH (Fortune and Armstrong 1977). . In the theca, under the influence of LH, cholesterol is converted to pregnenolone and metabolised through a series of substrates ending in androgen production. The two-cell, two-gonadotrophin model comes into play with androgens produced by the theca cells transported to the granulosa cells where they are aromatised to oestrogens (Drummond 2006). 1.4.2 Classification of follicle stages In sheep, the stages of follicular development have been classified on the basis of the number of granulosa cells in the largest cross-section of follicles (McNatty et al. 1999), 1.4.3 Follicular development in primates 1.4.3.1 Oocyte growth and maturation Once follicles have been initiated to grow, the granulosa cells proliferate to form the different stages of follicular development (Telfer et al. 2000). During follicular activation and early development in mice, for example, the oocyte growth occurs rapidly with an approximatly 300-fold increase in volume during the 2-3 week growth phase (Wassarman and Albertini 1994), which is also accompanied by a 300-fold increase in RNA content (Sternlicht and Schultz 1981) and a 38-fold increase in absolute rate of protein synthesis (Schultz et al. 1979). These events are indicative of a period of cell growth with high metabolic activity (Wassarman and Albertini 1994). Oocytes complete most of their growth phase before the formation of a follicular antrum (Wassarman and Albertini 1994), and the increase in oocyte diameter and volume during antral follicular growth is relatively small (Eppig 2001; Wassarman and Albertini 1994). If the oocyte is to be capable of fertilization and subsequent embry onic development, it must acquire the ability to resume meiosis. Oocytes from immature follicles are unable to resume meiosis (Iwamatsu and Yanagimachi 1975) however, by the time the follicles have reached the antral stages the oocytes of most species have acquired the ability to resume meiosis (Mattioli and Barboni 2000; Telfer 1998). 1.4.3.2 Follicular growth Early in oocyte growth, a homogenous glycoprotein layer called the zona pellucida (ZP) is secreted shortly after initiation of follicular growth (Epifano and Dean 1994). It forms a translucent acellular layer separating the oocyte from the surrounding granulosa cells. However, contact between granulosa cells and the oocyte is maintained via cytoplasmic processes, which penetrate the zona and form gap junction at the oocyte surface. Progressively, follicles become secondary follicles. In addition to oocyte growth and granulosa cell proliferation, the preantral follicle also increases in size through formation and growth of ovarian stromal cells on the outer membrane of the follicle forming the theca layers of the follicle. The thecal cells can be distinguished as two distinct layers: highly vascular theca interna, surrounded by a fibrous capsule, the theca externa. The granulosa cells continue to proliferate, resulting in a further increase in follicular size. The formation of the follicular antrum marks the beginning of the antral phase of development. The appearance of an antral cavity starts with the development of small fluid-filled cavities that aggregate to form the antrum. As the follicular antrum grows, the oocyte, surrounded by a dense mass of granulosa cells called the cumulus oophorus which become suspended in fluid. It is connected to the rim of peripheral granulosa cells only by a thin stalk of cells. Attached to the zona pellucida, which surrounds the oocyte, is a small ring of granulosa cells called the corona radiata, these cells will be expelled with the oocyte during ovulation. In humans and monkeys, follicles pass from the preantral to the early antral stage at a follicular diameter between 180 and 250 ÃŽ ¼m (Koering 1983; Bomsel-Helmreich et al. 1979). Further, growth of the follicle is under the influence of follicle stimulating hormone (Gougeon 1996). The follicle is then termed a Graafian follicle. When the proper ho rmonal balance is present, normally one Graafian follicle in mono-ovulatory mammals (e.g. primates, ruminants, equine) and several ones in poly-ovulatory animals (e.g. rodent, porcine) fully develop and the oocyte matures and ovulate (Hafez 1993). 1.4.4 Regulation of follicular development 1.4.4.1 Oocytes somatic cell communication Oocyte growth is dependent on signals, growth factors and nutrients from granulosa cells; at the same time oocytes play an important role in the proliferation and differentiation of granulosa cells. Communication between oocytes and somatic cells have a crucial role in ovarian follicular development (Albertini and Barrett 2003; Eppig 2001). Several studies have shown the importance of oocyte-derived factors such as growth and differentiation factor-9 (GDF-9) and bone morphogenetic protein-15 (BMP-15) in female reproduction. GDF-9 and BMP-15 promote the proliferation of granulosa cells from small antral follicles (Hayashi et al. 1999; Vitt et al. 2000; Otsuka et al. 2000). Mutation of the GDF-9 gene in mice prevented the development of somatic cells beyond the primary follicle stages (Dong et al. 1996). C-kit receptor or (Kit) is expressed at the surface of mammalian oocytes at all stages of follicular development in postnatal ovaries of the mouse, the rat and humans (Driancourt et al . 2000b; Horie et al. 1991; Manova et al. 1993). An in vivo study by (Yoshida et al. 1997) has indicated the requirement for C-kit in development of the ovarian follicle in mice. In this study, postnatal mice were injected with Kit-blocking antibody ACK2, and the first wave of follicular development was studied. The blockade of Kit signalling was found to disturb the onset of primordial follicle development, primary follicle growth and follicular fluid formation of preantral follicles (Yoshida et al. 1997). On the other hand, primordial follicle formation, ovulation and luteinization of the ovulated follicle were not affected by ACK2 (Yoshida et al. 1997). 1.4.4.2 Gonadotropins Before the onset of puberty, the normal fate of growing follicles is atresia. After puberty, stimulation by cyclic gonadotropins allows the survival and continued growth with only a limited number of antral follicles that will reach the preovulatory stage. Activation and maintenance of normal follicular function is dependent on gonadotropins secreted by the pituitary. Follicle stimulating hormone (FSH) and Luteinizing hormone (LH) are glycoprotein, secreted by gonadotrophs in the anterior pituitary under the influence of hypothalamic GnRH (Gonadotrophin releasing hormone) neurones, which regulate the synthesis and secretion of those hormones). Gonadotropins are probably not involved in the initiation of follicle growth (Wandji et al. 1992; Fortune et al. 2000; McNatty et al. 1999). Whilst there may not be an absolute requirement for FSH at these early stages the presence of FSH receptor (FSHr) in granulosa cells of immature follicles in cow (Wandji et al. 1992), human (Zheng et al. 1 996) and sheep (Eckery et al. 1997) suggests an involvement. A role for LH in the early stages of development has not been described, although expression of LH receptor (LHr) mRNA is first detected when the theca interna forms around the granulosa cells (Bao et al. 1998; Bao and Garverick 1998). FSH and LH are involved in endocrine control of follicle development, FSH stimulates granulosa cell division and the formation of glycosaminoglycans that are essential components of antral fluid (Hillier 1991). FSH is vital for the formation of the antral cavity (Nayudu and Osborn 1992) in mouse ovarian follicles cultured in vitro. Granulosa cells are the only cells in the female body possess FSH receptors, and binding of FSH to its receptor on the cell surface altered expression of multiple genes crucial to cytoproliferation and differentiation (Richards 1994). Granulosa cell genes that are responsive to FSH include: aromatase (P450arom) the steroidogenic cytochrome P450 crucial to estrogen synthesis (Simpson et al. 1994); cholesterol side-chain cleavage (P450scc) (Richards 1994) and LH receptors (Segaloff and Ascoli 1993). FSH and LH are important factors for the proliferation and survival of follicular somatic cells and the cyclic recruitment of antral follicles. Suppression of serum gonadotropins after hypophysectomy leads to atresia and apoptosis of developing follicles (Nahum et al. 1996). Whereas FSH treatment of cultured early antral follicles prevents the spontaneous onset of follicular apoptosis (Chun et al. 1996). Although FSH is the central regulator of dominant follicle survival and development, LH signalling pathways play fundamental physiological roles. LH-dependent signal pathways in the theca interstitial cells induce changes in gene expression that are critical for estrogen production (Erickson et al. 1985). Activation of the LH receptors in theca cells leads directly to the stimulation of high levels of androstenedione production. The major physiolog ical significance of this LH response is to provide aromatase substrate to the granulosa cells where it is metabolized by P450 aromatase to E2. Additionally, the preovulatory surge of LH is responsible for ovulation and corpus luteum formation. Also, LH is essential for P4 and E2 production by the CL during the early and midluteal phase of the menstrual cycle. The hypothalamus produces and secretes luteinizing hormone-releasing hormone (LHRH) into a system of blood vessels that link the hypothalamus and the pituitary gland. LHRH stimulates the pituitary gland by attaching to specific molecules (i.e., receptors). After the coupling of LHRH with these receptors, a cascade of biochemical events causes the pituitary gland to produce and secrete two hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH and FSH are two of a class of hormones commonly known as gonadotropins. They are secreted into the general circulation and attach to receptors on the ovary, where they trigger ovulation and stimulate ovarian production of the hormones estrogen and progesterone. Adapted from (Kanis 1994) 1.4.4.3 Growth factors A number of locally produced growth factors are known to be important for follicle development, they exert paracrine communication within follicles. During preantral follicle development, growth factors such as epidermal growth factor (EGF), transforming growth factors (TGF) may influence folliculogenesis (van den and Zhao 2005). Vascular endothelial growth factor (VEGF) (Danforth et al. 2003) and mullerian inhibitory substance (MIS) (McGee et al. 2001) have been reported to stimulate preantral follicle growth. It has been demonstrated that bone morphogenetic proteins (BMP) can alter bovine granulosa cell steroidogenesis and proliferation in vitro (Glister et al. 2004). Transforming growth factor-ÃŽ ² (TGF-ÃŽ ²) superfamily contains a range of proteins, including inhibins and activins. The precise roles of these factors are not known, but it is likely that they are involved in follicular differentiation by enhancing the action of gonadotropins (Campbell and Baird 2001; Knight and Gli ster 2001; Montgomery et al. 2001). Insulin growth factors (IGF) and their receptors play important role in follicle growth and development (Poretsky et al. 1999). The IGF family comprises of IGF peptides, IGF receptors which are family of proteins called insulin-like growth factor binding proteins (IGFBP) that regulate the availability of the IGF to their target cells, and IGFBP proteases (Giudice 1992). The IGFs affect biosynthetic processes in granulosa and theca cells and have an influence on mitotic activity in the granulosa cells (Giudice 1992; Poretsky et al. 1999). Additionally, a functional link between the IGF system and FSH action has been demonstrated by the finding that IGFBP-4 is a potent inhibitor of FSH