These Are the Hardest AP Classes and Tests for You

These Are the Hardest AP Classes and Tests for You SAT / ACT Prep Online Guides and Tips Thinking of signing up for AP classes? Want the greatest possible challenge? Or are you trying to avoid biting off more than you can chew? In this post, we’ll explain what makes an AP class hard, list the hardest AP classes, and help you prepare for them. What AP Passing Rates Tell Us You might think that the best way to tell which AP classes are the hardest is to look at the national data about how many students pass each test each year. We’ll start our discussion here, but beware that the passing rates don’t automatically tell you which classes are hardest. Want to get a perfect 5 on your AP exam and an A in class? We can help. PrepScholar Tutors is the world's best tutoring service. We combine world-class expert tutors with our proprietary teaching techniques. Our students have gotten A's on thousands of classes, perfect 5's on AP tests, and ludicrously high SAT Subject Test scores. Whether you need help with science, math, English, social science, or more, we've got you covered. Get better grades today with PrepScholar Tutors. This a complete list of passing rates on each AP exam with the most recent (2019) data. Exam Name Passing Rate (3+) Studio Art: Drawing 91.1% Spanish Language and Culture 89% Chinese Language and Culture 88.3% Studio Art: 2-D Design 86.4% Calculus BC 81.5% Physics C: Electricity Magnetism 81.1% Seminar 80.7% French Language and Culture 76.7% Research 76.2% Japanese Language and Culture 75% Computer Science Principles 72.7% Spanish Literature 71.9% Physics C: Mechanics 71.1% German Language and Culture 70.5% Studio Art: 3-D Design 70.1% Computer Science A 69.9% Microeconomics 68.4% Gov. and Politics - Comparative 66.2% Biology 64.6% Italian Language and Culture 64.6% Psychology 64.4% Art History 63.9% Physics 2 63.5% Music Theory 63.4% Latin 63.1% Statistics 59.2% European History 58.4% Calculus AB 58.3% Macroeconomics 57.9% World History 56% Gov. and Politics - United States 55.2% English Language and Composition 55.1% Chemistry 54.6% United States History 54.3% English Literature and Composition 50.1% Environmental Science 49.6% Human Geography 49.1% Physics 1 44.6% Source: College Board. For language rates, "Total" includes all students, while "Standard" includes only those students who didn't indicate they speak this language at home or spent more than four weeks studying it abroad. You might be tempted to look at this table and say the tests with the lowest passing rates are hardest, and the ones with the highest passing rates are easiest. After all, if not many students can pass an AP test, doesn’t that mean it’s one of the hardest tests? But when you look at the data, the exams with the highest passing rates (Chinese, Spanish, Calculus BC) are often considered among the hardest. We're not including AP Seminar and the AP Studio Art scores in this assessment, since those grades are all portfolio-based, rather than exam-based. Meanwhile, some of the tests with the lowest passing rates (Human Geography, US Government and Politics, Environmental Science) are often seen as the easiest. So what’s going on here? The truth is, the national passing rates often say more about the students taking the exams rather than the exams themselves. Some of the exams with low passing rates have those low rates because they are often taken in freshman/sophomore year, while some of the exams with high rates have more stringent prerequisites at many high schools. This means that the harder exams tend to have older, better-prepared students taking them, which raises their pass rates. In short, we have to look beyond national passing rates when figuring out which tests are the hardest. A Possibly More Reliable Indicator: 5 Rate Since pass rates don’t actually tell us much, what about the 5 rate? Remember, a 5 is the highest possible AP score (read more about AP scores here). Shouldn’t we be able to find the hardest AP tests by looking at the exams with the lowest 5 rates? Below is a table with all the AP exams, this time ranked by the percentage of test-takers who got a 5. Exam Name 5 Rate Chinese Language and Culture 57.2% Calculus BC 43.2% Japanese Language and Culture 38.2% Physics C: Electricity Magnetism 35.9% Physics C: Mechanics 34.6% Computer Science A 27% Spanish Language and Culture 24.9% Microeconomics 22.2% Gov. and Politics - Comparative 22.2% Studio Art: 2-D Design 21% Music Theory 20.9% Studio Art: Drawing 20.8% Psychology 20.2% Calculus AB 18.9% German Language and Culture 18.4% Macroeconomics 17.6% French Language and Culture 15.5% Statistics 14.5% Computer Science Principles 13.6% Latin 13.1% Gov. and Politics - United States 12.9% Physics 2 12.6% United States History 12.1% Art History 12% Italian Language and Culture 11.8% European History 11.7% Research 10.8% Chemistry 10.7% Human Geography 10.7% English Language and Composition 10.1% Studio Art: 3-D Design 10.1% Environmental Science 9.5% Spanish Literature 9.1% World History 8.7% Biology 7.1% Seminar 6.8% English Literature and Composition 6.2% Physics 1 6.2% Source: College Board. For language rates, "Total" includes all students, while "Standard" includes only those students who didn't indicate they speak this language at home or spent more than four weeks studying it abroad. The 5 rate, in fact, a decent way to spot some difficult exams, including AP English Literature and Biology. They both have very low 5 rates (7.1 for Bio, 6.2 for English Lit). But on the flip side, a relatively easy exam, AP Environmental Science, has a low 5 rate of 9.5%. Furthermore, some decidedly hard exams, like Chinese, Calculus BC, and Physics C, have very high 5 rates- up to 57%+ for Chinese! In other words, just looking at 5 rates doesn’t tell the whole story, though some other articles have assumed that. This is why the best way to find the hardest AP exams is to focus on the ones with the most material to cover- as well as the most conceptually difficult topics, which we will do below. Disclaimer: Take Into Account Your School’s Variation Before we talk about which classes are the hardest, we want to clarify we mean the ones with the most difficult course material and hardest end-of-year exam. There is enormous variation in how the same AP class can be taught at different high schools, so we can't speak to the specific class difficulties at your high school. It may be there is an AP class at your school that is known as the most difficult since the teacher is really tough, even though nationally it might not be considered one of the easiest. Or maybe there is an AP class at your school most students see as a joke, even though the material is still very difficult. Since we can’t report on the specifics at different high schools, we are focusing on which classes have the most/hardest material to cover and have a reputation for difficulty at multiple schools. We’ll discuss below ways to explore how hard AP classes are at your school specifically so you can build an optimal schedule. Any AP class Professor McGonagall teaches would likely be super hard. Okay, Seriously, Which AP Classes Are the Hardest? United States History, Biology, English Literature, Calculus BC, Physics C, and Chemistry are often named as the hardest AP classes and tests. These classes have large curriculums, tough tests, and conceptually difficult material. We put together this list based on personal experience, online chatter, passing rates, 5 rates, and looking at their curricula in depth. We are not ranking these since their difficulty will vary quite a bit based on the student. For example, if you're a math whiz, Calculus BC will likely be easier than AP English Literature. But the opposite could be true for another student. But if you’re considering any of these, be prepared for a tough course! AP US History Even though most students are exposed to American History multiple times, beginning in elementary school, AP US History is still a very tough class. First of all, this is a harder history exam than AP World History or even AP European History, since it covers a narrower span of history and a smaller geographical area, meaning the curriculum is incredibly detailed. This means you can’t rely on general trends and observations like you can sometimes in World History- you have to know specific dates, movements, people, and laws. To take a small example, in a world history class, you might need to know that slavery ended in the United States during the Civil War. For a US history class, you would need to know the dates of the civil war, the exact year of the Emancipation Proclamation, and the dates and content of the 13th, 14th, and 15th amendments. You would also be expected to know about the major leaders and law-makers involved. The more detail you can remember, the better! This is because APUSH is known for having a very difficult multiple-choice section that requires a very detailed knowledge of US History from the pre-Columbian era up to the present day. Also, the more concrete evidence you can include in your free responses, the better essay scores you will get. If you have a knack for history, this class will be easier for you, but most students report it’s very challenging. It’s also likely to be a hard class to pass at many schools because teachers have to assign tons of reading and assignments to get through all the material before the AP test in May. Expect a fast-moving, assignment-heavy course. You can read College Board's full description here. If you think this is a figure from American History, you might want to consider fitting AP US History into your schedule. AP Biology This is a tough class and test, any way you slice it. Even with the redesign back in 2012, which was meant to make AP Biology more accessible and less memorization-heavy, you still have to memorize tons of material for the test, everything from super detailed chemical processes (Krebs Cycle, anyone?) to cell biology to evolution. This means AP Biology teachers have to pack a ton onto their syllabi for this class, including time for experiments. The huge volume of info, coupled with the fact that Biology can be conceptually difficult, makes this a tough AP course. If you have taken a strong prerequisite Intro to Biology course, this test will be more manageable. Check out a full course description here to learn more. AP English Literature Along with AP US History, this is one of the hardest AP courses in the humanities. While AP English Language is also challenging, Literature requires reading texts that are generally more difficult. Compare, say, AP English Literature staple Crime and Punishment to a non-fiction article about the criminal justice system you might read in AP English Language. Crime and Punishment is much more difficult! AP English Literature also tests more specific rhetorical/literary terms and requires you to have a more fine-tuned ability to close read a passage. You’re not just looking for the overall argument or effect like you are in AP English Language. You have to go under the hood and explain in detail how a piece of literature works. Finally, for AP Literature, you have to come prepared to write one of the essays about a book or play you read in class, but you can't actually bring the book or play with you to the exam. This means you have to study what you read in AP Literature very closely. So closely that you could write about a book, and even use quotes from it, without having the book with you! SparkNotes summaries won't cut it. In short, expect a longer and harder reading list, tougher multiple-choice questions, and more accountability for what you read in class. You can read the full College Board description of the test here. AP Chemistry Similar to biology, chemistry has a ton of material, lots of memorization, and requires a solid conceptual understanding of complicated chemical processes. AP Chemistry is known at many high schools for having tons of homework and tough tests- all necessary for students to learn enough to pass the AP exam at the end of the year. Don't attempt AP Chemistry unless you have already taken an introductory chemistry course. It would be impossible to learn everything you need to know about chemistry for the AP exam in just one year. You can read AP’s full course description here. AP Physics C Physics C is especially tough because not only are you learning physics material, which can be hard, you also need to know calculus alongside it. While AP Physics 1 and 2 are algebra-based, both Physics C courses (Electricity Magnetism and Mechanics) are calculus-based, meaning students need to know calculus well enough to apply it in physics. Some consider it â€Å"two classes in one† due to the necessary calculus knowledge. Furthermore, the material tested in Physics C is much more in-depth than Physics 1 or 2 (or the old Physics B). Physics C courses go into a great amount of depth about a few topics, while Physics 1 and 2 cover many topics with less depth. So just as US History is harder than World History, Physics C is tougher than Physics 1 and 2 because you need a greater depth of knowledge. Because of this, you should definitely have a physics prerequisite under your belt before taking Physics C, and you should have either already taken calculus or be taking it at the same time. You can read about Physics C at the course home pages for Electricity and Magnetism and Mechanics. AP Calculus BC Finally, AP Calculus BC is the toughest AP math exam, if not one of the hardest AP exams period. AP Calculus AB is also challenging, but covers less material and moves more slowly. AP Calculus BC often covers everything taught in Calculus AB in just the first semester of school- revealing one reason why it’s so hard: intense pacing. You move fast in Calculus BC, which means you need to be prepared to keep up. There is not a lot of time to be lost in this class. If you struggle with a concept at the beginning of the year, it can make it harder to learn everything after that. In fact, if you find yourself struggling, seek out extra help from the teacher or a tutor as fast as you can so you don't fall behind. In some schools, Calculus BC requires an extra period in the day to fit in all the material before the AP exam. You also get into more conceptually difficult calculus topics than Calculus AB. In short, be prepared to work very hard and be vigilant about keeping up with the course. You can read College Board’s description here. Want to get a perfect 5 on your AP exam and an A in class? We can help. PrepScholar Tutors is the world's best tutoring service. We combine world-class expert tutors with our proprietary teaching techniques. Our students have gotten A's on thousands of classes, perfect 5's on AP tests, and ludicrously high SAT Subject Test scores. Whether you need help with science, math, English, social science, or more, we've got you covered. Get better grades today with PrepScholar Tutors. Note on Language AP Exams You may be wondering how hard the AP language tests are- after all, you can take AP tests in languages from Chinese to Spanish to French. The difficulty of these is a bit tougher to quantify, since AP Language exams test multiple years of learning a language, as opposed to one year of material. For students with tons of foreign language knowledge these can be incredibly easy exams. If you’ve lived abroad or are fluent in a language, the AP language test will not pose much of a challenge. (Some students who are native speakers of a language will even take an AP language exam!) But for students who have just been taking a language in school, these exams can be difficult, particularly the listening portions. So if you’re thinking about an AP Language class, think about how many years of past experience you have. For example, if you’ve taken French for four years, you’re probably well-prepared for AP French. But if you’ve only taken it for two years, you will probably struggle. Most schools have pretty stringent prerequisites for AP language classes for this reason. Action Steps If you want to take any of these classes, you need to get info about the class at your school. Although they are all objectively difficult, there can be huge differences in how the classes are taught and graded. Ideally, these classes should be taught by excellent teachers who can not just teach the material clearly, but include plenty of review and AP exam practice. You should also think about your own strengths and weaknesses, and how well a tough AP class will fit into your schedule. Even though all of these AP classes have tough material, the difficulty of the class might vary from school to school. The class itself could be incredibly difficult (lots of assignments, reading, and hard tests)- and you should be prepared for that. However, the class could also be easy (not very many assignments, easy tests), meaning you will have to put in a lot of work on your own to be ready for the AP test. Knowing what the class’s workload is like, and how that prepares you for the exam, is crucial to being prepared once May arrives. If the class is easy and you don't actually learn the material, you could fail the test despite getting good grades in the class. The bottom line here is that you’ll have to work very hard to succeed in any of these classes. But that work could come at the behest of a teacher or from your own willpower. If you don't think you're learning the material well enough in class to pass the test, consider getting a prep book and studying on your own in the second half of the year. Get Info About a Class To get info about an AP class, first talk to your guidance counselor. Ask for the class's syllabus, the class’s passing rate on the AP exam for the last few years, and what other students tend to say about the class. This will give you an idea of how well-taught a class is. Your guidance counselor can also recommend good prerequisite classes and teachers. Next, speak to the teacher if you can, or speak to a teacher you have who teaches the prerequisite class (for example, the Honors Biology teacher if you’re thinking about AP Biology). The teacher can give you a sense of what the workload is like, what they expect of their students, and how much work they expect students to do on their own. Finally, find out what the word of mouth for the class is at your school by talking to older students. Don't rely too much on any one person's opinion, because students can exaggerate, but look for general trends. For example, if everyone says that AP Biology is really hard but they learned a lot and passed the AP exam, that's a sign the class is worth taking. Think About Your Strengths If you tend to do well in a subject, you will likely do well in a corresponding AP class, even if it's one of the hard ones. For example, even though AP Biology is hard, if you’ve done well in previous science classes, have a knack for memorization and critical thinking, you might be better prepared for AP Biology than, say, AP European History, even though that’s not seen as one of the hardest AP classes. On the flipside, if you really struggle with something- like writing or math- you need to be extra careful about taking a tough AP class like AP English Literature or AP Calculus BC. We’re not saying to avoid those classes if you think you might have a hard time. We are saying to be prepared to spend lots of time studying! Think About Your Overall Schedule How well you do in a hard AP class could also depend on your schedule. For example, AP Biology might be more feasible your sophomore or senior year since you won’t be worrying about the ACT/SAT. However, if you take it junior year, you might have a hard time balancing ACT or SAT studying with the AP Biology class. Also consider other classes, your extracurricular commitments, work schedule, and family commitments before signing up for any of these AP classes. You don't want a tough AP class to overload an already busy schedule. Along the same lines, do not feel pressured to overload on AP classes in general. More is not necessarily better, even if there is pressure at your school to take 5 AP classes in one year. It’s better to get two 4s than four 2s! And it's better to take AP classes that are interesting and meaningful to you. What’s Next? Find out about the flipside of this discussion, the easiest AP classes. Also read about how many AP classes you should be taking total. Also studying for the ACT/SAT? Come up with a target ACT or SAT score based on your top schools. When’s the ideal time in your high school career to take the ACT/SAT? Find out here. Want to improve your SAT score by 160 points or your ACT score by 4 points? We've written a guide for each test about the top 5 strategies you must be using to have a shot at improving your score. Download it for free now:

Discussion On Non-cargo Claims Case Study Example | Topics and Well Written Essays - 1500 words

Discussion On Non-cargo Claims - Case Study Example Loading and unloading of cargoes in piers must be fast and efficient. Parties who cause the slow pace of the turn-over of those goods do not contribute to the smooth movement of harbor activities and must be penalized. Imposing the sanctions will be an incentive for shippers, consigners, and other parties to make use of port facilities and equipment with the needed efficiency especially within the context of global modernization. Cargo owners are therefore charged with the duty to see the expeditious and orderly loading and unloading of their merchandise and are liable to pay demurrage for any delay in that connection. The payment of such demurrage may not be imposed only in cases of fortuitous or unforeseen events and force majeure or in instances where the guilty party is the carrier which includes its ship captain or master. (Becerra, Robert J. THE DEMURRAGE DILEMMA. December 24, 2007. ShippingDigest. [internet]). In the case at bar, the guilty party is the master of Flying Dustma n and his accountability to compensate for the damage is solidary with the owner of the ship. Horatio has thus nothing to do with the demurrage. It must be importantly noted that the contract between O and Horatio is one of voyage charter where the legal obligations are the burden of the carrier or the shipowner. These accountabilities cover the men and crew of the vessel including the master or the captain. (Compare and contrast the duties, responsibilities, and liabilities of the charterer towards the shipowner under both time and voyage charter parties. LAW ESSAYS UK. the law essay website. [internet]) The execution of the LOF with SCOPIC appurtenant to the Flying Dustman relating to both salvage contractors Pugwash and Saviour does not have any bearing on the possible controversy because the vessel to be salvaged, Flying Dustman, or O, its owner, evidently failed to provide the initial security required by No. 4 of the SCOPIC CLAUSE of SCOPIC 2007 within two working or office da ys from the time that the said SCOPIC CLAUSE was invoked. (SCOPIC CLAUSE. SCOPIC 2007. [internet]) Under this set of facts, Pugwash and Saviour, may opt or choose not to apply the provisions of the said SCOPIC CLAUSE in its totality and may instead go back to the provisions of any subsisting contract in conjunction with Article 14 of the International Convention on Salvage, 1989 (also herein referred to as Convention for brevity) which defines, delineates and enumerates the terms of a special compensation available to salvors or salvage contractors. (Article 14. Special compensation. Chapter III RIGHTS OF SALVORS. International Convention on Salvage, 1989. Admiralty and Maritime Law Guide. International Conventions. [internet]) The rights of the salvors are clearly outlined in the above-cited Convention. At this juncture, it has to be mentioned that the parties are all citizens or subjects of states parties which are likewise members of the International Maritime Organization. The l atter enacted the Convention. The states parties involved are the United States from where the cargoes came and the United Kingdom because of its territory Monserrat where the goods are to be delivered.

Bilateral Trade in the Economies of Various Countries Essay

Bilateral Trade in the Economies of Various Countries - Essay Example Trade flows from traditional partners is becoming complicated. This means that distance is also an important factor in the bilateral trade. Bilateral trade plays an important role in the economies of various countries. However, a country’s trade with another or others depends on a number of factors. Due to the developments in bilateral trade such as regional integration are major factors (Brun, Carrere and Guillaumont 99). These coupled with the distance between trading partners they impact on bilateral trade. These forces countries to find viable options that help attract trade flow. This study analyses USA’s situation with relation to its traditional trade partners from Europe, Asia, Africa and South America. The countries used in this study were selected on the basis of their GDP, exports volume and traditional trading activities with the USA. As a result, bilateral trade flows’ gravity model is estimated between the USA and its trading partners for the periods 1990 and 2011. The general hypothesis is: The gravity equation is considered probably the most applied empirical trade device for more than a decade now. Its main advantage is that when it is applied to extensive variety factors and goods moving across national and regional borders under varying circumstances, it always produces a good fit (Anderson and Eric 170). This makes it an ideal device for econometric methods of measuring trade. Nonetheless, with the emergence of new economic theory, advancement in international trade, and globalization, a unique empirical application of the model with respect to a country’s GDP and export capability in bilateral trade is required. The Gravity trade model helps in predicting the flows of the bilateral trade and these predictions are with the distance between units in their respective  economic directions as the basis of prediction. The model can be applied in various circumstances to provide an explanation in the flow of commodities on the international scale (Anderson 106).  

donepezil hydrochloride

donepezil hydrochloride Abstract- This article describes the discovery processes of donepezil hydrochloride which is inhibitor of acetylcholinesterase enzyme. Cholinergic hypothesis and other studies proved that deterioration in cognitive functions in Alzheimer disease is due to deficit in cholinergic neurotransmission and target to treat Alzheimer disease is to inhibit acetylcholinesterase enzyme. Position emission tomography (PET) study has shown that donepezil distributes in all acetylcholineterase rich brain regions and binds to it. Structure activity relationship (SAR) and quantitative structure activity relationship (QSAR) has also revealed that donepezil hydrochloride is gives optimum actylcholinesterase inhibition activity than its other analogues. Many methods are available for synthesis of donepezil hydrochloride with their merits and demerits. Keywords- Donepezil hydrochloride, Aricept, acetylcholinesterase inhibitors, PET study, indanone derivatives. Abbrevations AD(Alzheimer disease), PET(position emission tomography), QSAR(quantitative structure activity relationship), Acetylcholinesterase inhibitor(AchEI), Aim To study different processes involved in drug discovery of Donepezil hydrochloride. Objectives- The main Objectives of this project are given below To study overall literature review of donepezil hydrochloride . To discuss discovery process involved in discovery of donepezil hydrochloride such as target identification, target validation and lead optimization Introduction- Donepezil hydrochloride is the reversible acetylcholinesterase enzyme inhibitor having N-benzylpiperidine and indanone moiety in it (Sugimoto Hachiro et al, 2008). It is referred as E2020 in most of the pharmaceutical literatures. This is the second drug approved by U.S FDA for treatement mild and moderate Alzheimer disease (Stahl Stephen M et al, 2006). It is Patented and marketed in United states of America, some European and Asian countries under the trade name Aricept by Eisai.co.,Ltd (Stahl Stephen M et al, 2006) (Tripathi KD , 2006) (Dale Rang H et al, 2006). Drug Discovery of donepezil- The drug discovery process of donepezil involves various phases as follows Target identification Target validation Lead recognition Lead optimization Target identification Target identification of drug means molecular recognition of site to which it will bind. For many drugs target is protein molecules. Target identification needs information about pathophysiology of disease and identification of particular biochemical steps that leads to therapeutic intervention. Conventional stratergies of target identification are mainly based on pathphysiology of disease. But newer stratergies of target of identification are based on proteonomics and genomics (Rang H PB et al, 2006). About 50-60% of Alzheimer disease patient are of over 65 year age (Sugimoto Hachiro et al, 2006). It is the neurodegenerative disorder with mean duration of 8.5 years between onset of action and death of patient (Sugimoto Hachiro et al, 2006). Symtoms of this disease includes gross and progressive impairement of cognitive functions. The most affected areas in the alzheimers disease are hippocampus and neocortex which are important for mental functions. Pathophysiology of disease consis ts of external deposits of amyloid precursors and intracellular formation of neurofibrillary tangles leads to neuronal synapses loss (Francis Paul T et al, 1999) Beta amyloid is the main component of sensile plaque formed by proteolysis of amyloid precursor proteins. Tangles are abnormally hyperphosphorylated tau proteins and regulated by balance between multiple kinases and phosphates. Hyperphosphorylation of tau proteins carry out sequestration of normal tau and other microtubule associated protein leads to impairment of axonal transport. This tau becomes prone to aggregation into insoluble fibril in tangles (Bartonili Manuala et al, 2003) (Andrisano Vincenza et al, 2003) According to cholinergic hypothesis, deterioration in cognitive functions in Alzheimer disease is due to degeneration of cholinergic neuron into forebrain and consequently decreased cholinergic neurotransmission in cerebral cortex and hippocampus (Francis Paul T et al 1999). Cholinergic neuron synthesizes acetylcholine, which is the acetic acid ester of choline. Acetylcholine is synthesized from the acetic acid and choline with the help of cholineacetylase. After stimuli vesicles discharge acetylcholine at the nerve ending and binds to postsynaptic receptors. Acetylcholine is stored into the synaptic vesicles which are accumulated at the nerve endings, also prevents its hydrolysis. Acetylcholine is hydrolises by acetylcholinesterase into acetic acid and choline(Tripathi KD 2006). Thus in Alzheimer disease cholinergic neurotransmission can be enhanced by inhibiting preventing the hydrolysis of acetylcholine, choline precursor,acetylcholine release facilitators ,M1 and M3 agonists ,Nicotinic agonistics but all these drugs were not effective to improve cognitive function in Alzheimer disease except cholinesterase inhibitors. Cholinesterase drugs have shown significant improvement in cognitive functions of Alzheimer disease. This has proved that cholinestera se inhibition is the main target to improve cognitive functions in Alzheimer disease (Sabbagha Marwan N et al, 2008) (Fisher Abraham et al, 2008). Target validation of donepezil- Target validation is the investigational approach by which potential drug target can be tested and given further reliability. Target validation is pharmaceutical approach in which influence of drug is observed. (Rang H PB et al, 2006). According to cholinergic and other studies acetylcholinesterase inhibition is the main target to improve imrove cogntitive functions in alzheimer disease patient. Okamaru Nobuyuki et al studied invivo binding of donepezil in the brain of alzheimer disease patient. They radiolabled donepezil as [11c-methoxy]-donepezil for position emission tomography imaging. Evaluation of binding and distribution of donepezil performed on mild and moderate Alzheimer disease patients. Normal control group volunteers had neither cognitive function impairements nor cerebrovascular lesions on magnetic resonance. PET study carried out after three months of neuropsychological medical examination. Region of interest analysis was carried for validation of regional distrubution of donepezil. PET images demonstrated that high volume of [11C]-donepezil distributed in all regions of brain like striatum, thalamus, striatum, and neocortex which are rich in acetylcholinesterase. Tissue time curves of [c11] -donipezil shown initial rapid uptake of donepezil in brain followed by gradual clearance in both elderly normal and alzheimer disease patients. Specific distribution volume was calculated from region of interest by metabolite corrected plasma time activity curve. Donezpezil shown linear regression on logan plot analysis in all brain region as shown in figure -1. (Okamura Nobuyuki et al, 2008) (Yanai Kazuhiko et al, 2003) Lead generation A lead compound is a new chemical entity that could potentialy developed into new drug by optimizing its valuable and minimizing side effect. High throught screening is mainly used for lead generation(Rang H P et al, 2006). Many drugs were trialed to improve the cognitive functions in Alzheimer disease like cholinergic agonist such as oxetremorine, choline precursor phosphatidylcholine but that were inffective. Numerous clinical trials carried out on acetylcholinesterase inhibitors such as physostigmine, this trial shown that this class of drug resulted in improvement of cognitive functions in Alzheimer disease patients. However these clinical trials also proved that physostigmine has poor brain Penetration and thus less active (Muramoto,M et al, 1979). In 1981 summers et.al gave intravenous injection of tacrine to Alzheimer disease patients which were until that time used as antiseptic. These doses of tacrine shown measurable improvement in alzheimer symtoms but tacrine had shown ma ny side effects such as hepatotoxicity( Farlow SI et al, 1992). Later then scientist focused on development of new acetylcholinesterase inhibitors. Research and development of donepezil started in 1983 in Eisai .co .Ltd. Kawakami et al started to develop nontoxic tacrine derivatives but they failed to develop such tacrine derivative. While random screening scientists observed that N-benzylpiperazine (compound-A) has moderate anticholinesterase activity which was previously being synthesized for antiarterial sclerosis(Kawakami Yoshiyuki et al 2000)). During subsequent screening Kawakami et al used benzylpiperazine as seed compound and synthesized around 700 derivatives. Succeeding this experiment, it was observed that increase in acetylcholinesterase activity by replacing n-benzylpiperazine with N-benzylpiperidine moiety(compound-B). It was also found that slightly increase in activity by replacing ether group with amide group(compound-C) and removal of nitro group from benzamide moeity (compound-D) decreases activity. ((Kawakami Yoshiyuki et al 2 000). From these results Kawakami et al synthesized benzsulfonyl derivative and found that it is a most potent acetylcholinesterase inhibitor than benzpiperazine derivative. Benzsulfonyl derivarive showed very selective activity towards acetylcholinesterase but very poor bioavaibility. On the basis of this result they used benzoylsulfonyl derivative as lead compound. In next screening they replaced amide moiety with ketone moiety and maintained activity. Then Kawakami et al synthesized various indanone derivatives among them he found that donepezil has good acetylcholinesterase activity and bioavaibility(Sugimoto Hachiro et al, 1992). STRUCTURE ACTIVITY RELATIONSHIP OF DONEPEZIL Indananone derivatives were tested on rat for acetylcholinesterase inhibition activity according to method of Ellman et al. donepezil structure is divided into four rings as follows. Part 1- Indanone ring Part 2 -linkage moeity Part 3- piperidine moeity Part4 -benzyl moiety Modification at Indanone moeity If indanone moeity is replaced with ÃŽ ±-tetralone ,1-benzene suberone , 5,6 dimethoxy indene greately decreased activity ,while 25 fold increased activity by introducing methxy group at 5,6 position of indanone moeity .Carbonyl group is important for activity.Introduction of methoxy group at R3 position increase in activity by 20 fold .A methoxy group at R4 position increases activityby 10 fold . also slightly increase in activity on substitution to of methoxy group at para position in the benzoyl group moeity enhanced binding to the active site of acetylcholinesterase enzyme(Camps Pelayo et al, 2008). 2) Modification at linkage moiety- Various bridging group between indanone and piperidine moeity were tested for cholinesterase activity. If both indanone and piperidine rings joined directly then it dicreases activity .Increase in acivity with different bridging group in the following order prophylene >methylene>penthylene> ethylene >butylenes. (Sugimoto Hachiro et al , 1990). (3)Modification at piperidine moeity- Activity is depend on location and no of nitrogen atom .Nitrogen atom at 1-position of benzpiperidine is important for activity since N atom at 4-position of benzpiperidine decreases activity .If piperidine ring is replaced with piperazine moeity .then it dicreases activity(Sugimoto Hachiro et al, 2008). 4)Modification at benzyl moeity- 3-position substituted benzyl derivative showed greater activity among -2,-3,-4, substituted reioisomers .If benzene ring is substituted with electron withdrawing nitrogen group and electron donating methyl group shows similar activity .Replacement of benzyl group with phenylethyl group and 2-napthyl group decreased activity(.Kawakami Yoshiyuki et al, 2000)( Sugimoto Hachiro et al, 1990). Lead development of donepezil Once lead compound is identified then it is optimized and characterized for different aspects such as QSAR (quantitative structure activity relationship), SAR(structure activity relationship),synthesis method . Synthesis of donepezil If any compound shows optimum activity in above lead optimization processes then that compounds enter in further stage of lead optimization process. For physicochemical properties, pharmacokinetic, pharmacokidynamic study of lead compound highly purified and large amount of drug is required. Therefore synthesis method for lead compound is important. Sugimoto and co-workers discovered method for synthesis of donezepil with an overall yield of 27.4%. This process involves synthesis of ÃŽ ±, ÃŽ ² substituted ketones(compound 11) from 1-indanone by aldol condensation. This unsaturation product is catalytically reduced by Palladium to compound (13) but this method needs subzero temperature (-78%) and very toxic chemicals, such as n- butyl litium.( Tsuchiya Yutaka, 1992). Also many other method have been reported, which are too time consuming or not suitable for large scale production. Stephen discovered efficient synthesis method for donepezil and its analogue. This method involves hydrogenation of pyridine analogues ( compound 7) by using platinum oxide [scheme 2, path A] which is very expensive .If platinum oxide replace with less expensive 5% palladium carbon then it synthesizes compound (8) and compound (11).(US patent 6252081). Chandrashekhar R et al developed economical and efficient method for donepezil synthesis (scheme 2, path ÃŽ ²). In first step they condensed 5,6 dimethoxy -1-indan 1-one [ compound 2] with isonicotinaldehyde compound(3) by modification in standard procedure .By this condensation they formed intermediate compound (6) with 95.8% yield. Afterward he carried out hydrogenation of pyridine ring by using palladium carbon then he observed two main impurities compound (9) and compound (10) due to competitive side reaction of carb onyl ring. In this method they not only maintained different reaction conditions like reaction time, hydrogen pressure, and different solvent but also hydrogenated compound (6) in methanol under hydrogen pressure with 90% yield and 98.5% purity. Final step of donepezil involves benzylation of compound (8). In benzylation nature of solvent and quality benzylbromide plays important role in controlling dibenzyl product ( Elati Chandrashekar R et al, 2006). If acetone, dichloromethane, acetonitril, isopropylether and dichloromethane gives very poor yield. Conclusion- In conclusion donepezil hydrochloride is the novel and efficacious cholinesterase inhibitor than other acetylchlinesterase inhibitors. Cholinergic hypothesis shown that cholinergic degradation is the main reason for Alzheimer isease. By target validation it is also proved that donepezil bind to the acetyl cholinesterase and inhibits it. By the target validation it is also proved that donepezil inhibits cholinesterase mainly into the cortical and other areas where high concentration of cholinesterase is situated Is Donepezil has strongly proved cholinergic hypothesis and Also shown that cholineterse inhibition is the main target for treatement of alzimer disease than acetylcholine agonists and acetylcholine precursor. After different structure replacement and attachment to the lead compound of donepezil it is also proved that donepezil has good specificity and activity than other analogues .QSAR study of donepezil and its analogues also shown that donepezil is strongly binds to cholin esterase than other indanone derivatives. Sugimoto and their co workers also synthesized different pyridine and indanone derivatives they also got good efficacy of the results . For donepezil synthesis different methods have been developed all have some disadvantages and problems regarding hydrogenation step. But chandrashekhar elati et al method has overcome this problems by modifying synthesis methods. Acknowledgement- I thanks to Dr Kevine Devine, Dr Annie Bligh, Dr Dhaya Perumal for their guidance to study drug discovery technology module and prepare project(Dissitation) on donepezil discovery processes.

Berkshire Hathaway Essay

ISSUES Warren Buffet invoked the substance-over-form concept to justify accounting for the GEICO and General Foods transactions as dividends distributions rather than sales of stock. Do you agree with Buffet that the substance of each of the proportionate redemptions was a dividend and not a sale of stock? In deciding how to account for an unusual or unique transaction for financial reporting purposes, should one consider the tax treatment applied to the transaction? Did Peat Marwick have a right to change its position on the proper accounting treatment for the stock redemptions? What factor or factors may have been responsible for Peat Marwick’s decision to change its position regarding these transactions? FACTS In 1983, GEICO announced plans to purchase several million shares of its outstanding common stock for $60 per share. Among GEICO’s largest stockholders was Berkshire Hathaway, Inc., an investment company. Executives of the two companies decided that Berkshire would tender approximately 350,000 if its GEICO shares in the stock buyback plan, which would allow Berkshire to treat the transaction as a proportionate redemption. In a proportionate redemption, the percentage equity interest of on company in a second company is maintained at the level that existed immediately before the transaction. For federal taxation purposes, the proceeds received by the investor company in a proportionate redemption are taxed as dividends by applying the effective intercorporate dividend tax rate. In 1983, that tax rate was approximately 6.9 percent. Berkshire also chose to treat the proceeds from the redemption of the GEICO stock as dividend income in its 1983 financial statements. Berkshire’s audit firm, Marwick, Mitchell & Company, approved that accounting treatment. In 1984, another company in which Berkshire had a significant equity interest,  General Foods, announced a stock buyback plan. Again, Berkshire structured the sale of stock to General Foods so that the transaction qualified as a proportionate redemption. Berkshire also opted to report the proceeds received from General Foods as dividend income in its 1984 financial statements. In late 1984, representatives of Peat Marwick told Berkshire executives that the proceeds of the General Foods stock redemption should not be considered dividend income for financial reporting purposes. Instead, Peat Marwick maintained that the transaction should be recorded as a sale of stock with the difference between the selling price and cost reported as a capital gain on Berkshire’s income statement. This treatment of the transaction was less favorable for financial reporting purposes that the option preferred by Berkshire since it did not allow the total proceeds received from General Foods to be reported as revenue. Peat Marwick’s recommendation annoyed Berkshire’s executives. The accounting firm’s next decision irritated those executives even more. Marwick insisted that Berkshire restate its 1983 financial statements to reflect the GECICO stock redemption as a sale of stock rather than as a dividend distribution. Warren Buffet, Berkshire’s CEO, discussed the GEICO and General Foods stock redemption at length in his company’s 1984 annual report. Buffet disputed Peat Marwick’s contention that the transactions should be treated as sales of stock and not as dividend distributions. He then explained why he eventually agreed to accept the audit firm’s position by saying â€Å"†¦to avoid a qualified auditor’s opinion, we have adopted Peat Marwick’s 1984 view and restated 1983 accordingly.† Buffet as confirmed that Marwick’s decision had no effect on Berkshire’s business with GEICO or General Foods, their cash, taxes, and market value and tax basis of our holdings all remain the same. However, treating the General Foods transaction as a sale of stock reduced Berkshire’s 1984 net income by 8 percent. Applying that accounting treatment to the 1983 GEICO transaction reduced Berkshire’s previously reported net income for 19 83 by 1 percent. The Wall Street Journal reported the disagreement between Berkshire  executives and Peat Marwick that evolved from the proportionate redemption transactions. When asked to comment on Buffet’s criticism of Peat Marwick in his company’s 1984 annual report, a Peat Marwick partner simply noted, â€Å"It’s the client’s prerogative to disagree. Our report speaks for itself.† Another prerogative of an audit client is to change auditors. In 1985, Berkshire retained Touche Ross & Company to audit its financial statements. As required by the Securities and Exchange Commission, Berkshire filed an 8-K statement with that federal agency to disclose the change in auditors. In that statement, Berkshire reported it was â€Å"dissatisfied† with Peat Marwick’s inconsistency regarding the proper accounting treatment for stock redemptions. AUTHORITY/ANALYSIS The substance over form accounting concept means that the economic substance of transactions and events must be recorded in the financial statements rather than just their legal form in order to present a true and fair view of the affairs of the entity. Preparers of the financial statements should use their judgment when employing the substance over form concept, which helps to derive the business sense from the transactions and events and to present them in a manner that best reflects their true essence. In some instances the legal aspects of transactions and events may have to be disregarded in order to provide more useful and relevant information to the users of financial statements. The concept of substance over form is imperative to the representation and reliability of information contained in the financial statements. A proportionate stock redemption is a transaction in which ownership interests are redeemed proportionate to the total shares outstanding. As a result, each shareholder owns the same percentage of the company after the redemption as before. Buffet was justified in recording each of the proportionate redemptions as a dividend and not as a sale of stock, because although GEICO and General Foods repurchased their stocks, Berkshire still maintained the same percentage of equity interest as it did before the transaction. Also, Buffet followed federal taxation purposes, which stated  that the proceeds received by the investor company in a proportionate redemption are taxed as dividends; therefore the transaction was recorded as dividends not sale of stock. By placing the responsibility on the preparers of the financial statements to actively consider the economic reality of transactions and events to be reflected in the financial statements, it will be more difficult for the preparers to justify the accounting of transactions in a manner that does fairly reflect the substance of the situation. According to the PCAOB’s AU Section 316.66, â€Å"†¦the auditor may become aware of significant transactions that are outside the normal course of business for the entity, or that otherwise appear to be unusual given the auditor’s understanding of the entity and its environment. The auditor should gain an understanding of the business rationale for such transactions and whether that rational (or the lack thereof) suggests that the transactions may have been entered into to engage in fraudulent financial reporting or conceal misappropriation of assets.† (PCAOB, 2002) AU Section 314.21 states that the auditors’ understanding of the entity and its environment consists of an understanding of several aspects, including industry, regulatory, and other external factors (PCAOB, 2002). Taxation would be an example of the regulatory aspect; therefore, one should consider the tax treatment when deciding how to account for unusual transactions. In the case of Berkshire Hathaway, Inc., since the IRS considers proportionate redemptions to be equivalent to dividend distributions, and the proceeds from the repurchasing of stock are taxed as dividends; to ensure consistency, the transaction should have been recorded as dividends. The PCAOB states that the auditor should recognize an adjustment to correct a misstatement in previously issued financial statements to ensure the company’s financial statements remain consistent in the auditor’s report, especially if the matter has a material effect on the financial statements (PCAOB, AU 508.16, 2004). Since Peat Marwick was the auditing firm, it had the right to change its position on the proper accounting treatment for the stock redemptions, and since Berkshire wanted to preserve the unqualified  opinion, the company complied with the auditors. In order for Peat Marwick to maintain its reputation as professional auditors and providing quality audits, the firm decided it was in their best interest to record the GEICO and General Foods transactions as sales of stock by Berkshire, rather than as the receipt of dividends. Under this accounting approach, a portion of the cost of the Berkshire’s investment in the stock of each company would be charged against the redemption payment and any gain would be reported as a capital gain, not as dividend income. This is an accounting approach only, having no bearing on taxes; although, Peat Marwick agreed that the transactions were dividends for IRS purposes. Since the change in accounting treatment reduced Berkshire’s net income by 1% and 8% in 1983 and 1984, respectively, Peat Marwick might have deemed this as material and thought it was necessary to correct the way the transactions were recorded. According to the PCAOB, in evaluating consistency of financial statements, the auditor should evaluate a change in accounting principle to determine whether: the newly adopted accounting principle under GAAP, the method of accounting for the effect of the change is in conformity with GAAP, the disclosures related to the accounting change are adequate, and the company has justified that the alternative accounting principle is preferable (PCAOB, AU 508.17A, 2004). Any of these factors may have been responsible for Peat Marwick’s decision to change its position regarding these transactions. Although recording the stock redemption as a dividend complied with taxation rules under the IRS, it may not have been in accordance with GAAP. Berkshire may not have justified that recording the stock redemption as a dividend was preferable. Although it was preferable to Berkshire, because total proceeds from General Foods would have been reported as revenue, increasing Berkshire’s net income; it may not have been preferable to all the users of Berkshire’s financial statements, because net income would have been over stated. Lastly, in Berkshire’s letter to its shareholders, it stated that the GEICO and General Foods transactions were â€Å"virtually† identical, except  that General Foods repurchased its stock over a period of time in the open market, whereas GEICO had made a â€Å"one-shot† tender offer. In the General Foods case we sold to the company, on each day that it repurchased shares, but left Berkshire’s ownership percentage unchanged. Maybe this difference triggered Peat Marwick to look back into the stock redemption, where they found discrepancies with the accounting treatments and recommended that Berkshire make adjustments to report the transactions appropriately. RECOMMENDATIONS/CONCLUSIONS After Berkshire’s 1984 audit, the company released Peat, Marwick, Mitchell & Company as its auditing firm. Berkshire reported that it was â€Å"dissatisfied† with Peat Marwick’s inconsistency regarding the proper accounting treatment for stock redemption. Corporate non-liquidating distributions to shareholders are usually treated as dividends income; however, distributions that qualify as stock redemptions are treated the same as a sale of stock by the investor to the investee. Therefore, capital gain treatment normally results. Corporate shareholders prefer stock redemptions to be treated as dividend income, because corporate shareholders received the benefits of the dividends, which are deductible and in most cases escape taxation. Qualifying stock redemption results in capital gains that are fully taxable at the corporation’s highest marginal rate. Warren Buffet employed the substance over form concept while accounting for Berkshire’s stock redemption transactions. Since the IRS considers proportionate redemptions to be equivalent to dividend distributions and are taxed accordingly, Buffet justified the accounting treatment used to record these truncations. References http://www.accountax.us/Taxation-%20Corporations%20Lecture%20V.pdf http://www.aicpa.org/Research/Standards/AuditAttest/DownloadableDocuments/AU-00314.pdf http://pcaobus.org/standards/auditing/pages/au508.aspx http://www.berkshirehathaway.com/letters/1984.html http://pcaobus.org/standards/auditing/pages/au316.aspx#au_316.52

A Family Systems Approach For Michelle Family - 1823 Words

Genogram from a Family Systems Approach for Michelle Family The most fundamental of a family is interaction. The interconnectedness among family members help to maintain a family structure. According to McGoldrick (2006), family patterns repeat from one generation to the next generation. These triangular patterns are impacting functioning, relationships, and family structure. Looking at the current and historical context of the family, the genogram illustrated some repetitive patterns in Michelle’s family. There are many intergenerational losses and lack of connections among the family members. The unresolved mourning can be traced to the generation of David’s parents. Starting from the generation of David’s parents, there were a few losses, such as miscarriage or potentially stillbirth. It is likely that David’s parents were grieving over the loss of his brother, therefore David was named after his elder brother. This may be a form of remembrance or he may be a replacement child of his elder brother. It is also likely that David’s mother; Edith did not have the space for grieving over her miscarriages that contributed to her having an affair with their best friend, Bob. At the same time, it is also likely that David’s father was sharing the same emotions as Edith. Consequently, when he lost his children and best friend, he turned to alcohol for coping. Apart from experiencing losses of siblings at a younger age, David lost his parents and wife when he is aShow MoreRelatedThe Amazing Flexible You Is A Social Thinking Curriculum For Preschool And Early Elementary Years852 Words   |  4 Pagesyears. It was adapted from Michelle Garcia’s Social Thinking curriculum that provides an interactive tool kit. The program introduces the concepts of: Thinking Thoughts and Feeling Feelings, The Group Plan, Thinking with Your Eyes, Body in the Group, and Whole Body Listening. 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plot,setting, resolution, conflict, point of view,...

Creole Democracy I.Synopsis â€Å"Creole Democracy† is a clear presentation of one fundamental defect from of government. Democracy is based on the concept of the rule â€Å"of the people, by the people, for the people. â€Å"The success of a democratic form of government is based on the nature and condition of the electorate--- that they are literate enough to express their will in the ballot, that they have sufficient education to understand and analyze and decide on vital issues, and that they canimpose discipline on their emotions and themselves. To meet these requirements of democracy, Fambona tells us, most developing countries are still incapable. So the story ends in tragedy and death with the participants not really knowing it is all about.†¦show more content†¦Quick! Off to the mountains!† The vaquero didn t know that what he did was a crime as a sign of an uneducated man who just his leader: â€Å"Then it is true that this was a crime?† All that he thought was to kill t he other party with one reason at all. That he is an enemy. Realizing his mistake he turned himself to justice. Having regrets of his ignorance and still confused: â€Å"But weren t we supposed to conquer them? Weren t they our enemies? â€Å"The people of Camoruco are not yet ready for democratic changes. For them to have a successful democracy, the public and the electorates should be first educated about the meaning of democracy. The story proved that education of people and the leaders will only turn into chaos. The leaders should not think about themselves and be selfish but rather to put into mind that democracy is â€Å"of the people, by the people and for the people†. Each of the public should have a contribution for the success of the country not just merely being influenced by powerful leaders. The leaders of both party in the story don t have a clear goal of what they will do in their country, can t even notice the issues they are facing and discipline themselves rather all they want is to be in