Antisense Technology and Its Applications

Antisense Technology and Its Applications ANTISENSE TECHNOLOGY AND ITS APPLICATION INTRODUCTION: The tool that is used for the inhibition of gene expression is called Antisense technology. The antisense nucleic acid sequence base pairs with its complementary sense RNA strands and thus prevents it from being translated into a protein. The complementary nucleic acid sequence can be either a synthetic oligonucleotide, like oligodeoxyribonucleotides (ODN) having less than 30 mucleotides or longer antisense RNA (aRNA) sequences (Sczakiel, 1997). Example of sense and antisense RNA is: 5’ A C G U 3’ mRNA, and 3’ U G C A 5’ Antisense RNA. Dr. Hal Weintraub first developed this technology at Basic Science Division. Firstly, they showed that aRNA inhibits the gene expression in mouse cells by Berg, 2002. Dr. Meng-Chao Yao in 1996 showed that aRNA that was incorporated into non-conserved regions of ribosomal RNA (rRNA) disrupts translation and this was done by altering interaction of the mRNA, and the rRNA, mRNA chimera. Sequence transcription of antisense DNA strand into the sense mRNA strand, which is then translated into polypeptide (Kimball, Nov 2002). The inhibition in which the theory works are as follows: When the RNA binds to the complementary mRNA, it forms a double stranded RNA (ds RNA) complex which is similar to double stranded DNA . The dsRNA complex do not allow translation to occur. This translation process was not known. Several theories include: dsRNA prevents ribosome from binding to the sense RNA and translating. dsRNA cannot be translated from nucleus to cytosol, where the translation occurs. dsRNA is susceptible to endoribonucleases that does not affect single stranded RNA, but degrade the dsRNA. ANTISENSE OLIGONUCLEOTIDES: Oligonucleotide-based antisense techniques represents the most successful approach to genetic message element. Zamecnik and Stephenson first demonstrated the antisense effect of synthetic nucleotide. Zamecnik and Stephenson identified a repeated sequence of 21 nucleotides (nt) that was crucial to viral integration with the help of nucleotide sequences from the 5’ and 3’ ends of the 35S RNA of Rous sarcoma virus (RSV). They synthesized a 13-mer oligonucleotide, d(AATGGTAAAATGG), complement to the portion of this viral sequence. Viral production got inhibited when synthetic oligonucleotide was introduced into cultured fibroblast cells.Thus, they concluded that oligonucleotide was inhibiting viral integration by hybridizing to the crucial sequences and blocking them. They introduced the term ‘hybridon’ to describe such oligonucleotides. At the same time, Tennant et al and Miller et al reported similar effects for synthetic oligonucleotides in other systems. These results focused on the ability of synthetic oligonucleotides to interfere with gene processes. Synthetic oligonucleotides are foreign to the cells into which they are introduced and thus becomes prey for endogenous nucleases. Synthetic oligonucleotides were protected from endogenous nuclease when they attained the persistence level in cell. There are three possible sites on a nucleotide where protective modifications could be introduced. The three possible sites are Base, Ribose (2’ OH group) and the Phosphate backbone. In RNA nucleotides the 2’ hydroxyl group, missing in DNA nucleotides, can be modified. The alteration was thus introduced in the protective modifications of nucleotides that protects against the nuclease degradation which does not at the same time eliminates the desired effect of the oligonucleotide sequence by blocking the complementary hybridization or harming of the cells. In the late 1960s, Eckstein and colleagues successfully introduced the first-generation antisense-motivated nucleotide modification. They replaced one of the non-bridging oxygen atoms in the phosphate backbone with a sulfur atom. This modification was called as phosphhorothioate that achieved the goal of nuclease resistance measured by an increased half-life for a phosphorothioated oligonucleotide upto ten hours in human serum as compared to that of one hour of an unmodified oligonucleotide having the same sequence. Moreover, Matsukura and colleagues demonstrated that phosphorothioated oligonucleotides were effective hybridons against the HIV replication in the cultured cells. On the other hand, phophorothioated oligonucleotides displayed slightly reduced hybridization kinetics and a tendency towards unspecific binding with certain proteins which resulted in cytotoxicity at high concentrations. Thus, the dose-response was added to the mix of issues for antisense agents and hence the useful modifications continued. The so called second-generation class of modifications directly addressed the non-specific and cytotoxic issues which was raised by the phosporothioates by the introduction of RNA oligonucleotides with alkyl modifications at the 2’ position of the ribose sugar. The two most important of these modifications are 2’-O-methyl and 2’-O-methoxy-ethyl RNAs. Antisense nucleotides contains these modifications and displayed the nuclease resistance in concert with lower toxicity and major drawback of 2’-O-alkyl modifications is that the antisense agents containing them are unavailable to the most powerful antisense mechanism called RNase H cleavage. Steric block mechanism are affected from these agents. Thus, the 2’-O-methyl oligonucleotides have been used to increase the desired expression of alternate splices in certain proteins by suppressing the undesired splice variant. Since RNase H cleavage is the most desirable mechanism for antisense effect. Nuclear resistance rarely have 2’-O-alkyl modifications which is a hybrid oligonucleotide, constructs incorporating both the characteristics has been appeared in the form of the â€Å"gapmer† antisense oligonucleotide, containing central deoxynucleotide blocks sufficient to induce RNase H cleavage which was flanked by the blocks of 2’-O-methyl modified ribonucleotides, thus protecting the internal blocks from nuclease degradation and these irrelevant cleavage appears because of binding short stretched nucleotide in most of the genomes. For example, a 15-mer can be viewed as a series of eight overlapping 8-mers. mRNA has less potential random targets, while in RNase H cleavage it is still high. This theoretical potential became real in the case of 20-mer phophorothioate oligonucleotide targeted to the 3’-untranslated region (UTR) of the protein kinase C alpha gene (PKCÃŽ ±). While unmodified oligo-deoxynucleotides forms desired DNA:DNA and DNA:RNA duplexes. A variety of nucleic acid analogs have been developed by that increased the thermal stabilities when hybridized with the complementary DNAs or RNAs as compared to unmodified DNA:DNA and DNA:RNA duplexes. These are third generation antisense oligonucleotide modifications and the analogs are: peptide nucleic acids, 2’-fluro N3-P5’-phosphoramadites, 1’, 5’-anhydrohexitol nucleic acids, and locked nucleic acids. The newest and most promising third generation modification is the locked nucleic acid (LNA), introduced by Koshkin et al, Obika et al and Singh et al. LNA, is thus composed of locked nucleotides into a single conformation through a 2’-0’, 4’-C methylene linkage in 1,2:5,6-di-O-isopropylene-ÃŽ ±-allofuranose. LNAs increased the thermodynamic stability and enhanced nucleic acid recognition. Ribozymes: Ribozymes are RNA enzymes were first described by Cech in Tetrahymena thermophilia. Antisense agents immediatley seized the RNA processing capabilities of these enzymes. Thus, the hammerhead ribozyme was characterized. This enzyme was first isolated from viroid RNA by Ulhenbeck and Haseloff and Gerlach. RNA Interference (RNAi): RNA interference (RNAi) was first described by Fire and colleagues in Caenorhabditis elegans. Long-double stranded RNAs were introduced into C. elegans. RNAi generated enormous interest by both those who view it as a potentially powerful antisense tool and recognize it like ancient eukaryotic cellular defense mechanism. ANTISENSE MECHANISM: The overall goal in introducing an antisense agent into the cells either in vitro or in vivo is to suppress or completely block the production of the gene product. The normal transcription and translation is affected due to transition between DNA and amino acid sequence. DNA strand is transcribed into pre-mRNA at step one. In step two, through the action of 3 separate processes like 5’ capping, intron excision and polyadnelyation, pre-mRNA is converted into mature mRNA. In step three, transportation of mRNA is carried out in ribosomes into the appropriate poly-peptide. The first target is transcription step to achieve antisense knock-down or knock-out, in which antisense agent is targeted to DNA itself, thus preventing transcription of the primary message. Dagle and Weeks noted that there are three ways in which this strategy can be carried out viz, minor groove binding polyamides, strand displaying PNAs, and major groove binding , triplex forming oligonucleotides. According to White at al, pyrrole-imidazole are minor groove binding polymers that achieve sequence-specific action through side-by-side pairing of pyrrole and imidazole amino acids. Less than 7bp appears in the target sequence of short stretched DNA. While PNA agents are longer and their mode of operation binds to complementary strand of DNA helix, displacing the complement. This process is thus aided by the fact that PNA:DNA duplexes are more stable than the DNA:DNA duplexes so that former is thermodynamically favored over the latter duplex. Triplex forming oligonucleotides have longer sequences and these agents create stable triplex DNA instead of binding to one of the DNA helix, while displacing the other helix of DNA. Both involves the interaction of TFO having purine bases in a polypurine:polyrimidine stretch of duplex DNA. Watson-Crick bonded is the target dsDNA sequence and triplex forming oligonucleotides binds to duplex through Hoogsteen hydrogen binding: T-A:T and C-G:C triplets. This strategy necessitates that only the purine-pyrimidine dsDNA can be targeted and the cytosine in TFO must be protonated. Thus the cytosine protonation is due to the requirement for the acidic conditions. Sorensen et al reported that the LNA containing TFOs stabilizes the triplex formation at physiologic pH. A 15-mer having seven LNAs raised the temperature for the triplex to duplex transformation from 33 °C to ~66 °C at pH 6.8. The next level of antisense attack focuses on the processing of the pre-mRNA and the intron excision mechanism. In this process, the oligonucleotide-based agent is used. The sequence-specific binding of the oligonucleotide to the pre-mRNA is required to prevent intron-excision. The antisense agent is then targeted to the mature rRNA and interferes with the transcription apparatus in either due to presence of the oligonucleotide which prevents formation of the ribosomal complex. In ribosomal complex, short RNA oligonucleotides are not stable due to presence of helicase enzymes, while longer RNA oligonucleotides activates RNAi pathway. Finally the most used mechanism is that of the RNase H degradation of mRNA. RNase H is an endogenous enzyme which cleaves the RNA moiety of an RNA:DNA duplex. In both cytoplasm and nucleus, RNase H is found. During DNA replication it removes the primers of RNA from Okazaki fragments. The most powerful weapon assessing functions of gene is called RNase H activation antisense. Kurreck thus listed 15 antisense oligonucleotides in total that are used in clinical trials against the diseases like cancer and asthama. APPLICATIONS OF ANTISENSE TECHNOLOGY: In Medicine: James Watson and Francis Crick proposed deoxyribonucleic acid, which consists of two deoxyribonucleotide molecules each having 5’and 3’end that defines a polarity for the DNA strand. After binding of these strands in antiparallel orientation 3’ of one being juxtaposed to 5’end of the other, they compose a complete DNA molecule. The two stands are bound together by pairing four complementary bases in each strand such that adenine present on one strand binds to second thymine, while cytosine binds to guanine in the second. Each strand contains all the genetic information called as mirror image. This structure permits transmission of genetic information by allowing a complementary strand produce for a single strand. One strand can therefore produce an entire DNA molecule, occurring during the cell division. Each triplet set of nucleotides on a strand of DNA encodes an amino acid. In this process, one or another portion of one strand (a gene) is copied by ribonucleic acid polymerase II producing a compelementary molecule of ribonucleic acid, or RNA. This messenger RNA (mRNA) therefore, contains the same information which is contained in the gene that has been transcribed. Mature RNA molecule is left when the introns are excised. RNA molecule is thus exported to the cell, directing protein synthesis at ribosome. This takes place after intron excision and additional process. Formulation of Antisense Technology: DNA/RNA physiology is applied in various methods. Antisense technology is the most important application used. Here, oligonucleotide is introduced into cell which binds to its target mRNA through complementary based-pairing. This binding forms RNA dimer in cytoplasm and halts the protein synthesis. . Application of Antisense Technology invitro: Antisense technology is used successfully in two general areas. The first one is fundamental research where antisense oligonucleotides introduced helps to determine the role of a specific gene. Cell growth and other changes occurred due to the production of angiotensin II. Cellular renin angiotensin system played an important role in variety of cardiovascular disorders like artherosclerosis and vascular hypertrophy. Oligonucleotides were developed to inhibit the synthesis of angiotensin as it was difficult to demonstrate cellular system to be operative. It is a substrate form which the cells make angiotensin II. Cells make their own angiotensin II having growth promoting effects with the help of this technology. Therapeutic Application of Antisense Technology: Viral infections can occur when the antisense oligonucleotides are complementary to viral RNAs. Similarly, antisense oligonucleotides directed towards the oncogene product plays an important role to reduce growth of cancer cells. The most widely used application of this technology is in gene therapy. In this case, a variety of vectors are used to introduce antisense encoding genes into larger number of cells in a patient or animal to produce long term inhibition of protein. For example, vectors having angiotensin II receptor sequences when introduced in animal models can cause long term normotension in hypersensitive animals. REFERENCES: Damha, Masad. 2002 Oct 17. Making sense of Antisense. http://www.erin.utoronto.ca/mbiotech/menu/damha.htm> Accessed 2003 Feb 11. Tennant RW, Farelly JG, et al. (1973) Effects of polyadenylic acids on functions on murine RNA tumor viruses. Journal of Virology, 12: 1216-1225. Kurreck J. (2003) Antisense technologies: Improvement through novel chemical modifications. European Journal of Biochemistry, 270: 1628-1644. Miller PS, Braiterman LT, and Ts’ o POP. (1977). Effects of a trinucleotide ethyl phosphotriester, Gmp(Et)Gmp(Et)U, on mammalian cells in culture. Biochemistry, 16: 1988-1996. 1

Immune to Reality Essay

â€Å"Upon my back, to defend my belly; upon my wit, to defend my wiles; upon my secrecy, to defend mine honesty; my mask, to defend my beauty. † (William Shakespeare Troilus and Cressida) (Gilbert 133)This quote pertains to the mind protecting and or lying to you to not be harmed, which has been proved in test today. Immune To Reality written by Daniel Gilbert is a piece about how the mind can play tricks on us by covering up the truth with a believable lie, how we â€Å"cook facts† (134), and how our mind’s choices can affect our feelings. Throughout this essay I will be discussing a real life situation of my own, and the studies and the outcomes and whether they make sense or not. They say the mind protects us from ourselves, but we also â€Å"cook facts† (134) which happen to go hand in hand. Cooking facts are â€Å"†¦deliberate attempts to generate positive views†¦Ã¢â‚¬  (134) a few examples are failing miserably on the test but tell yourself there is always next time and you’ll study harder for the next one and example from the book being is that your fiance left you at the altar but saying â€Å"She was never really right for me†¦Ã¢â‚¬ (134). The mind tries to protect us from remembering bad things or bad experiences. I’ve seen some of my friends try and deny the fact that his father had died of cancer, he just didn’t believe it until the day of his funeral. But in the end they made it in their mind that he was in a better place and no longer suffering. In my own case, my family and I were coming back from a trip to Florida on a coach bus which ended up being hit by another car and flipped on its side on a four lane highway which ended up being hit by two more cars. I am thankful to say that I was buckled so I only came out of the crash with a concussion, but it still affects me every day. My vision has never been the same, yeah sure I can read really fast when I’m reading to myself but when it comes to reading out loud. It’s a completely different story. There’s no medical term for it but the best way they could put it is that I have an acute form of dyslexia. I just thank to this day that it actually isn’t worse than it could be and this being my cooked facts. To this day I cannot remember anything about the crash, this being the way my mind protects me from pain. Our minds and feelings are always going to have some sort of connection since it is our brain that tells our body us what we are feeling. Studies show that what we choose can really affect our moods for the time being or even throughout a week. On pages 135-136 a study shows a group of volunteers went through a job interview. â€Å"Some of the volunteers were told that their interview would be seen by a judge†¦Ã¢â‚¬  (135) â€Å"Other volunteers were told that their interview would be seen by a jury†¦Ã¢â‚¬  (315) the volunteers not knowing that everyone would be rejected the job. The Pre Rejection Prediction shows that the volunteers wouldn’t have really cared if they were rejected by the solo judge or the jury group, but what the results showed is that the group of volunteers that were rejected by the jury was much more upset than the ones rejected by the solo judge. I mean I’d be upset if 12 people told me I wasn’t capable to do a job, you automatically think that something is wrong with you. But with the judge your mind just makes up excuses to make you feel better, examples being he doesn’t know the real me or I don’t really need that job anyway. The mind is very deceiving, but it is sometimes for the best. When you need protection from yourself or whether it’s to give you a boost. We just need to be able to tell when and when not our mind is doing these things. References: * Gilbert, Daniel. â€Å"Immune to Reality. † The New Humanities Reader. By Richard E. Miller and Kurt Spellmeyer. 4th ed. Boston, MA: Wadsworth, n. d. 133-50. Print.

The Formation of Black English and Its Influences on...

1. Introduction African American Vernacular English (AAVE) is one special dialect of American English, and it is different from Standard American English. African American Vernacular English can also be called as Black English, Black Vernacular English or African American Language (AAL).Black English had been discriminated for a long time in history. There was a saying that â€Å"Black English is not a language†. The saying is not correct. According to Montgomery, culture should not be biased, but should be including all that are produced and shared by the society( Montgomery 7). Even though Black English is different from Standard English, Black English has its unique linguistic system. It has its own system in phonetics, lexicology and†¦show more content†¦Well-known linguist William Labov is the first one to system study Black English. On June of 1979, Detroit court judged that Black English is a language. That means Black English finally earned its status. 3. Characteristics of Black English In his book Information to Those Who Would Remove to America, Benjamin Franklin recorded a short paragraph as follows: Boccarorra [a form of buckra white man]make de Black Man workee, make de Horse workee, make de Ox workee, made ebery thing workee; only de Hog. He, de Hog, no workee; he eat, he drink, he walk about, he go to sleep when he please, he libb like a gentleman. (Franklin 606) This short paragraph is a clear evident that the Black English has its own characteristics in some aspects. Its phonetics, grammar and lexicology are different The Black English has its own characteristics in some aspects. Its phonetics, grammar and lexicology are different from Standard English. Even though there are some differences in certain aspects of language between Black English and American English, after all, Black English is a variant of English. So the differences are only in some degree rather than fundamental. 3.1 Phonetics The first generation of black American was all African slaves, so their African tone was inevitable when they spoke English. The African tone mixing with Standard English tone makes the special Black English tone.Show MoreRelatedA Day Road Is An Appropriate Novel For High School Students1429 Words   |  6 Pagesthe belief that one’s culture is superior to another’s culture. Although every culture faces its own struggles and hardships. Racism and discrimination has been noticeable in our world. In the Great War, Native Canadians Indian men volunteered to join and serve the Allied forces in European battlefields, inspiring people around the world with their achievements and sacrifices. 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Eth 125 Work Sheet Essay example - 633 Words

Associate Program Material Discrimination Worksheet Write a 100- to 200-word response to each of the following questions. Provide citations for all the sources you use. †¢ What is discrimination? How is discrimination different from prejudice and stereotyping? †¢ What are the causes of discrimination? †¢ How is discrimination faced by one identity group (race, ethnicity, religious beliefs, gender, sexual orientation, age, or disability) the same as discrimination faced by another? How are they different? What is discrimination? The Google dictionary defines discrimination as being a noun; the unjust or prejudicial treatment of different categories of people or things, especially on the grounds of race,†¦show more content†¦As whereas stereotyping is unreliable generalizations about all members of a particular group without considering a individuals differences.I feel that discrimination has many forms aside from race,age,sexual orientation or wealth. Resource: â€Å"studymode.com† What are the causes of discrimination? Discrimination covers any scenario where an individual or company treats a person or group of people unfairly due to a particular characteristic. The most commonly referred to typesof discrimination include prejudicial behavior that is based on skin color,gender,disability,religion or sexual orientation. However, discrimination can be based on any attribute that is viewed as marking the victim out as being different. For example, discrimination might be on the basis of age,weight,height,nationality, or any number of attributes. In order to tackle this hurtful and damaging behavior, it is important to identify the causes of discrimination. Discrimination is often based on ignorance,fear and stereotypical viewpoints. For example, religious and/or sectarian discrimination is often fuelled by people living and working in separate communities and therefore not having ample opportunity to interact with people from other groups. Resource: â€Å"Life 123† How is discrimination faced by one identy group (race,ethnicity,religious beliefs,gender sexual orientation,age or disability) the same as discrimination faced by another? How are theyShow MoreRelatedBusiness Study At Mathrubhumi Printing And Publishing Company Ltd9893 Words   |  40 Pages2015 Under the guidance of Submitted By Mrs Anvesha Sharma (ASCO) Jithin Sethumadhavan Assistant Professor A7021314001 Mrs Uttara Navin (Mathrubhumi) HR Executive Amity School of Communication Amity University, Sector-125, Noida, Uttar Pradesh-201301 DECLARATION I, JITHIN SETHUMADHAVAN, hereby declare that the project report, entitled â€Å"Report on the Organization study at MATHRUBHUMI PRINTING AND PUBLISHING COMPANY LTD†. Submitted to Amity School of Communication, AmityRead MoreEncouraging the Heart10264 Words   |  42 PagesOthers Presentation Date: November 5th, 2005 Recommended Length: One hour minimum, One hour 15 minutes maximum Recommended Content • Key take-aways • Practical applications • Entertaining • interactive Presentation Outline: 0:00-0:05 Introduce ETH, Concept of Caring Leader (5 minutes) 0:06-0:10 Most Meaningful Recognition, Need for Encouragement (5 minutes) 0:11-0:50 The Seven Essentials of Encouraging the Heart (40 minutes total) • Open Discussion Idea Exchange • Answering of Reflection QuestionsRead MoreHbr When Your Core Business Is Dying74686 Words   |  299 Pages 20 FORETHOUGHT Firms from developing countries are making a global mark†¦McDonald’s isn’t afraid to bite off more than it can chew†¦Women at Fortune 1,000 companies are securing top jobs faster than men†¦Make your employees prove their ideas’ worth†¦Work with Chinese ï ¬ rms to build respect for IP†¦Alchemists turn bad feedback into gold†¦Don’t discount the power of the QA†¦Consumers are slow to notice changes in product quality, for better and for worse†¦How outside directors can reduce their legal riskRead More65 Successful Harvard Business School Application Essays 2nd Edition 147256 Words   |  190 PagesAfter branding season, I joined the fencing crew, five men led by the oldest hand, Morris. We worked ten...hour days planting railroad ties and anchoring fence braces. I admired Morriss expertise and calm demeanor. But Morris never did any physical work, and he constantly aired his disdain for fencing. After two weeks, Morr is abruptly quit. Tony approached me. He said that I had earned his trust and wanted me to lead the crew. I replied that I would be honored but first wanted to consult Lon, now