1.1 Overview
Learning to read and write is among the most important skills required for a child’s academic success at school as well as in his/her future education. Learning literacy skills will influence one’s performances in other disciplines. Literacy can have substantial impacts on developing livelihood. As claimed in a report by The World Bank (2002), people who had fulfilled literacy courses were shown to be more enthusiastic to improve their livelihoods. In addition to that, Eldred (2008) mentioned that literacy is associated with specific job skills as well as developments in critical thinking and problem solving. Similarly, Ekpo, Udosen, Afangideh, Ekukinam and Ikorok (2007) asserted that:
Over the years, there’s been a tremendous body of research conducted on the factors that affect literacy learning and development (Pretorius ; Mampuru,
2007). However, while researchers have come to an agreement about the different linguistic, socioeconomic, sociocultural and developmental elements in various contexts such as home, school and classroom which directly or indirectly influence the language and literacy achievements, a considerable debate about the best ways of teaching literacy to children continues to exist in the English- speaking countries (Harrison, 2004). In the past, as Chall (1983) put it, at the center of this great debate was the disagreement among those researchers, educators and policy makers who emphasized the bottom-up approaches (i.e. phonics) to literacy which focused on breaking the code and those who placed emphasis on whole-language (i.e. top-down) approaches in which meaning- emphasis was the center of attention.

In recent years, however, with the growth of convincing evidence from cognitive science which displays a strong relationship between success in literacy, phonemic/phonological awareness, and phonological skills (Anderson, 2004; Goswami; Bryant, 1990) and with the educational ministries of English-speaking countries seeking verification from ‘scientifically’ based research (Schemo, 2002), phonics has been adhered to as the best method of teaching literacy especially in primary stages.
1.2 Statement of the Problem
English as a foreign language is not the medium of communication in daily conversations and everyday life activities in Iran. Therefore, students’ exposure to English is only restricted to the English classroom and there do not have any chance of practicing English for learners outside the classroom setting.

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Iranian’s students start their formal English learning in the first grade of secondary school when they are about 12 or 13 years old. However, student’s English language learning has got importance for Iranian parents. Parents know the international place of English all over the world and the determining role that mastery of English holds in children’s educational future and job opportunities, many parents are willing to have their children start their English language learning as soon as possible. Hence, to attract registrations, lots of private primary schools and even kindergartens offer English language teaching in their curriculum. Nonetheless, because the government does not include English language teaching in primary levels, and thus is not among the main subject matters of primary school curriculum, English is placed at the last hours of school days as an extracurricular school course which also requires extra tuition from the parents. As a result, children who are already exhausted at these very last hours of the day at school do not take English seriously as a major school subject and this will result in a poor language attainment on the part of learners. In addition to these reasons, since English is usually considered just as a means of attracting customers in private primary schools, the quality of its teaching is not very desirable and satisfactory. Worse than that, the quality of formal English education in secondary school is very poor too. The textbooks which are written and presented under the supervision of Ministry of Education in Iran are based on very old methods of teaching English.

All in all, because of the overall disappointing conditions of English language teaching at schools and the late beginning of official English teaching in the Iranian educational system, parents resort to language institutes in the hope of giving their children the privilege of good English education. The quality of English teaching in language institutes is usually satisfactory compared to that of schools and the methods of teaching are often based on the ones offered by the new and popular textbooks such as Backpack (Herrera ; Pinkley, 2009), First Friends (Lannuzzi, 2011), Family and Friends (Simmons, 2010), etc. which have been written for ESL and EFL purposes by native authors. However, no systematic attention to learners’ literacy learning is observed in the language institutes in Iran. Phonics which has been identified as the best method of teaching literacy over the years (Beck, 2006) is used occasionally and from time to time rather than regularly and systematically. In other words, the method of teaching early literacy in most language institutes is the rote traditional phonics. Teachers start by teaching the letters of alphabet and their associated sounds followed by teaching some example words that start with those specific alphabet letters (e.g. apple is introduced as an example word for the letter sound a). This procedure is usually done through repeated drills in which the teacher chants the words and students repeat after the teacher in unison. As noted by Eshiet (2012), “This method lacks any form of motivation for the pupils as the knowledge gained through rote learning is not easily applicable when they see new words” (p. 3).

Due to the absence of Teacher Training Course (TTC) workshops to train teachers on how to teach phonics systematically, the teachers worsen the situation by their lack of competence in presenting systematic phonics to students and teaching English literacy appropriately. Therefore, the same as what Ekpo et al. (2007) describe, “The consequence is that some students just memorize some words without any clue to how those words are formed or pronounced. At the primary stages, words and short sentences are forced into the children’s memory through constant drill and memorizations”.

Ohiaeri (1994) and Ekpo (1999) have identified some obstacles to young learners’ ability to read at appropriate age in Nigeria, some of which are also true in Iranian EFL context:

1. High cost of books and lack of class readers by most pupils
2. Inadequate instructional time
3. Teachers are not prepare on reading at initial teacher training institutions
4. Adoption of poor teaching methods
5. Lack of appropriate variation in the teaching approaches to reading, for instance, the use of activities such as picture recognition, storytelling, card games, news reading, cartoon collection, posters, flash cards, role play, story club, reading competition, leisure reading, etc. can be incorporated into reading lessons for variety to generate interest (Edem, 2005).
6. Lack of commitment on the part of the teachers due to poor job satisfaction

As is clear from the factors enumerated by Ohiaeri (1994) and Ekpo (1999), the reason for the failure of most children in mastering English literacy is not because they are incapable to learn but to a great extent is because of the poor teaching methods adopted in teaching literacy. The teachers in schools and language institutes in Iran are required to thoroughly depend on and stick to the prescribed course materials offered by the relevant language institute or by the Ministry of Education in the case of secondary schools. Consequently, the learners are not provided with the right kinds of learning experiences which enable their appropriate mastery of literacy skills.

The irregularity of English writing system that is influenced by other languages adds fuel to this fire. For example, ch sounds sh in champagne which is the effect of French. Another instance is ch as in Christmas which sounds k and is the influence of Greek language. “Several centuries ago, the first dictionary was printed and once the words went into print, that’s how they were spelt. But pronunciation changes over the years and yet the link to the letters is not always the same” (Lloyd, 2012). The result is that there are only 26 letters but about 42 sounds in the English language and that’s what makes it more difficult to learn to read and write in English.

Jolly Phonics is a fun and child-centered approach to teaching literacy which has actions for each of the 42 letter sounds of English and teaches five key skills for reading and writing by using a synthetic multisensory approach. These five skills include (i) learning the letter sounds which consist of the alphabet sounds as well as diagraphs (e.g. sh, ai, etc.), (ii) learning letter formation, (iii) blending, (iv) segmenting, and (v) tricky words that have irregular spellings and children learn them separately in this method (“Teaching Literacy with Jolly Phonics”, 2014).
1.3 Purpose of the Study
Given the importance of literacy skills and the difficulties that young learners face with in reading and writing English at primary levels, this study aims at lighting upon a way to help children to learn reading and writing. To fulfill this objective, the present study seeks to discover the possible effects that the synthetic multisensory phonics (i.e. Jolly Phonics) can have on facilitating children’s early learning.
1.4 Significance of the Study
English, more than a century of debate has occurred over whether English phonics should or should not be used in teaching beginning reading. As a solution to overcome the above-mentioned barriers in the way of EFL/ESL children’s English literacy, the present study seeks to find out whether adopting a the synthetic method of Jolly Phonics is going to have significant impacts on helping young Iranian EFL learners to break through their reading and spelling difficulties. Despite the work of 19th century proponents such as Rebecca Smith Pollard, some American educators, prominently Horace Mann argued that phonics should not be taught at all. This led to the commonly used “look-say” approach ensconced in the “Dick and Jane” readers popular in the mid 20-th century.
Beginning in the 1950, however, phonics resurfaced as a method of teaching reading. Spurred by Rudolf Flesch’s criticism of the absence of phonics instruction (particularly in his popular book, why johnny can’t read, 1995) phonics resurfaced.
Spoken language is used in contexts that offer much support for meaning often from familiar and helpful adults who know the child and interact with him or her regularly. On the other hand, a child faced with a written text has support only from previous knowledge, from what the writer can build in, or through pictures or diagrams that illustrate the text. The writer is much more distant from a reader than is the case with speaking, and this distance can place a high demand on a reader to construct an understanding of the text (Reid, 1990 as cited in Cameron, 2001, p. 127).

As is maintained by Reid, it is clear that learning reading and writing skills are much more challenging for young learners than acquiring aural/oral skills. “Phonics teaching focuses on letter-sound (grapho-phonemic) relationships, building literacy skills from the bottom up. The usual way involves showing children the sounds of the different letters in the alphabet, then how letters can be combined. Phonics teaching works if it directs children’s attention to letter-sound level features of English and helps children make the mental connections between letters and sounds” (Cameron, 2001, p. 149). To achieve this, the present study seeks to apply a synthetic multisensory approach toward teaching phonics to the young learners and therefore offer them a helping hand in facilitating the troublesome task of learning literacy skills. Besides, phonics is usually regarded as “dry, boring and demotivating” (Cameron, 2001, p. 149). Therefore, Cameron (2001) suggests that phonics should be combined with fun activities which raise children’s interest such as songs and rhymes, and in stages of oral task. The present study may pave the ground to tackle these crucial issues, which have for long been neglected regarding the bore of phonics teaching, by adopting a fun synthetic multisensory approach to phonics which is believed to enhance learners’ motivation towards literacy learning.

1.5 Research Questions
Based on the purpose and the problem under focus in the present study, the following research questions are addressed:
1. Does the synthetic multisensory approach to phonics (i.e. Jolly phonics instruction) have any significant effect on Iranian young EFL learners’ reading skills?

2. Does the synthetic multisensory approach to phonics (i.e. Jolly phonics instruction) have any significant effect on Iranian young EFL learners’ spelling skills?

1.6 Null Hypotheses
Consequently, based on the aforementioned research questions the following hypotheses were formulated:

H1: The synthetic multisensory approach (Jolly Phonics method) adopted for teaching early literacy does not have any significant effect on the reading skills of Iranian EFL children.

H2: The synthetic multisensory approach (Jolly Phonics method) adopted for teaching English literacy does not have any significant effect on the spelling skills of Iranian EFL children.

1.7 Definition of the Key Terms
1.7.1. Phonics or Phonetic Method

According to Richards and Schmidth (2002), phonics is “a method of teaching children to read, in which children are taught to recognize the relationship between letters and sounds. They are taught the sounds which the letters of alphabet represent, and then try to build up the sound of a new or unfamiliar word by saying it one sound at a time” (p.398).

1.7.2. Multisensory Approach to Phonics

“Using a multisensory teaching approach means helping a child to learn through more than one of the senses” (Bradford, 2008 as cited in Ureno, 2012). According to Mohler (2002) he defines multisensory Approach to Phonics as follows: “Multisensory instruction received its name because all information was presented via sight, sound, voice, and kinesthetic means.

1.7.3. Synthetic Phonics

“The synthetic phonics method adopts the direct, systematic and rapid teaching of letter sounds to pupils. This is immediately followed by teaching them how to blend the letter sounds to form words. In English, pupils are taught the first group of letter sounds which make up a large number of 3-letter words; s, a, t, i, p, n. These sounds can be used to make several 3-letter words e.g. pin, sat, sit, tip, tin, pit, pat. The whole program is sometimes taught within a few months– usually
9 to 16 weeks with a great deal of emphasis on word reading. Sight words are taught at key points and carefully selected decodable readers are used alongside the program” (Eshiet, 2012, p. 6).

1.7.4. Jolly Phonics

“Jolly Phonics is a fun and child-centred approach to teaching literacy through synthetic phonics. With actions for each of the 42 letter sounds, the multi-sensory method is very motivating for children and teachers, who can see their students achieve” (“Teaching Literacy with Jolly Phonics”, December 2014).

1.7.5. Literacy

Richards and Schmidth (2002) define literacy as “The ability to read and write in a language” (p. 313).

1.7.6. EFL Young Learners
Mckay (2006) refers to young learners as follows: “Young language learners are those who are learning a foreign or second language and who are doing so during the first six or seven years of formal schooling. In the education systems of most countries, young learners are children who are in primary or elementary school. In terms of age, young learners are between the ages of approximately ?ve and twelve”. She further explains that “Young language learners may be foreign language learners, learning a language in a situation where the language is seldom heard outside the classroom. They may be learning languages like Vietnamese, Spanish or Chinese in Germany or the United States or they may be learning English as a foreign language (EFL) in countries like Turkey, Malaysia or Spain”.

1.8 Limitations and Delimitations of the Study
Like many other studies conducted in this area, the present one has suffered from a number of limitations which might jeopardize the generalizability of its findings. This study was implemented in a small language institute one of the limitations of this study, it was to some extent narrowed down in terms of the number of participants. Consequently, further research could take place with the inclusion of a larger number of participants within several larger schools or language institutes.

Furthermore, the participants of our study were 3-6 year-old students. Thus, the findings cannot be generalized to learners of other age groups. Subsequently, replicating the study with a group of other age group can be suggested.

Cancer arises from a single cell that is unable to repair their mutations produced in DNA which leads to abnormal cell division, invasion and metastasis 1. Normal cells can transform into tumor cells due to various reasons, such as genetic factors, radiation, chemical carcinogens such as asbestos, tobacco smoke, BPA and biological carcinogens infections from viruses, bacteria, and parasites. Among cancer’s cervical is the second most common cancer and predominant gynaecological cancer in women, causing most cancer related deaths world over 64 2. There are several factors which contribute to high incidence of this disease are early age of marriage, multiple sexual partners, multiple pregnancies, poor genital hygiene, smoking and use of oral contraceptives. Cervical growth is a malignancy emerging from the cervix 3. It is because of the irregular development of cells that can attack or spread to different parts of the body. Initial stage of development there was no indications are seen. Later indications may incorporate unusual vaginal bleeding and pelvic pain. While bleeding after sex may not be serious, it may also indicate the presence of cervical cancer 4.
Cervical cancer is the commonest cancer cause of death among women in developing countries. Mortality due to cervical cancer is also an indicator of health inequities, 2 as 86% of all deaths due to cervical cancer are in developing countries 5. Every year in India, 122,844 women are diagnosed with cervical cancer and 67,477 die from the disease. India has a population of 432.2 million women aged 15 years and older who are at risk of developing cancer 6. It is the second most common cancer in women aged 15–44 years. India also has the highest age standardized incidence of cervical cancer in South Asia at 22, compared to 19.2 in Bangladesh, 13 in Sri Lanka, and 2.8 in Iran. Therefore, it is vital to understand the epidemiology of cervical cancer in India 6.

Figure 1.1. Structure of the female reproductive system
1.1.1. Signs and symptoms
The early phases of cervical malignancy might be totally free of side effects. Vaginal bleeding, contact bleeding or a vaginal mass may show the nearness of danger. Similarly the, direct agony amid sex and vaginal release are side effects of cervical growth. In cutting edge ailment, metastases might be available in the midriff, lungs, or somewhere else 4. The major Side effects of cervical disease such as : loss of voracity, weight reduction, pelvic torment ,weakness, leg torment, back torment, overwhelming vaginal dying ,swollen legs, bone cracks, spillage of pee or dung from the vagina. Seeping subsequent to douching or after a pelvic exam is a typical side effect of cervical malignancy 4.
1.1.2. Causes
Infection with HPV is the most serious danger element for cervical tumor, which is induced by smoking 7. Similarly HIV disease mediated a danger also variable. The majority of the reasons for cervical malignancy are not known, a few may be an unknown cause 8.
1.2. Human Papillomavirus
Human papillomavirus sorts are the major reason for 75% of cervical malignancy cases, while 25% are the another reasons 109Ladies who have numerous sexual accomplices have a more serious danger of the HPV infection. Genital warts, are a particular type of amiable tumor of epithelial cells, which are additionally brought by different strains of HPV 4. Some of the HPV serotypes are generally not identified with cervical malignancy. It is very rare to have different strains in the mean time, including those that can bring about cervical growth along side those that cause warts. Disease with HPV was move suscetable get cervical tumor 10.
1.3. Smoking
Cigarette smoking, both dynamic and uninvolved, leads to the danger of cervical malignancy in women. Among HPV-contaminatedwomen, present and previous smokers have showed approximately a few times higher rate of obtrusive growth 11. In active smoking connected with expanded danger, however to a lesser degree. Smoking has connected with the development of cervical disease. Smoking can build the danger in ladies a couple of various ways, which can be immediate or backhanded strategies 12. An immediate method for getting this tumor is a smoker has a higher shot of CIN3 happening which has the capability of shaping cervical malignancy 10. At the point when CIN3 sores lead to disease. Therefore the majority of can get HPV infection, yet that is not generally the situation, which is the reason it can be viewed as an immediate connection to cervical malignancy. Overwhelming smoking and long term smoking appear to get a more danger of getting the CIN3 sores than the lighter smoking. Albeit smoking has been also connected to cervical tumor, it helps in the advancement of HPV which is the main source of this sort of malignancy. Likewise, not just does it help in the advancement of HPV, additionally if the women is now HPV-positive; she has the prominent probability of getting cervical malignancy 13.
1.4. Oral contraceptives
Long term utilization of oral contraceptives can leads to expanded danger of cervical cancer development. Ladies who have utilized oral contraceptives for 5 to 9 years have higher frequency of obtrusive growth, and the individuals who utilized them for a long time can have around more high danger of getting cervical cancer 4.
Having numerous of pregnancies is connected with an expanded danger of cervical tumor 14. Among HPV-contaminated ladies, the individuals who have had seven or all the more full-term pregnancies have the higher danger of cervical cancer growth .Any pregnancies, and a few times the danger of ladies who have had maybe a couple full-term pregnancies 14.
1.5.1 Biopsy
The Pap smear can be utilized as a screening test, however there was a more change of getting false negative to half of 15. Aconfirmation analysis of cervical malignancy or precancer requires a biopsy of the cervix 16. This is frequently done through colposcopy, an amplified visual assessment of the cervix supported by utilizing weaken acidic corrosive 17. Therapeutic gadgets utilized for biopsy of the cervix incorporate with puncher using forceps, SpiraBrushCX, SoftBiopsy, or Soft-ECC etc . Colposcopy impression, the appraisal of malady seriousness in light of the visual review, frames part of the conclusion. Supplementary indicative and treatment strategies are loop electrical excision procedure and conization, which the internal coating of the cervix is expelled near be inspected pathologically. These are finished the biopsy affirms serious cervical intra epithelial neoplasia. This enormous squamous carcinoma (base of picture) has wrecked the cervix and attacked the lower uterine sector 4. The uterus similarly has a round leiomyoma up higher. Regularly before biopsy, the specialist requests healing imaging to discount different reasons for lady’s side effects. Imaging modalities such as ultrasound, CT output and MRI has been utilized to investigate for exchanging malady, spread of tumor and impact on nearby structures. Regularly, they show up the heterogeneous mass in the cervix 18.
1.5.2. Cancer Subtypes
Histologic subtypes of obtrusive cervical carcinoma integrate the additional: Though squamous cell carcinoma is the cervical growth with the most frequency, the rate of adenocarcinoma of the cervix has been expanding in late decades 19.
• squamous cell carcinoma (around 80-85% (citation needed))
• adenocarcinoma (around 15% of cervical tumors in the UK 38)
• adenosquamous carcinoma
• small cell carcinoma
• neuroendocrinetumor
• glassy cell carcinoma
• villoglandular adenocarcinoma
Noncarcinoma malignancies which can once in the while occur in the cervix integrate melanoma and lymphoma.The FIGO stage does not incorporate lymph hub involvement as different to the TNM arranging for most different growths. For cases treated surgically, data acquired from the pathologist to be utilized as a part of relegating a different pathologic stage however is not to supplant the first clinical stage. Stage 0: The carcinoma is confidential to the surface layer (cells coating) of the cervix, Similarly called carcinoma in situ (CIS).4
1.6.1. Screening
Checking the cervix by the Papanicolaou test, or Pap smear, for cervical disease has been credited with drastically decreasing the quantity of instances of and mortality from cervical tumor in created nations 20. Pap smear screening at regular intervals with fitting follow-up can decrease cervical disease rate up to 80% 21. Unusual results may propose the nearness of precancerous changes, permitting examination and conceivable preventive treatment. The treatment of second rate injuries may antagonistically influence ensuing fruitfulness and pregnancy. Individual solicitations urging ladies to get screened are compelling at improving the probability they will do as such. Instructive materials likewise improve the probability ladies will go for screening, however they are not as successful as solicitations 4.
As indicated by the 2010 European rules, the age at which to begin screening ranges somewhere around 20 and 30 years old, “yet specially not before age 25 or 30 years”, and relies on upon weight of the illness in the populace and the accessible assets In the United States, screening is prescribed to start at age 21, paying little heed to age at which a lady started having intercourse or other danger variables. Pap tests ought to be done like clockwork between the ages of 21 and 654 . In ladies beyond 65 years old, screening might be stopped if no unusual screening results were seen inside the past 10 years and no history of CIN 2 or higher exists 22. HPV inoculation status does not change screening rates. Screening can happen like clockwork between ages 30 and 65 when a mix of cervical cytology screening and HPV testing is utilized and this is preferred 23. However, it is adequate to screen this age bunch with Pap spread alone at regular intervals. Screening is not helpful before age 25 as the rate of illness is low 4. Screening is not gainful in ladies more seasoned than 60 years on the off chance that they have a background marked by negative results 4.
Fluid based cytology is another potential screening technique. In spite of the fact that it was presumably proposed to improve the exactness of the Pap test, its fundamental favorable position has been to decrease the quantity of lacking smears from around 9% to around 1% 24. This lessens the need to review women for a further spread. The United States anticipatory Services Task Force bolsters screening at regular intervals in the individuals who are somewhere around 30 and 65 years when cytology is utilized as a part of mix with HPV testing 4. Pap smears has not been as viable in creating nations. This is a imperfect extent in light of the fact that a number of these nations has a bankrupted social insurance framework, excessively few prepared and talented experts, making it impossible to get and interpret Pap smears, naive ladies who motivate lost to postliminary, and a protracted pivot time to get results 4. These substances have brought about the examination of cervical screening approaches that utilization less assets and offer fast results, for example, visual assessment with acidic corrosive or HPV DNA testing 25.
1.6.2. Barrier protection
Obstruction security and/or spermicidal gel use amid sex diminishes malignancy hazard. Condoms offer insurance against cervical growth 26. Proof on whether condoms secure against HPV disease is blended, yet they may ensure against genital warts and the forerunners to cervical growth.. They additionally give assurance against different STIs, for example, HIV and Chlamydia, which are connected with more serious dangers of creating cervical growth Condoms may likewise be helpful in treating conceivably precancerous changes in the cervix 4. Presentation to semen seems to expand the danger of precancerous changes (CIN 3), and utilization of condoms causes these progressions to relapse and clears HPV 27. One study proposes that prostaglandin in semen may fuel the development of cervical and uterine tumours and that influenced ladies may profit by the utilization of condoms. Forbearance likewise forestalls HPV contamination 4.
1.6.3. Vaccination
Two HPV antibodies (Gardasil and Cervarix) diminish the danger of malevolent or precancerous changes of the cervix and perineum by around 93% and 62%, individually3 .The antibodies are somewhere around 92% and 100% influential against HPV 16 and 18 up to less than 8 years. HPV antibodies are commonly given to age 9 to 26 as the immunization is just powerful if given before contamination happens. The immunizations has been appeared to be powerful for less than 4 to 6 years, and they are conventional to be convincing for more; be that as may, the term of adequacy and whether a supporter will be required is incomprehensible 4. The high cost of this antibody have been a reason for anxiety. A few nations have considered (or are thinking about) projects to subsidize HPV inoculation.
Since 2010, young ladies in Japan have been qualified to get the cervical disease immunization for free. In June 2013, the Japanese Ministry of Health, Labor and Welfare mandated that, before overseeing the antibody, therapeutic foundations must educate ladies that the Ministry does not prescribe it. In any case, the immunization is still accessible at no expense to Japanese ladies who acknowledge the inoculation 4.

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1.7. Nutrition
Vitamin An is connected with a lower hazard as are vitamin B12, vitamin C, vitamin E, and beta-carotene 28.
1.7.1. Treatment
The treatment of cervical disease differs around the world, to a great extent because of access to specialists gifted in radical pelvic surgery, and the rise of “fertility-sparing therapy “in created countries. Since cervical malignancies are radiosensitive, radiation might be utilized as a part of all phases where surgical alternatives don’t exist 4.
Microinvasive malignancy (stage IA) might be dealt with by hysterectomy (expulsion of the entire uterus including part of the vagina). For stage IA2, the lymph hubs are evacuated, too. Options incorporate nearby surgical methods, for example, a circle electrical extraction strategy or cone biopsy. For 1A1 infection, a cone biopsy (cervical conization) is viewed as therapeutic 29. In the event that a cone biopsy does not deliver clear edges (discoveries on biopsy demonstrating that the tumor is encompassed by malignancy free tissue, recommending the majority of the tumor is expelled), one more conceivable treatment choice for ladies who need to protect their ripeness is a trachelectomy. This endeavors to surgically expel the disease while safeguarding the ovaries and uterus, accommodating a more moderate operation than a hysterectomy . It is a practical alternative for those in stage I cervical tumor which has not spread; be that as it may, it is not yet considered a standard of care, as few specialists are talented in this system. Indeed, even the most experienced specialist can’t guarantee that a trachelectomy can be performed until after surgical infinitesimal examination, as the degree of the spread of tumor is obscure. On the off chance that the specialist is not ready to infinitesimally affirm clear edges of cervical tissue once the lady is under general anesthesia in the working room, a hysterectomy may in any case be required 4. This must be done amid the same operation if the lady has given earlier assent. Because of the conceivable danger of growth spread to the lymph hubs in stage 1b diseases and some stage 1a tumours, the specialist may likewise need to expel some lymph hubs from around the uterus for pathologic assessment 4. A radical trachelectomy can be performed abdominally or vaginally and conclusions are clashing as to which is better. A radical stomach trachelectomy with lymphadenectomy typically just requires an a few day healing center stay, and most ladies recuperate rapidly (around six weeks) 30. Difficulties are exceptional, in spite of the fact that ladies who can imagine after surgery are defenseless to preterm work and conceivable late unnatural birth cycle. Hold up no less than one year is by and large prescribed before endeavoring to end up pregnant after surgery. Repeat in the leftover cervix is extremely uncommon if the tumor has been cleared with the trachelectomy. However, ladies are prescribed to hone watchful anticipation and subsequent consideration including Pap screenings/colposcopy, with biopsies of the rest of the lower uterine section as required (like clockwork for no less than 5 years) to screen for any repeat notwithstanding minimizing any new exposures to HPV through safe sex hones until one is effectively attempting to imagine 4 .
Early stages (IB1 and IIA under 4 cm) can be treated with radical hysterectomy with evacuation of the lymph hubs or radiation treatment. Radiation treatment is given as outer shaft radiotherapy to the pelvis and brachytherapy (inner radiation). Ladies treated with surgery who have high-chance components found on pathologic examination are given radiation treatment with or without chemotherapy to lessen the danger of backslide 31.
Bigger early-arrange tumors (IB2 and IIA more than 4 cm) might be treated with radiation treatment and cisplatin-based chemotherapy, hysterectomy (which then as a rule requires adjuvant radiation treatment), or cisplatin chemotherapy took after by hysterectomy. At the point when cisplatin is available, it is thought to be the most dynamic single specialist in occasional sicknesses 32. Propelled stage tumors (IIB-IVA) are treated with radiation treatment and cisplatin-based chemotherapy. On June 15, 2006, the US Food and Drug Administration affirmed the utilization of a mix of two chemotherapy drugs, hycamtin and cisplatin, for ladies with late-organize (IVB) cervical disease treatment. Blend treatment has noteworthy danger of neutropenia, frailty, and thrombocytopenia symptoms. For surgery to be therapeutic, the whole growth must be expelled with no tumor found at the edges of the evacuated tissue on examination under a magnifying instrument. This methodology is known as exenteration 4.
1.8. Prognosis
Forecast relies on upon the phase of the malignancy. The possibility of a survival rate around 100% is high for ladies with minuscule types of cervical disease .With treatment, the five-year relative survival rate for the soonest phase of obtrusive cervical tumor is 92%, and the generally speaking (all stages consolidated) five-year survival rate is around 72%. These insights might be enhanced when connected to ladies recently analyzed, remembering that these results might be incompletely in light of the condition of treatment five years back when the ladies concentrated on were initially analysed 4.With treatment, 80 to 90% of ladies with stage I disease and 60 to 75% of those with stage II tumor are alive 5 years after conclusion. Survival rates reduction to 30 to 40% for ladies with stage III tumor and 15% or less of those with stage IV growth 5 years after analysis 4. As per the International Federation of Gynecology and Obstetrics, survival enhances when radiotherapy is joined with cisplatin-based chemotherapy 33.
As the tumor metastasizes to different parts of the body, visualization drops significantly on the grounds that treatment of nearby injuries is for the most part more powerful than entire body medicines, for example, chemotherapy 34. Interim assessment of the lady after treatment is basic. Intermittent cervical tumor recognized at its most punctual stages may be effectively treated with surgery, radiation, chemotherapy, or a mix of the three. Around 35% of ladies with obtrusive cervical malignancy have tenacious or repetitive sickness after treatment 4. Normal years of potential life lost from cervical malignancy are 25.3. Around 4,600 ladies were anticipated to pass on in 2001 in the US of cervical tumor, and the yearly rate was 13,000 in 2002 in the US, as figured by SEER. In this manner, the proportion of passings to frequency is around 35.4% . Consistent screening has implied that precancerous changes and early-organize cervical malignancies have been distinguished and treated early. Figures recommend that cervical screening is sparing 5,000 lives every year in the UK by averting cervical tumor 96. Around 1,000 ladies for every incredible cervical tumor in the UK. The greater part of the Nordic nations has cervical malignancy screening programs set up. Pap smear was coordinated into clinical practice in the Nordic nations in the 1960s 4.
In our study Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of telomerase enzyme that maintains telomere ends by the addition of telomeric repeats to the ends of chromosomal DNA and that may generates immortal cancer cells. Hence, the activity of telomerase is raised in cancer cells including cervical cancer. Unique siRNAs targeting hTERT mRNA sequences were designed to knockdown the expression of hTERT. Methods The siRNA is easily degraded in the cytoplasm of many cells and also has low sustainability. To overcome this problem, ThesiRNA loaded chitosan coated Poly lactic-co-glycolic acid (PLGA) nanoparticle was synthesised by double emulsion solvent diffusion method (DESE). Characterisation of nano formulation were measured to determine efficient siRNA delivery. MTT, RT-PCR and Western blot were performed to evaluate silencing efficiency of Nano-formulation.
2.1. Nanoparticles
Nanoparticles (NPs) are key components of nanomedicine. Currently, there are varies types nanoparticle of cure exist 35. Therefore, terms such as engineered nanomaterials, nonbiological complex drugs (NBCDs), nanomedicals/nanomedicines, etc. are commonly used. Many nanomaterials can replicate some functions of globular biological macromolecules. 36 Many of these nanoscale materials have unique size- and shape dependent optical, electronic, and magnetic properties, and these properties are dependent upon methods to synthesize, to purify, and to characterize them. Many researchers stated that small changes in size and shape can significantly affect the properties of the NPs. Precision syntheses are therefore necessary to produce samples with tightly focused distributions in order to achieve the targeted functions specifically and to correlate observed functions with specific NP characteristics.37 .The characterization of NP samples that are used in a medical application is also critical because one must know and understand what is being injected into the body. In addition to using nanomedicine to diagnose and to treat diseases, it is also important to establish NPs’ efficacy and safety in biological systems. 36 If they do not get cleared, the long-term fate of the NPs is not clear. These particles may degrade and get cleared renally because they are small enough to transport through the kidney’s filtration slits,35?37 or they may accumulate in different organs and interact with off-target cells. The in vivo fate of NPs can potentially be a dynamic process, and thus, there is a need to understand nanobiokinetics (nanopharmacokineticsand pharmacodynamics), which may relate to unique and interesting toxicological responses of NPs. Many of these concepts are still at the early stages of development, but some have already reached clinical practice.38
Magnetic nanoparticles have been widely used as a magnetic resonance imaging (MRI) contrast agents for medical diagnoses of the liver, spleen, and bone marrow.81 In addition, recent studies have attempted to apply magnetic nanoparticle-based gene delivery systems for simultaneous diagnostic and therapeutic functions in vivo.39 For effective gene delivery, it is necessary to modify the surface of magnetic nanoparticles for the stable attachment of therapeutic molecules. This surface functionalization process can allow the effective loading of siRNA onto magnetic nanoparticles. Nanoparticles are physical entities with a characteristic length of 1–100 nm. 40 They can be considered as a unit in term of physicochemical properties. In nanotechnology, the synthesis and characterization of these objects is a broad field in constant development, heading towards “smart” structures with superior capabilities in various scientific and technological contexts, including catalysis, energy conversion, sensors, and actuators. The most promising and rapidly growing applications of nanoparticles are directly linked to biomedical issues, with cellular trafficking and accurate in vitro and in vivo tracking of biological systems being two examples of the new frontiers opened up for biological study by the application of luminescent inorganic nanoparticles.Nanoparticles can be categorized as organic or inorganic according to the bulk constituent materials in their structure. Classifications based on size, shape, surface, structure, and chemical behavior can be devised. Overall, what is particularly attractive about nanostructures is their surface to volume ratio. Nanosized entities enable a very limited volume to provide an enormous surface area for transport, chemical reactions, and interaction with biological systems 41.These features, combined with enhanced permeability to biological barriers, make nanoparticles the basis of nanomedicine and a powerful and promising tool in the design of new diagnostic and therapeutic devices. Interest in nanoparticles has consistently grown in every branch of medicine.42 It has been driven by the potential of nanoparticles to achieve a high therapeutic index and corresponding clinical success with improved patient compliance and reduced side effects. Nanoparticle-based drug delivery systems play an important role in the development and future applications of new pharmaceutical formulations.43. They may be capable of improving bioavailability and reducing the frequency and dosage needed for currently available drugs. With this novel type of drug formulation, in which nanoparticles act as drug carriers, it may be possible to: improve drug stability and carrier capacity; target drug molecules to a specific diseased cell or tissue, avoiding toxicity to normal cells; confine release of the drug to the site of interest; allow efficient permeation of epithelial and endothelial barriers; and combine therapies with codelivery of two or more drugs.44 . Nanoparticles suitable for multistage drug delivery systems are hybrid nanostructures (for instance, with a core-shell structure) designed to reach injured tissues in a selective manner. Each part of the hybrid nanoparticle responds differently in the biological environment.42
Liposomes are among the most advanced nanoparticle drug delivery systems successfully applied in the clinic.Nanoparticles can be engineered in terms of size, surface functionalization, and core structures to overcome these barriers. Nanoparticles have often been reported to have systemic toxicity, mostly in the liver. Hemolysis, thrombogenicity, and complement activation can also occur as a consequence of certain physical or chemical features of nanoparticles. It is important that the nanomaterial carrier is able to be eliminated harmlessly from the body in a reasonable period of time after releasing its cargo, and, in case of theranostic nanoparticles, accomplishing a desired diagnostic function.45 The drug could be adsorbed, dissolved, or dispersed throughout the matrix of the nanoparticles, or, alternatively, it can be covalently attached to the surface or inside the matrix. In the body, the drug loaded in nanoparticles is usually released from the matrix by diffusion, swelling, erosion, or degradation. There are two kinds of targeting strategies are possible, ie, passive targeting and active targeting. Passive targeting does not require surface modification of the nanoparticles, and is achieved using the unique pathophysiology of diseased cells and controlling particle mobility through human tissues, according to particle size and route of administration. Thus, the optimal diameter of nanoparticles for intratumoral delivery, avoidance of the reticuloendothelial system, and renal clearance should be in the range of 5–100 nm 46 . The higher interstitial fluid pressure found in solid tumor tissue could prevent diffusion of nanoparticles. Strategies adopted to overcome this issue could include normalizing the tumor vasculature (eg, with antiangiogenic therapy) and using nanoparticles with a diameter larger than that of normal vessel fenestrations. The molecules must also face the extracellular matrix, and often the desmoplastic process in cancer creates difficulties in this respect 47. Nanoparticulate systems have emerged in last few years as an alternative material for advanced diagnostic and therapeutic applications in medicine. Compared to molecular medicine, nanoparticles offer many advantages that overcome a range of challenges and barriers summarized in the previous section, particularly, bioavailability and biodistribution of therapeutic agents 48.The first remarkable property of nanoparticles is their superior in vivo retention by decreasing enzymatic degradation and sequestration by phagocytes of the reticulo-endothelial systems. This is mostly attributed to their immunochemically inert surfaces in contact with the biological environment. Increased deposition to the diseased sites viacompromised vasculatures in the phenomenon called enhanced permeability and retention effect also contributes to their improved deposit to diseased sites and efficacy 49. There are various types of polymers today, such as chitosan, polyethylenimine (PEI), dendrimers, cyclodextrin (CD), and metallic core nanoparticles. In this sense, nanoparticles are designed to be part of a delivery system and it is necessary to consider the overall behavior of such systems, ie, carrier, payload, and host system properties, as well as mutual interactions 50. In a gene delivery context, a key feature of the carrier is the ability to protect the gene payload until it reaches the target site, with no modification in molecular structure of the gene or its biochemical activity. The pursuit of gene delivery has been undertaken using viral-based and nonviral-based vectors 41. These topics have already been extensively reviewed, so are not discussed in depth in this paper.Some tumor characteristics can be exploited for drug delivery. The enhanced permeability and retention effect takes advantage of the abnormal neovascularization typical of many cancers. This effect is often found in tumors as well as at sites of inflammation and body tissue with other types of disease. The blood vessels are either disrupted or not fully formed, allowing molecules of a certain size to be retained to a greater extent in abnormal tissues than in healthy ones. 51. It has been shown that therapeutic nanoparticles can accumulate in specific target tissues as a result of this effect, potentially allowing for drug release over a longer period of time than for the same drug administered as a conventional preparation.The development of nanoparticles to aid in the delivery of a drug to the brain via inhalation holds considerable promise for the treatment of neurological disorders such as Parkinson disease, Alzheimer disease, and multiple sclerosis 46. Indirect techniques use X-rays or neutron beams and obtain their information by mathematically analyzing the radiation scattered or diffracted by the nanoparticles. The techniques of greatest relevance to nanoscience are small-angle X-ray scattering (SAXS) and small-angle neutron scattering (SANS), along with their surface-specific analoguesGISAXS and GISANS, where GI is “grazing incidence,” and X-ray or neutron reflectometry (XR/NR). The advantage of those techniques is that they are able to simultaneously sample and average very large numbers of nanoparticles and often do not require any particular sample preparation. Indirect techniques have many applications. For example, in studies of nanoparticles in raw sewage, scientists used SANS measurements, in which neutrons readily penetrated the turbid sewage and scattered strongly from the nanoparticles, to follow the aggregation behaviour of the particles over time 52.
The isolation of nanoparticles from colloidal and larger matter involves specialized techniques, such as ultra centrifugation and field-flow fractionation. Such laboratory-based techniques are normally coupled to standard spectroscopic instrumentation to enable particular types of chemical characterization. These features, combined with conventional targeting against upregulated cell surface antigens, allow precise spatiotemporal drug delivery in selected areas of the host system. Furthermore, in the design of nanocarriers, it is possible to achieve stimuli-responsive behavior using pH-sensitive and/or temperature-sensitive materials 53.These carriers hold promise for realizing effective spatiotemporal delivery of drugs. Silica and silicon-based delivery systems have emerged in drug delivery applications due to their controllability in nanopore formation and surface modifications. This enabled a multi-component and multi-functional bio-delivery systems that can possibly perform a sequence of functions at various stages of the delivery route. Several spherical mesoporous silica nanoparticles (MSNPs) with core size range from 50 to 200 nm and modified with polyethyleneimine 54.
2.2. RNAi
In 1998, Fire and Mello et al. discovered that potent and specific RNA interference can be induced by double-stranded RNA (dsRNA) in Caenorhabditis elegans . Further investigations confirmed that similar dsRNA-triggered phenomena also exist in many other species such as plants , Drosophila , and mammalian cells . The past decade has witnessed an explosion of research on small regulatory RNAs that has yielded a basic understanding of many types of small RNAs in diverse eukaryotic species and the functions of key protein factors amidst the RNA silencing pathways.55 RNA silencing is recognized as a widespread mechanism of gene regulation in eukaryotes. The key machinery of RNAi pathway is that dsRNA molecules, experimentally or naturally occurring, can be recognized and cleaved into 21-23 nucleotide duplex termed small interfering RNA by Dicer homologues that have dsRNA binding domain and sRNaseIII-like enzyme activity, The siRNAs are incorporated into the multi-subunit effector complex called RNA-induced silencing complex (RISC), therefore activate the helicase activity leading to cleavage of the sense strand of siRNA 56 The remaining antisense strand recognizes the homologue region with base-pairing and degrading the target messenger RNA (mRNA) mediated by the Argonaute (Ago) family proteins with endonuclease activity, which is the catalytic core of active RISC, resulting in inhibition of gene expression . RNAi technology has become a routine laboratory research tool for gene functional study and is making its way as a revolutionary class of therapeutics for treatment of cancers and different viral infections. The RNAi was considered as a highly conserved natural mechanism that controls the gene expression triggered by a long dsRNAin the cytoplasm.6Cancer is a disease that is often characterized by mutations in multiple signal transduction pathways, leading to uncontrolled cell proliferation. It is thus difficult to identify the key genes governing cell proliferation or survival which should be targeted to induce cell death 57. RNAi technology can be useful for cancer therapy because of its high efficacy and specificity in downregulating gene expression, and it is clearly important to understand the role of altered genes in the development of cancer. It must be stressed that blockage of a single gene is not sufficient to cure or control most cancers. One of the major likely benefits of the RNAi technique in the treatment of cancer is the feasibility of developing combination therapeutic RNAi approaches to inhibit multiple oncogenes or genes of proteins involved in tumorigenesis 58. A unique approach could involve hitting multiple pathways simultaneously and/ or combining gene silencing with other therapies. Many in vitro and in vivo studies have evaluated the silencing of genes involved in pathways that drive cancer, such as oncogenesis, apoptosis, cell cycle regulation, cell senescence, tumor-host interaction, and resistance to conventional therapies. Moreover, because miRNAs may work as both tumor suppressors and oncogenes, these molecules could also be investigated as therapeutic targets, in that they could be knocked down when expressed in excess or replaced in cells when they have been pathologically reduced or lost 59. Deregulated miRNA could also serve as a helpful biomarker for diagnosis and monitoring of disease. Biomarkers are easily and objectively measurable biological characteristics which can be used as indicators of normal and pathological processes. Remarkable, miRNAs can be detected in body fluids, such as blood and cerebrospinal fluid, enabling noninvasive and early detection of disease. A further example of the potential applications of miRNA is expression profiling in order to distinguish cancer from normal tissue and to classify, eg, cancer subtypes or the origin of metastatic cancer tissue 60. The clinical utility of RNAi is still a matter of debate. There has been increasing interest in harnessing this versatile and multifaceted mechanism as a novel pharmacological approach to the treatment of human disease. As has already happened in other developing human therapeutic fields, including gene and antibody therapy, there has been a cooling off after initial enthusiasm. This was driven by a realistic understanding of the various complex milestones that needed to be reached for efficient RNAi-based therapy, before eventual approval for use in human therapy. This trend is now reversing as a result of the excitement generated by the advent of nanomedicine as a potential way of overcoming the challenges in this field. In recent years, there has been an increase in the numbers of preclinical and clinical RNAi-based trials being undertaken. Early proof-of-principle studies in animal models have strengthened the usefulness of RNAi as specific and powerful inhibitors of gene expression without significant toxicity. Translation of animal studies has in some cases progressed to early human trials 42.

In particular, the research interest is strongest when the aim is targeting genes with single nucleotide polymorphism mutations, as found in dominant-negative disorders, genes specific for pathogenic tumor cells, and genes that are critical for mediating the pathology of various other diseases. In these cases, RNAi could represent the only entities providing an opportunity for a potent and specific approach 61.
The relevant clinical trials have addressed many kinds of disease, including retinal degeneration, dominantly inherited brain and skin diseases, viral infections, respiratory disorders, cancer, and metabolic disease). However, large-scale Phase III clinical trials and regulatory approvals remain distant. Use of RNAi for respiratory tract and neurological disorders, metabolic disease (such as hypercholesterolemia), and hepatic cancer has been widely revised in recent times. Most of the more advanced clinical trials focus on the treatment of age-related macular degeneration, which is a leading cause of blindness arising from excessive growth of blood vessels and their rupture within the cornea. . However, effective and well controlled in vivo delivery is challenging, and presently limits the use of RNAi in the clinic .In fact, these molecules, without any other modifications (“naked”), encounter several obstacles that reduce their therapeutic efficacy. To be efficacious, they need to reach the cytoplasm of the cell in sufficient amounts to enable sustained target inhibition 41.
RNAi is a fundamental regulatory pathway for most eukaryotic cells. It consists of complex enzymatic machinery able to control post-transcriptional gene expression through homology-dependent degradation of target mRNA by siRNA, ie, nontranslated dsRNA molecules. siRNA molecules are 21–23 nucleotides in length with a characteristic and highly specific structure (2–3 nucleotide 3? overhangs and 5? phosphate and 3? hydroxyl groups) to prevent erroneous gene silencing. They also contain a sense (passenger) strand and an antisense (guide) strand. On the other hand, the potential advantage of DNA-based RNAi is its stable introduction into cells as gene therapy, bypassing transient effects, so avoiding repeated or continuous administration in the clinical setting 62. Intact RNAi machinery is clearly essential for mammalian cells, as suggested by the early embryonic lethality of Dicer knockouts. The advantage of siRNA as therapeutics is that siRNA can target many undruggable genes. Other than antibody-based therapeutics that mainly targets receptors present on the cell surface, only a very small number of targets, mostly kinases, have been validated for traditional small molecule drugs. In addition, it is found that diseases such as cancer, genes are often deregulated by high-level amplifications. Such genes are particularly interesting as therapeutic targets for treatment of patients that are refractory to existing therapies. The properties that have been validated in chemotherapeutics are also exploited for siRNA packaging and delivery. The effort began with stable association of siRNA molecules with the nanoparticles and their retention in circulation. Methods of conjugating siRNAs with other inert and biocompatible molecules, such as cholesterol and long-chain fatty acids have been reported. 11Unlike long dsRNA with over 100 bp, synthetic siRNA has 21 ~ 23 bp with a 2-nucleotide overhang at both of the 3′ ends. In addition, siRNA is incorporated into RISC without a Dicer processing step. Synthetic siRNA has attracted much attention because it can easily be designed and customized for any gene. Although many hindrances remain for applying these technologies in the treatment of cancer, early clinical results are exciting, and suggest that we are moving forward quickly and also highlight how far we have already come 63.
2.3. SiRNA
Small interfering RNA (siRNA) has proved to be a powerful tool for target-specific gene silencing via RNA interference (RNAi). Its ability to control targeted gene expression gives new hope to gene therapy as a treatment for cancers and genetic diseases 64. However, siRNA shows poor pharmacological properties, such as low serum stability, off-targeting, and innate immune responses, which present a significant challenge for clinical applications. In addition, siRNA cannot cross the cell membrane for RNAi activity because of its anionic property and stiff structure 65. Therefore, the development of a safe, stable, and efficient system for the delivery of siRNA therapeutics into the cytoplasm of targeted cells is crucial. Several nanoparticle platforms for siRNA delivery have been developed to overcome the major hurdles facing the therapeutic uses of siRNA.
An example of the clinical feasibility of siRNA application for cancer therapy is represented by chronic myeloid leukemia. In more than 90% of cases, this disease is caused by a chromosomal aberration, ie, the so-called Philadelphia chromosome. This abnormality is due to fusion between the Abelson (Abl) tyrosine kinase gene at chromosome 9 and the breakpoint cluster (Bcr) gene at chromosome 22, resulting in the chimeric oncogene Bcr-Abl and a constitutively active Bcr-Abl tyrosine kinase implicated in the pathogenesis of chronic myeloid leukemia. The findings of this study imply that the clinical application of synthetic siRNA is feasible and safe, and has real potential for a genetic-based therapy using a synthetic nonviral carrier 64. In this small Phase I clinical trial, nanoparticles packed with siRNA were administered systemically on days 1, 3, 8, and 10 every 21 days via a 30-minute intravenous infusion to patients with melanoma refractory to standard of care. This new “drug” was able to deliver its cargo to melanoma cells and to silence the targeted gene.Terminal modification (5? or 3?) of siRNA molecules using cholesterol is a useful strategy for increasing their stability and cellular uptake. In particular, it increases binding to serum albumin, with consequent improved biodistribution in certain target tissues, eg, the liver. The improvement in cellular uptake is mediated by in vivo interaction and incorporation into low-density and high-density lipoproteins. Cholesterol-modified siRNA are capable of silencing apolipoprotein B targets in the mouse liver and jejunum, and of ultimately reducing total cholesterol levels.65. However, although this type of chemical modification has improved siRNA delivery to tissues, it is often associated with impaired biological activity and increased toxicity. In addition, siRNA can be conjugated with other lipid-like molecules, such as long-chain or medium-chain fatty acids and bile salt derivatives. These interact with high-density and low-density lipoprotein receptors, enhancing delivery into the liver and gene silencing in vivo. Moreover, albumin serves as a primary carrier for siRNA conjugated to medium-chain fatty acids. . Among the successful in vivo demonstrations, are antibody-protamine fusions that bind siRNA 63. Along with antibodies, aptamers99 have been used for site-specific delivery of siRNA because of their high affinity and specificity for targets, with the advantages of a much smaller size (

1. Introduction
The sources of water supply are naturally from the snow, rain and droplets of water that falling from the clouds. The condensation process of water surfaces occurs when the heat radiated from the sun and form it into clouds. The amount of water vapor during the evaporation process depends on heat temperature. When the heat temperature drops which is lower than water vapor saturation point, the clouds will release excess moisture and descend to earth. The evaporation and condensation process will be repeated and this is known as rain cycle (Hall, 1987).
According to the surfaces water (Hall, 1987), is ‘soft’ and subterranean waters are found ‘hard’ depends on strata of earth comes contact with. There are two hardness of water that are temporary and permanent. Temporary hardness is when the water passes through strata containing a certain of amount salts (magnesium or carbonate of calcium) and will be taken into water which contains the amount of carbon dioxide present. However, for the permanent hardness is when the water passes through strata containing calcium sulphate, magnesium chloride or calcium chloride, it will dissolve without the carbon dioxide in water. For soft water are readily lathers and it is not suitable for drinking uses as it contains some hardness degree in the solution which can cause corrosion of zinc, iron, steel and even lead and copper. Based on Fig. 1.1 shows the process of base exchange for temporary and permanent hardness. This process will remove all the hardness from temporary and permanent of water efficiently by going through a steel cylinder containing zeolites (Hall, 1987).

Sodium Zeolite + Calcium Sulphate/Carbonate = Calcium Zeolite + Sodium Sulphate/Carbonate
Calcium Zeolite + Sodium Chloride = Sodium Zeolite + Calcium Chloride
Fig. 1.1 Base exchange process
2. Cold water system
When designing a cold water system for a certain residential building, it is important to know the requirement of Water Authority for local based on Table 1.1 and Table 1.2 by previous work (Hall, 1987). There are two types of distinct systems which are direct and indirect system and some of them are allow to be modified the systems based on Water Authority given. However, in terms of cost saving issues direct system are used in designing this cold water system.

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Table 1.1
Provision of cold water to cover 24-hour interruption of supply C.P Water Supply
Types of building
Storage in liters
Dwelling houses and flats (per resident)
Hostels (per resident)
Hotels (per resident)
Offices without canteens (per head)
Offices with canteens (per head)
Restaurants (per head/per meal)
Day schools (per head)
Boarding school (per head)
Nurses’ homes and medical quarters (per resident)
Table 1.2
Volumes of water, hot and cold, added together required for single use of appliances
Volume required in liters
Wash basin
hand wash
hand and face wash
hair wash
Washing machine
wash up
3. Direct system
This system frequently used in northern districts, where they can provide an efficient main supply by the large high-level reservoirs. For all sanitary fitting in the system are provided from cold water through directly by the main based on Fig. 1.2 (Hall, 1987) and a cold water feed cistern need only to consume from the hot water storage cylinder. The main supply are usually supplies a cold water for showers, baths, basins for example and it required to double the capacity in liters for the uses of hot water cylinder in the direct system. The capacity in liters of hot water cylinder required more than the capacity in liters for cistern used. Based on Water Regulations, the cistern required 114 liters (minimum) capacity and it also enough for accommodated in the pipework and sanitary systems shown in Fig. 1.3 (Hall, 1987).

# drawing
Fig. 1.2 Connection to water main
Fig. 1.3 Detail of cold water cistern
4. Back siphonageBack siphonage occurs when the presence of negative or reduced of pressure (vacuum or partial vacuum) in water which mainly located in the drinking water main supply. This is usually created in the pipe connected to a valve or tap, with submerged the outlet into water and also can cause contaminated. This thing may be happening when the water main supply is adequate to snag the water and evacuate a partial vacuum. To prevent the back siphonage occurs, the following statement or points must be perceived. For example, the taps outlets must be connected to baths, sinks and the basins should be above from level of flooding for the fitting, all fitting that have water inlet with low-level version such as bidets must be supplied by from a cold water storage and not from the main supply and in the overflow pipe, the ball valves in water storage cisterns must be situated above the pipe and same goes for the outlets of silencer pipe which must be situated above position of valve (Hall, 1987).

5. Distribution of water for cold water supply and hot water supply
There are five type of pipe which are commonly used in small low-rise residential building for direct system such as communication pipe, supply pipe, service pipe, overflow pipe and warning pipe. Communication pipe are the main pipe which supply the water directly from the resources (Severn Trent Water) and pass through the supply pipe with a minimum 15mm of diameter into the residential building. The communication pipe that running from the main water to the boundary of a property can allow a structure to connect with a multiple water supply. The underground service pipework must be laid at a minimum depth of 750 mm to guard against frost and mechanical damage and must be no deeper than 1350 mm so that it is accessible for repair (Fang, 2018). Polythene plastic services pipe are commonly used in underground applications. It is uncommon for the underground pipes to be expose for inspection unless there are presence of leaking or damage have been reported (Noy, 1994). For old building, they usually use lead underground pipes and because of the medium quickly decay it have been forbidden.

The water from supply pipe will flow to the service pipe and distributed directly to the sink, basin, bath, W.C cistern and to the cold water storage tank with a minimum 100 litres capacity of water for direct system. The stop valve installed between the supply pipe and service pipe to stop the flow of water when there are presence of leaking in pipe. However, the service pipe will drain most of the water to a cold water storage tank. The cold water storage tanks must be located in the tanks room or roof spaces according to the regulations requirement and must be covered by dust-proof cover for health and safety. According in previous research (Seeley, 1987), there are many failures occurred when using copper pipes for connecting the galvanized steel tank because there are certain types of water which comes from the hot water system pipes that are capable in dissolving amount of copper particles. When the water comes into the galvanized tank, there will be a certain amount of copper will be deposited with zinc and it will equivalent amount of zinc is dissolved into it. The zinc and copper will produce electrolytic that can cause the ultimate perforation and coating of zinc, then rusting begins to take place and cause the tank to leak slowly. In generally, for a hot water system is best constructed throughout of copper, unless previous experience in the district shows it to be safe to use these materials together based on previous inspection (Seeley, 1987). To prevent the galvanized steel cold water tank from becomes rusting and leaking is by painting the internal surfaces with non-toxic bituminous solution which can give protection coating to the surfaces. Furthermore, using plastics tank and glass fibre can help the tank to last longer. Based on the article, Building Research Establishment (BRE) have found where trussed rafter members have been distorted because the tank bearers were incorrectly sized and positioned, pipe joints disturbed and chipboard tank platforms have become wetted by condensation and collapsed. Moisture damage has also been caused by overflow pipes having too small bore, sagging or having inadequate slope (Seeley: 1987).

The water from cold water storage tank will flow through the distribution pipe into hot water cylinder. During supplying the hot water in this direct heating systems, there are few components in the system that are cold water supply pipe, boiler, hot water cylinder, expansion pipe, the flow and return pipes. The gas-fired boilers are used in this system as it usually can be mounted on wall and connected to a conventional or balanced flue. Sometimes, there are two types of difference device to operates the boilers which are the automatic electric ignition and a permanent pilot light. The boilers are usually installed in a kitchen area depends on the layout in a domestic property. If is not permitted, the boilers can be installed in a specific cupboard and provides a ventilation for the compartment. The two air vents must be provided and both can be either through directly outside air or a room that can be ventilated located at low level and at high level. The full way gate valve are attaches to distribution pipe in order to control the fluids in low-pressure systems and have less resistance of fluids flow than the globe valve (Hall, 1987). The distribution pipe is a pipe within the structure that convey water from the water services that connected to a cold water storage tank to the point of utilization. The flow pipe must be located at higher position at water tank because if the ball valve were damage or broken, this pipe will help the water to flow to the other pipe. It will need to be mounted slightly above the full water tank that supplying water to overflow in the event of damage to the ball valve and pipe. Based on Fig. 1.5 are the design sketches for water services.

Fig. 1.4 Design of direct system of cold water supply and hot water supply
6. Sanitary fittings in pipework
The sanitary appliance discharge through the stack pipes or the multi-use discharge pipes in single stack plumbing. For this pipe design, the stack for a bath waste must be above at least 200 mm below entry in a WC pipes. The sink waste, baths and basins also required 75 mm deep seal and 50 mm for WC deep seal. Based on Approved Document H1 of the Building Regulations 1985, it requires 3 m maximum pipe length of 40 mm and 4 m pipe length of 50 mm. Within a good functional of WC flushing cistern must be filled water in 2 minutes per once when used and the orifice valve must be exactly have the same supply pressure in flushing cistern to give required flow for water. Wash basins, baths and sinks must be installed without using the overflows passage. The length between the bottom of cold water cistern and shower rose is 900 mm to maintain the water pressure from cold water cistern.
Based on article (Stauffer: 2018), a low-flow toilet is commonly known as a flush toilet which use a special cistern and siphonage design to remove waste and use less of water. This toilet is designed specially to less in water use than a full-flush toilet. Basically, the low-flow toilet required less than 6 or litres of water to remove for urine only and it can operate by using gravity and vaccum. During previous research (Stauffer, 2018), the user needs to use two or more flushes in order to clean the bowl which is precisely they need a large volume of water. For this case, they have decided to modify the passageways in toilet bowl to reduce amount of water use which it can provides a different volume of flush to solid waste and liquid waste contains two button for each uses. For now, they also use and automatic low-flow toilet that can provide
7. Conclusion
In order to further improve the performance efficiency and economic of industrial center for water service in future, a strategic design approach water use have been constructed in this report. Based on the explanation above, the design have been focusing on how the distribution of cold water supply and hot water supply for small low-rise residential building which are more into total usage of waters by users in property and the quality of water. It is important to control the usage of water as it can minimize the cost to regain water supply. For water quality section, the water have to go through various water treatment. The water must be undergoes a few process such as pre-chlorination, aeration, coagulation, sedimentation, filtration and disinfection. However, for domestic uses, the water will be in softening process (ion exchange) to disinfect and removes large metal ions.

Hall, F. (1987). Building services and equipment. Volume 1. 2nd ed. Harlow, Essex: Longman, pp.1-16.

Noy, E. (1994). Building surveys and reports. 2nd ed. Blackwell Publishing Ltd, pp.227-246.

Seeley, I. (1987). Building maintenance. 2nd ed. Basingstoke: Palgrave, pp.177-180.

Fang, Y. (2018). Domestic Cold Water. Coventry: Dr Yueping Fang, pp.28-30.

Stauffer, B. (2018). Low-flush Toilets | SSWM – Find tools for sustainable sanitation and water management!. online Sswm.info. Available at: https://sswm.info/water-nutrient-cycle/water-use/hardwares/toilet-systems/low-flush-toilets Accessed 2 Nov. 2018.

Architects, Z. (2018). Blog · Ziger/Snead Architects. online Zigersnead.com. Available at: http://www.zigersnead.com/current/blog/post/waterless-urinals-how-do-they-work/12-15-2007/555/ Accessed 3 Nov. 2018.

PIPELINE (2000): Alternative Toilets Options for Conservation and Specific Site Conditions. Morgantown: National Small Flows Clearinghouse Accessed: 8 Nov. 2018

1.1 Introduction
The basic issue of this research was to focus on the indiscipline cases in some selected five (5) Secondary schools in Imotong State-Torit (South Sudan) which are listed as follow: 1) Torit Day Secondary School 2) Dr.John Garang Memorial Secondary School 3) Bishop Akio Secondary School, 4) Torit Progressive Secondary School 5) Fr. Saturlino Ohure Secondary School.
This research consists of Background of the study which concentrates on the core understanding of the paper, Significance of the study focuses on identifying types and causes of indiscipline and how the stakeholders will look for appropriate solution. The Objectives of the study was to find out the causes of indiscipline cases among the Students in Imotong State. Problem of study was to identify possible solutions and put indiscipline to an end, research question was to find out the views of the students, teachers, head teachers and parents. Literature review focused on the types, causes, importance and control of indiscipline among the Secondary School Students. The research methodology used was mix quantitative and qualitative methods with (75) participants comprises of Students, teachers, and head teachers Parents, which was conducted in Imotong State Torit South Sudan, data analysis and conclusion were summarized and finding recommended.
The number of Students’ drop out is increasing due to poor performance caused by the misbehavior in the Schools such as late coming, smoking, fighting, and many others which will create another gap in the young generation stage and will lead to destruction of the State since youth are the back born of the country. According to Hell (1904) viewed adolescence as a time when “the wisdom and advice of parents and teachers is overtopped and I ruder natures may be met by blank contradiction” (vol.2, p-79). He viewed this as due not only to human evolutionary history but also to the incompatibility between adolescents” need for independence and the fact that “parents still think of their off-spring as were children, and tighten the rein where they should loosen it”(vol.2, p,384). In most cases, corporal punishment creates hatred and opposition that will disconnect understanding between students, teachers and administrators in the school. Sullivan, Johnson, Owens and Conway (2014), siting Slee (1995), advance that, suspension as a means to reforming students behavior does not help the student because the school staff simply get rid of the troublesome students rather than changing the school environment in such a way as to prevent or reduce discipline problem.
However, discipline as part of educational and lifelong training must be carried out in the context of peace and needs to deal with in school in order to reduce the concern. Discipline is a required set of actions by a teacher towards a student after the student’s behavior disrupts the ongoing educational activity or breaks a pre-established rule created by the school system. Therefore, guides the children’s behavior or sets limits to help them learn to take care of themselves, other people and the world around them.

1.5 Assess the risks attached to making judgments based on limited or unrepresentative samples
There are a number of risks which are attached to the making of conclusions. First unrepresentative samples may be misleading. This is because; they may only show one side of the topic under study. Hence, the information obtained from limited and unrepresentative samples will not provide reliable information which is vital in making the reliable findings about a research topic.
Secondly, limited samples are affected by few variables. For example, a study on a small population which is only affected by cholera may not provide sufficient information on a topic relating to the study of all waterborne diseases. More so, a researcher will not be able to make satisfactory wide conclusion about a study topic since the information presented by a limited sample is limited. Lastly, unrepresentative samples put the research work at the risk of christened as one that creates a sense of conflict of interest. This is because, limited samples provide less information which creates a niche for nuanced understanding about a topic of interest.
1.6 Assess the risks attached to generalising research findings
Generalisation of findings is risky because it may be misleading. Generalisation uses a representative idea which may not apply to all. For example, generalisation about certain behaviours in a population may not provide a vivid explanation because the behaviour in question may be affected by variables like age, gender and/or social statuses. Additionally, generalisation creates the risk of unreliability of data and findings. A study which is deemed to be unreliable is not applicable in the context of research.
For example, a generalisation on certain cultural norms of a target population may lead to disagreements within the population under study. Those who do not agree with the findings may render the research findings as untrue which make them unreliable. Lastly, it creates the risk of conflict of interests. Herein, generalisation may be deemed as the idea of the researcher. Therefore, the generalised idea may be perceived as the personal stipulation of the researcher which also makes the validity of research findings questionable.
1.7 Explain different formats and techniques for the presentation of the analysis
• Graphical format. This involves bar and line graphs. It consists of both the independent and dependent variables located on each axis of the graph.
• Pie charts. These show the specific share of each item under study.
• Scorecards. They show the specific rating of a specific item under study.
• Maps, texts and Images. These show the specific location, appearance and meaning of certain aspects regarding to the topic of interest under study.


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