Developing Anti-Mycobacterial Therapeutics

Developing Anti-Mycobacterial Therapeutics Using a specific example discuss a possible target for the development of anti-mycobacterial therapeutics. Introduction It is estimated 1.8 billion people worldwide are infected by tuberculosis (TB)- an infectious disease caused by the etiologic agent Mycobacterium tuberculosis (Mtb) (Fullam et al., 2012). This bacterium is responsible for 2 million deaths each year and remains a continuing threat (Ouellet, Johnston and Montellano, 2011). 70-90% of individuals infected carry latent TB and never develop the disease, on the other hand, 10-30% of individuals infected can develop active TB. Over the years, the threat of TB has increased alarmingly due to the rise of multi-drug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). The rise of MDR-TB and XDR-TB threatens to overwhelm all currently available drugs (Yam et al., 2009). Hence, the need to develop new anti-mycobacterial therapeutics. Currently, there have been numerous potential targets identified for the development of novel inhibitors. This review focuses on Mtb DNA gyrase as one such possible target (Mdluli and Spigelman, 2006). Structure and Function of DNA Gyrase DNA gyrase is an essential tetrameric enzyme involved in DNA synthesis and is understood to be the only type II topoisomerase present in Mtb. The structure of DNA gyrase consists of two subunits called GyrA and GyrB which initially form homodimers, called A2 and B2, and then form a larger heterodimer, called A2B2. The two subunits carry out different functions with the GyrA subunit carrying out cleavage of positive supercoiled DNA, while the GyrB subunit promotes ATP hydrolysis. The GyrA and GyrB subunits are products of the gyrA gene and gyrB gene. The gyrB gene is 34 base-pairs upstream to the gyrA gene and both genes are located close to the origin of replication (Unniraman, Chatterji and Nagaraja, 2002). Mtb reproduce by binary fission. During DNA replication, DNA helicase binds to the DNA double helix and begins to unwind the parental strands by utilising ATP to break the hydrogen bonds between the base-pairs. Single-stranded binding proteins help to stabilise the unwound DNA strands and prevent them from re-pairing. The point at which the two strands of DNA separate are known as replication fork. DNA polymerase then moves along each strand of DNA behind each replication fork synthesising new DNA nucleotides. As the replication fork expands, positive supercoils begin to accumulate ahead of the replication fork. For DNA replication to continue, the positive supercoils need to be removed. Supercoiling causes the DNA to form a more compact structure. DNA gyrase inserts negative supercoils to Mtb DNA. DNA gyrase binds to a circular, supercoiled DNA molecule and this alleviates one positive supercoils. Gyrase first introduces a double-stranded break in the DNA, then a segment of DNA pass es through the break to the opposite side of the gyrase protein. This movement of the DNA requires ATP hydrolysis by gyrase, and introduces a negative supercoil into the DNA molecule. Subsequently, the break in the strands is repaired and gyrase is released from the DNA. Thus, a DNA molecule with one positive supercoil now has one negative supercoil. The GyrA subunit consists of two domains called the GyrA N-terminal domain (GyrA-NTD) and GyrA C-terminal domain (GyrA-CTD). The GyrA-NTD whereas, the GyrA-CTD stabilises the binding of DNA gyrase to DNA. The residue Tyr-122 of GyrA is the site of covalent attachment to DNA. Similarly, the GyrB subunit consists of two domains called the GyrB N-terminal domain (GyrB-NTD) and GyrB C-terminal domain (GyrB-CTD). The GyrB-NTD contains the ATP binding sites. DNA gyrase is absent in eukaryotic organisms even though a less homologous enzyme does exist. Fluoroquinolones Fluoroquinolones (FQs) bind to the enzyme-DNA complex. By targeting GyrA, the duration of treatment can be shortened making it a validated target. C-terminal Domain of GyrA  Ã‚   The ability of Mtb DNA gyrase to bind and insert negative supercoils into DNA is mediated by the C-terminal domain of the GyrA subunit (GyrA-CTD). Several highly-conserved residues in GyrA-CTD were selected as potentially participating in DNA binding and bending. The use of site-directed mutagenesis resulted in the identification of four key residues which were R691A, Y577A, R745A and D669A. Substitution of these four residues resulted in a total loss of DNA binding activity by GyrA. This in turn caused a loss in supercoiling activity and relaxation. The ability of Mtb DNA gyrase to carry out its function only occurs when the GyrA subunit is combined with the GyrB subunit. Mutagenesis of R691A, Y577A, R745A and D669A not only results in loss of DNA binding activity of GyrA in the absence of GyrB, but also results in a loss of DNA binding activity in the presence of GyrB. This again led to a loss in loss in supercoiling activity and relaxation. The findings of GyrA-CTD to be essential for Mtb survival strongly promotes the idea of a new potential drug target. GyrB Subunit of Mtb DNA Gyrase The emergence of fluoroquinolone-resistant tuberculosis has meant there is a need to develop new classes of drugs targeting Mtb DNA gyrase. A lot of emphasis is often focused on targeting the GyrA subunit and this had led to research in developing novel inhibitors targeting the GyrB subunit (Medapi et al., 2015). The GyrB subunit is an attractive target for the development of anti-mycobacterial therapeutics for several reasons. Firstly, the GyrB subunit is present in a single copy. Secondly, it is an essential gene for the survival of Mtb. Thirdly, there are no alternatives to GyrB present in Mtb which could carry out the same function if it is inhibited because it contains the ATP binding pocket. Fourthly, the various strains of Mtb have a 99.9% homology for GyrB. Fifthly, GyrB exerts the same phenotypic effects on Mtb viability as FQs. Finally, the development of inhibitors targeting GyrB can be effective in shortening the duration of TB treatment and delaying the emergence of drug resistance (Chopra et al., 2012). The residues involved in ATP binding are found in the GyrB-NTD and are between residues 1-220. Moreover, two further residues, Gln335 and Lys337, found in the GyrB-CTD are also involved in ATP binding. To the date, there are hundreds of potential novel inhibitors which have been identified to inhibit the activity of GyrB. Inhibitors could be design to target the ATP-binding site or the non-ATP-binding site, however, little is known about structure of the non-ATP binding site. Novobiocin is the only approved antibiotic which has shown to inhibit the activity of GyrB. However, novobiocin has been withdrawn from the market because it is extremely toxic and has low permeability. Another drug class of drugs, aminobenzimidazole, are another strong candidate for inhibiting GyrB due to their excellent efficacy against MDR-TB strains (Chaudhari et al., 2016).

Christianity vs. Islam Essay -- Christianity Islam Compare Contrast E

Christianity vs. Islam Christianity and Islam are two of the world’s largest religions. The two are different in beliefs but are similar in origin. Like many religions both Islam and Christianity claim to be the one and only true way to God. Although Islam and Christianity differ in major ways, they also share some similarities. Islam teaches that in order to achieve true peace of mind and surety of heart, one must submit to God or â€Å"Allah† and live according to His revealed Law. Being a Muslim requires willful submission and active obedience to God and living in accordance with His message. Conversely, Christianity does not teach absolute submission to God, but teaches that man is sinful and can never inherit eternal life in the presence of God as a result of the sins of our first parents, Adam and Eve, as well as our own personal sin. Therefore it became necessary for God to become man in the person of Jesus Christ, who as the Son of God was sinless and unblemished. His purpose was to suffer and die in atonement for the sins of all whom accept his sacrifice for sin. Muslims believe all of God’s prophets, who include Abraham, Noah, Moses, Jesus, and Muhammad brought the same message of Pure Monotheism. For this reason, the Prophet Muhammad was not the founder of a new religion, as many mistakenly think, but he was the Final Prophet of Islam. The Qur’an, the Muslim Bible, is believed to be the last book of God sent to mankind. This is believed to have been given t...

Challenging environment Essay

Mrs. Dae is a 28 year old Caucasian female. She presents clean and well dressed. She is approximately 5’ 6†, 145 lbs. She appears healthy and in shape. No visible physical deformities. She has normal gate. She is open and cooperative. She has a normal rate of speech and makes appropriate eye contact. Mrs. Dae expresses herself appropriately. In discussing family history, Mrs. Dae has little trouble recalling events. She is unaware of some family history on her father’s side. Mrs. Dae is orientated x 4. She has logical thought process. Mrs. Dae is alert, however, states she has been busy lately and is tired today. She reports getting approximately 6-8 hours of sleep nightly. Mrs. Dae is able to count backward from 100 by 7’s. She displays logical thought processes. No report of hallucinations or delusions. Mrs. Dae appears to have good judgment and insight. She is of high intelligence and is able to appropriately explain the meaning of a common proverb. (â€Å"A rolling stone gathers no moss†) (â€Å"How to†). Mrs. Dae appears happy and confident, with appropriate affect. During the interview Mrs. Dae was relaxed and participated in spontaneous conversation. She denies any suicidal or homicidal ideation. Strengths/ Weaknesses: Mrs. Dae is highly educated. She appears confidant with high self esteem. She reports she enjoys caring for others. She has good insight and appears to have good coping skills. Mrs. Dae has a supportive family. In terms of weaknesses, Mrs. Dae admits to taking on too many activities at once and at times she feels â€Å"burned out†. Family History: Mrs. Dae is the second of three children and grew up in a typical middle class American home. She has an older brother and a younger sister. Mrs. Dae’s parents were divorced when she was 7 years old. Ms. Dae and her siblings lived with their mother. Mrs. Dae reports her father was verbally and physically abusive toward her mother. This was the reason for the divorce. She does not recall being the victim of such abuse herself. However, she reports that her mother tells her that her father was â€Å"mean to all of us† (referring to Ms. Dae, her siblings and mother). Mrs. Dae denies any sexual abuse. Shortly after the divorce, Mrs. Dae reports all three children stopped seeing their father. She currently has no relationship with her father, however she reports speaking to him on the phone occasionally. Aside from these events, Mrs. Dae reports a normal childhood. She reports discipline as a child in the form of â€Å"grounding, which rarely occurred†. Mrs. Dae is currently married. She has been married for the past 8 years. She denies any previous marriages. Ms. Dae describes her marriage as â€Å"good†. She states she and her husband attended marriage counseling for approximately 3 months earlier in their marriage. Mrs. Dae reports that her husband has a well paying job. She denies any current financial hardship. The couple recently bought their first home. She reported some stress during the process. However, she did not think it was â€Å"more then would be expected when buying a home†. Mrs. Dae and her husband have one child, a 5 year old girl. Education and Work: Mrs. Dae graduated high school in the top 10% of her class and went on to college. She majored in psychology and graduated Cum Laude. She continued to earn her Master of Science degree. Mrs. Dae currently works with at risk youth in the prevention and advocacy department of a non-profit company. She has been with her current employer for one year. She reports being satisfied with her job. She states she makes â€Å"good† money and the work she does is rewarding. Mrs. Dae stated she plans on returning to school in the near future for her PhD in Psychology. Her long term goal is to go into private practice serving youth. Mental/ Physical Health: There is no known history of mental illness on her mother’s side of the family. Mrs. Dae reported there may be depression on her father’s side. Mrs. Dae denies any form of depression aside from â€Å"the blues† every now and then. Mrs. Dae reports history of cancer on both sides of her family. Mrs. Dae participates in annual physical examinations. According to her last physical she is in good health. Mrs. Dae denies substance use. She stated she will drink a glass of wine â€Å"once in a while†. Mrs. Dae denies tobacco use. Legal History: Mrs. Dae denies any significant legal history, aside from a few traffic tickets. Social: Mrs. Dae reports she has a group of friends, other married couples, that she and her husband spend time with. She is also a member of her church and participates in social events at the church. As her child recently started attending elementary school, Mrs. Dae stated she has joined the school’s Parent-Teacher Association. Spiritual: Mrs. Dae reports growing up Catholic but she did not go to church often as a child. She states that she no longer practices Catholicism, however, she does go to a non denominational Christian church. She goes to church on a regular basis. She feels strongly about her beliefs. Mrs. Dae reports that she prays on a daily basis and stated â€Å"this keeps me grounded†. Hobbies/Activities: Mrs. Day states she enjoys reading, yoga, and going to the spa with friends. She admits she has little time to spend on these activities. However, she reports that she and her husband give each other time with their friends, time together, and family time on a regular basis. References How to do a Mental Status Exam. Retrieved on November 9, 2007 from http://www.psychpage.com/learning/library/assess/mse.htm

Integrated Case Study: Bandon Group, Inc. Essay

This paper is the continuation of Bandon Group Inc. integrated case study. This part of the case study mines feasibility of an ERP system at Bandon Group and evaluate alternative ERP and CRM packages for Bandon Group and make recommendations for a solution which will meet their needs. Step 8: Determining the feasibility of an ERP system From the description of the executive managers of the divisions, it is pretty clear that Bandon Group has encountered big challenges with the current IT situation. Many of the issues discussed possibly will be solved by restructuring and re-engineering the organization, the business process and by placing the legacy systems with an ERP system. ERP provides the backbone for an enterprise wide information system. A primary benefit of ERP is easier access to reliable, integrated information. A related benefit is the elimination of redundant data and the rationalization of processes, which result in substantial cost savings (Lau, 2003). From the case study, we have learned that the co-owners are requesting eBusiness know-hows, on-demand reports that generates electronic reports, the need to address for more information for tactical and strategic management, the need to standardize business process and the need for more targeted marketing (Sumner, 2005). The dilemma was to decide whether the system should be centralized or decentralized. The implementation of the CRM softwares in the divisions were decentralized and the division mangers were seeking better management  information but they were encountering data relational problem. In general, when we look at the current IT situation especially the use and implementation of CRM and OMD application, it is intolerable. The problem get worse when the company plans to expand its business with the existing situation. The answer for Bandon Group should pursue and EPR solution absolutely is yes. That would be my recommendation. Basically ERP implementation requires organizations to re-engineer their key business in fundamental ways and restructuring the overall organization system because the ERP is there to address business issues and to place the company in a better competitive environment and position. Kumar (2010) emphasize that managers must conduct a feasibility study of the current situation to assess the organization’s needs by analyzing the availability hardware, software, database ad in house computer expertise and make the decision to implement ERP where integration is essential. To decide whether Bandon Group should purse for ERP solution, we should reconsider the benefits of implementing ERP. As Sumner (2005) outlines the benefits. Some of the main benefits ERP he mentioned. ERP maximizes throughput of information Minimize response time to customers and increase interaction with customers, Increase interaction across the enterprise, Improve on-time delivery, Reduce direct operating expense, Increase interaction with suppliers, etc. When we come to the Bandon Group practical case, integration problem was critical for all divisions. Some of the areas that ERP overcome are: Coordination: after implementing ERP, it has been confirmed that ERP has the ability to support coordination across business functions. Database: by implementing ERP, it is possible to integrate data so that data will have the same meaning across multiple functions. Process: after implementing ERP, it has been realized consistent business processes which are based upon an information model. Information: Pursuing ERP makes real-time information consistent Information system: ERP has enabled stand-along systems to become integrated systems. Once again, it is my recommendation to Bandon Group to purse CRM solution. Like ERP, it is an integrated approach to managing relationships by focusing on customer retention and relationship development  (Chen and Popovich, 2003) and CRM initiatives increases competitiveness. Adding to their notes, they said that CRM offers customization, simplicity, and convenience for completing transactions, regardless of the channel used for interaction. Sumner (2005) share their idea. The main characteristics he distinguished CRM facilitates customer contact and call list management, It maintains information on customer contacts in a database and forecast customer’s needs, It organizes marketing campaigns, Enables queries to a product marketing database,  Delivers on-line systems that enables customers to configure products on-line, Handles customers’ services. It my recommendation to Bandon Group to implement EPR firs and CRM follows because ERP provides CRM software. Conceptually, ERP covers all the basic business process but CRM systems focus specifically on processes at the customer interface (Schubert, 2010). The current situation at Bandon Group is not limited to customer relationship or the problem of Bandon Group is not limited to lack of sales and marketing data, the billing system, web enabled support system, better invoice or the integration of the software but the company and its process need overall business restructure and re-engineering because that is all about ERP. Step 9: Determining ERP/CRM design issues Business processing workloads are among the most demanding workloads in the enterprise. These include transactional workloads reflecting the â€Å"engine† of a business’ orders and sales, ERP workloads for managing workflows, and CRM for managing customer relationships and decision management solutions. These workloads need to be available to end users, end customers, and business partners. To achieve that goal, they are typically supported by a combination of hardware characteristics, such as built-in reliability and scalability features, and software characteristics, such as system management and support for high availability. In light of this, my recommendation of ERP and CRM packages for Bandon Group would be implementing Microsoft Dynamics CRM. The Microsfot Dynamics ERP and CRM is designed to help any organization acquire and retain customers (Microsoft, n. d). The software enables to perform and automate common business tasks  including: Easily access information about business records from one place. Schedule activities, track them, and send e-mail. Generate reports. Manage marketing lists. Track advertising and marketing campaigns. Sort customer responses to sales and marketing initiatives. Keep detailed notes and an activity history for each business record. Microsoft Dynamics CRM also can run from within Microsoft Office Outlook. On top of the other benefits and functionalities mentioned above, Rhodus and Paris (2013) said that Microsoft CRM and ERP helps the company in integration by creating one view of customer experience, building stronger relationship and creating customer intimacy, improving management visibility, provide visibility and access to customer relationship, etc. I believe that Microsoft Dynamics is the best software solution for the current situation at Bandon Group. References Chen, I, J. and Popovich, K. (2003) Understanding customer relationship management (CRM). People, process and technology. Business process management journal, Vol. 9 No 5. Retrieved from http://cis.csuohio.edu/~ichen/CRM.pdf Kumar, P. (2010). Successful implementation of ERP in a large organization International journal of engineering science and technology. Vol. 2(7), 3218-3224. Retrieved from http://www.ijest.info/docs/IJEST10-02-07-151.pdf Lau, K, L. (2003) Developing successful implementation plan for issues and challenges. Retrieved from http://iacis.org/iis/2003/Lau_ERP.pdf Microsoft (n. d) Microsoft Dynamics CRM 4.0 User’s Guide. Retrieved from http://blogs.msdn.com/b/crm/archive/2008/07/21/crm-4-0-user-s-guide-now-available-in-pdf-and-word.aspx Rhodus, B. and Paris, E. (2013) CRM & ERP – better together. Retrieved from http://www.bkd.com/docs/webinars/2013/8-21-13-presentation.pdf Schubert, P. (2010) Realizing Benefits from Current ERP and CRM Systems Implementa tions: An Empirical Study. Retrieved from http://www.uni-koblenz-landau.de/koblenz/fb4/iwvi/agschubert/publication/mate rialien/bled-23.06.2010 Sumner, M. (2005) Enterprise resource planning. Pearson Prentice hall, Upper saddle river, New Jersey

Research Papers on Internet

Research Papers on Internet Internet is the word known to all even to those who have never experienced it. Whenever it comes to Internet related information Internet paper is the main issue for most of our students. When it comes to write or buy a paper on Internet there are many options including both good and bad. Whenever you need help to write a research paper on the Internet, you need to know the basics of Internet first. Finding basic information and developing know how on Internet will help you write a research paper on the Internet. While writing an essay on Internet one must be sure of the definition of Internet first. Internet is a virtual net work of millions of computers connected together. This network is owned by none but used by all. Many companies in form of search engines, portals, hubs, ISPs and servers make this happening possible. When it comes to specialized knowledge, it is also important if you are an advanced writer or your course needs it to explore in detail. Normally writing a research paper on Internet is not very difficult, all you need is a basic structure of what your teacher likes to include in paper. Then you would divide the whole theme in different parts with headings. After this division of an Internet essay, you will start filling the parts with acquired information. Some times the best solution for research paper on Internet is custom writing companies. When it comes to custom research papers on the Internet, you must understand there is a great variety of good and bad available online. Only a careful analysis of company can give you idea if this company is a good custom writing company to help you write a research paper on the Internet or not. When it comes to order a research paper on the Internet, one must be vigilant and select the custom writing company very carefully. Some companies claim good quality research paper on Internet but in fact, their quality of work is not up to standards and most of the time   they rip off their customer and disown their quality promises by leaving the students in trouble. In such situations, you can trust a good company like CustomWritings.com for all your needs of research papers on Internet. CustomWritings.com has many years experience of writing good quality research papers on Internet. When you like to have a quality paper, you should place your order of research paper on Internet with CustomWritings.com only. Company has good quality research paper writers who are well qualified and learned in their respective fields of education and professional life. Company offers completely original and non-plagiarized papers to its customers around the world. Trust and try the service, you will be proud of your decision, let CustomWritings.com write a good research paper on Internet for you.

Electrical design for a new leisure centre Essay

Electrical design for a new leisure centre - Essay Example Thirdly, the system design is justifiable because of the quality of lighting that comes from the bulbs and tubes provided. The brightness of the various lights and the colors are friendly to the eyes of the customers in the Leisure centre. The transmission voltage ranges are low, ranging from 2 kV to 35 KV because of the step down and step up transformers within the power system of distribution. Combined centre and the Ice rink areas consume more power units than the rest of the leisure centre. The final justification of the power distribution system design was that the continuous monitoring of the electric meters and circuit breakers. There are primary distribution lines, which carry the medium voltage power to the distribution transformers at the customer premises. Voltage is lowered to the utilization voltage through the transformers to suit the house hold appliances. At this voltage, power is transmitted through the secondary distribution lines. Residential and commercial customers are connected to the secondary distribution line while non-residential buildings and customers demanding larger amounts of power are connected to the primary distribution lines. Leisure centers have a large electrical load than residential buildings; therefore, electrical equipment installed should be more robust and larger. Leisure center’s owners should purchase electricity at large voltages since it comes in a cheaper rate. Owners, in this case, provide and maintain their own step-down transformer mounted in a transformer room inside the building or on a pad outside the room. . This is made to ensure the reduction of volta ges to their required levels. Electricity is therefore transmitted to switchgear, whose role is to distribute electricity efficiently and safely to various electrical closets within the building. Safety features contained in the switchgear include circuit breakers. In this system, circuit breakers allow power disruptions downstream, which may

Answer questions'' a doctors visit'' Essay Example | Topics and Well Written Essays - 250 words

Answer questions'' a doctors visit'' - Essay Example The assistant is hot-tempered: He gets upset when the governess said that the doctor of the factory had given Liz calibrate, but it’s high time to change. Korolyov said the factory doctor to continue attending the girl not to change. The family is as being desperate; this is shown when they say that they have gone to many doctors to seek treatment, but they have not succeeded. The family is seen to be loving and cooperative as shown by the strong concern for their daughter. The setting of the story reflects a desperate family that is very wealthy, but the inheritor of the wealth the only daughter is ailing. The family is striving to do anything for her recovery with the doctors coming at home. The initial diagnosis of the doctor he thought to be nerves problem that is common as the heart was normal. The doctors see the girl and by observation she is at the right age for marriage. This is a concern to him as the disease may be due to stress not merely heart disease. The doctors had not relieved Lizanka’s concern since after saying it could be related to nerves problem, not the heart she sobbed into tears. The doctor was upset when he heard that Liz was being cared by another doctor since the governess said she needed change of treatment he thought it better to be treated by one doctor. Madame Lyalikov pleads for him to sleep since she feared for the death of her only child. The doctors felt uneasy since his family was expecting him at Moscow, and that was a strange place but eventually accepted for sympathy of the girl. The doctor unable to sleep, walk outside and view the factories ad barracks. He thought of the family as having workers who are working under horrible circumstances being fine and undergoing starvation. The family is wealthy their cry is the cause of the Lizankas sickness. The doctor’s prejudices are being challenged when he sees the governess as the only happy person and is a figurehead, but the person whom