Presentation Styles of European/American Scientists and South Asian Scientists

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I have been attending some national and international symposiums and getting chance to listen seminars by veterans from many countries. Two weeks ago, I got chance to take part in two inauguration ceremonies in a day. It was really an exciting experience as two inaugurations in a single day. Surprisingly, a distinct way of presentation styles between South Asian scientists and European/American scientists that I have realized, however, may not be interacted with sufficient eminent scientists.
South Asian

1. The sentence starts as, I/my colleague discovered........
2. Content : most of the literature survey, and long introduction, and few result.
3. Slide filled with most of copied and pasted texts, and definitions.
4. Seminar deliver : just read text that written in slide somewhat similar to reading news and make audience sleep.
5. Spend time just to define few scientific terms.
6. Acknowledge : no or very few.
7. Don't care for allocated time limit.

European/American

1. The sentence starts as, we/our team discovered........
2. Content : most of their own result and less literature survey, and short introduction.
3. Slide filled with most of pictorial and graphical representation of their experimental findings.
4. Seminar deliver : describe picture or graph try to make audience understand of new discovery.
5. Spend time using scientific terms to describe the results, science and mechanism.
6. Acknowledge : whole team(s).
7. Aware of time limit.

Important, this is not intended to make a conclusion that all South Asian scientists do as mentioned above, and neither all European/American scientists can always do in this manner.

View a Glimpse and Visit Ravishing Nepal

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       Sometimes, lacking of development, and abhorring science and technology may be beneficial preserving natural beauty and ecosystem, ancient culture and heritage, etc. Nepal has the evidence of it.
       In spite of small territory, diverse flora and fauna, language, ethnic group and culture, religion along with the highest peak in the world (Mt. Everest), seraph of peace (Buddha) has been stowed in Nepal, which is not in other country.
       Nepal is celebrating 2011 as "Nepal Tourism Year 2011".


       Courtesy: http://www.vn2011.blogspot.com

Glorious Cricket era in Chhapiya

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“....Like disappearance of glorious and exemplary architecture and engineering of Pagoda from Nepal, cricket of Chhapiya only in memory......”
       These coldest days are rewinding and refreshing my nostalgic of decades ago. There was the biggest and well managed playing ground of Chhapiya, which was not only used for football and cricket but also for grazing of cattle in rainy season. After our school-time, whether it was 12 noon (more than 40°C in summer) or 5 pm (pleasant breezing), we used to spent few hours in that ground. As I remember, Jagat guru (same Jagat Tamata, national coach after Roy Luke Dias or different ? Oops! Foggy memory) had started his career as coach from Chaapiya. Everyday, all player had to practice and to run early in the morning for 2-3 hours, that's why our senior team was always fit to play. Although, not mandatory, we 'fucche', even in the coldest days before sunrise, used to run in parallel to them (circular path of a lesser diameter). I thank and express heartily gratitude to Jagat guru for his major contribution and wish a success for national team on his strategy.
       Our junior/fuchhe team hardly got chance to play/practice in that central pitch. Sometimes, we were gifted the damaged/repaired Bat and leather Ball, otherwise we had to rely on Stem (of tree) for Bat and rubbish plastic (after partial burning) for Ball, which was very hard. Although, I frequently contributed a good run score for 'Fuchhe team' but was censured due to missing catch and misfielding.
      Chhapiya (Bhetghat Club) has given birth to many national player of cricket. From first generation, Dal Bahadur Thapa and Tej Narayan Pokhrel were included in national team, but cricket of Nepal was inchoate and rarely exposed internationally, in those days. From second generation Hari Thapa, one of the fastest bowler of Nepal was selected in closed training session (but may be because of his inconsistency, Binod Das was selected instead of him). Aashis Karki, Narayan Pokhrel, Santhosh Thapa (Thakali), Laxman Poudel were other key players.
      Recently, Bhairahawa won the U-19 Wai-Wai cup, panegyrical congratulation !!!!...... Bhetghat club frequently won almost all matches of football and cricket and amazingly, colt of Chhapiya sometimes stunned full of veteran (Anup, Zafar, sorry, I forget others names), rich and elite team of Bhairahawa (MCC / Khukuri / ? Club) in cricket tournaments ,and other team were not competitive. This history of frequent wining in both kind of matches, probably never repeats. Nowadays, hardly there is a cricket / football team because young (16-40 years) generation is dispersed either to Kathmandu or many countries for higher education (after SLC/+2) or job. If a team could be made would be puny and hardly enter the second round in any tournaments.
      Why did glory of Chhapiya fall down to gloomy days and inconspicuous without any significant accident/abruption in the system, even in this era where Nepal has been recognized as potent leading nation in cricket ? My assumption are;
Patronization, Impecunious and Club's responsibility: Former skippers, veterans of Bhetghat club should have taken the leadership for team arranging and funding and to guide and peruse juniors but I have found, all of them are inert. Fuchhes don't have to worry about their accommodation and earning and even for bat and ball or football (parent may provide upon crying). But the elders and veterans have to look a secure future and/or their family, no one will for penurious life. Unfortunately, the club is neither arranging ball, bat, pads, gloves nor any kind of support to player.
 Change in Occupation: Previously almost all inhabitant of Chhapiya were dependent on agriculture, hence, were available in Chhapiya. Veterans were selected because of competition and option to choose among many players. Recent trend of exodus to Gulf, Korea, Europe, USA (according to their capability) is creating a vacuum of youth, which is the important reason, I think.
       Besides these, current politician and security situation also, exacerbating plethora of game along with reducing the number of tournaments and enthusiasm as there is a diverse ethnic and religious group living together, which is enervating development and economy.
                                                                                                                Adieu 2010.

Is Linux Virus or Malware Free?

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       It may be a coincidence or true? Six months ago, I used Evolution 2.28.3 of Fedora 12 (Equivalent to Outlook Express of Windows) for Gmail. Password was hacked and e-mailed (Viagra and other advertisements) to more than thousand recipients including contact persons from my email account. Thus, account was blocked by Google's e-mail service mentioning the violation of terms. After providing phone number and security question and answer, Google sent activation code through SMS. I analyzed the IP address to find place where  account was opened. It was found Mexico where I  had never been, even in Dream. Then, I changed the password and was going fine.
       The case repeated again a few days ago, when I retried the evolution of same version in the same operating system. Does it mean Linux has leak points for virus and other vulnerability and defects, which I have never thought as in my previous posts?

Nonage Memory Refreshing Migratory Birds

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Recalling my foggy memory of more than 17 years ago, my father used to declare the beginning and the ending of the season after observing the sky. I would have wondered, how he could prevised to do or don’t about agricultural work for neighbors, and astonished upon his forecast of rain on the blue sky.

Migratory birds seeking destination

Then, very high in the sky, I noticed inexplicit semi-circle patterns created by the flocks of migratory birds (at that time I didn’t know the term and concept of migratory bird, instead used to say “Maal Chara”). I didn’t know, where were they coming from and going to? But had noticed they were visible only at beginning and ending of seasons (rainy, summer, and winter), might be due to migration from both Northern part (Russia) and Southern part (Australia). Although very small area of swamp, wetland, and fen is available nearby my house, I have never seen alighting of these flocks of immigrant birds and neither tried to retrieve their alighting area. So, I couldn’t figure out which species they were and probably never because these swamp area are now converted to the private ponds for fisheries.

Migratory Birds

After a long time (near about to delete from memory), I could see them again but in different place to my house. The abstraction is the flight in lower height and could be clicked but not enough to recognize; early in the morning in those days vs. in the evening; number reduced by approx. four times. Really are they reduced? Due to global warming? Human occupy their habitat? I am unable to compare with the same condition and with the same place as nostalgia.

Endangered bird

My personal clarions to save these guests by maintaining swamp area and not poaching. So that, not only we could declare about seasons but also to patch up tourism in Nepal.

Fedora 14 Released

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Fedora 14 (A kind of Linux Operating System) has been released today and its feature can be found here and installation guide can be found here and here or pdf. You can Download different desktop environment of Fedora 14 from here.

Why Fedora ?

1. Benefit of Linux OS (Visit my previous article).
2. More than 2,000 (software) repository are available and free.
3. Release cycle is short (Approx. 6 months) so, latest discovery in Linux system is included in Fedora in comparison to other Linux OS (Fedora is leader, not follower). But, critics say that software/codes are tested in Fedora may cause instability and hamper on its reliability.
4. Easy to install not only whole Operating System but also software and applications using yum install ..... (good internet connectivity is beneficial).
5. Can be used as Home/Office Desktop environment even as Server (CentOS is preferred).
6. Available in many different languages.
7. Wide community support, just mention your problem here (registration is necessary) probably, get solution within 24 hour.

Remember you are getting everything free; don't aspect so much facility, however, you'll get almost your needs.

Want Expeditious and Persistent Memory? Medicate yourself and Dust off Your Musical Instruments for Child.

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By Bishnu Marasini

       Except some politicians and few others who only exploit public’s emotional believes to aggrandize and become supreme. We need an urbane brain not only for deep understanding of a subject but also a wide knowledge of diverse field is essential for better life in this competitive era.
       Neuronal cells are the important component of the brain and unable to divide. Millions of the cells in our skin die and regenerate everyday. But neuronal cells once died or damaged, hardly replaced/repaired. But, upon stimulation, they can be more branched as dendrites and the secondary cells (helper of neurons) like astrocytes, oligodandrocites, microglia; ependymal cells are increased in number as well which enrich the better communication of each other increasing efficiency.

Picture 1: Musical Keyboard (Source)

       Recent study reveals the power of music to enhance the brains exhibiting increased vocabulary, multilingual capacity, reading performance and other educational activities. Pleasant waves of music not only increase volume of Grey Matter but also increases the brain’s adeptness and competence. Musical instruments work by two ways; (1) Through pleasant wave of music; (2) Curiosity/learning of instruments to produce such wave. It is most efficient at the age of 7; the stage where brain-cells are actively growing (some are increasing in volume and some in number).
       Also, flash of bright light (especially blue colored) and electric current of 1-2 mA and repeated learning of object found to be effective for long term memory.
       Although, neurons and the memory are lost with the age but the rate of deterioration can be reduced with the meditation. Neuroscientists conduct experiments upon the Buddhist Monk of NEPAL after challenged by the  (Peace) Nobel Laureate; Dalai Lama. Significant improvements were found on the Monks comparing to non-meditating people. After this exciting result, more test done on those people previously unknown of meditation, with the 20 min/day of meditation, exhibited significant improvements.

Picture 2: Preparing for Meditation (Source)

       I also used to medicate early in the morning during examination period which helped to relief from pressure of exam phobia (nowadays lazy in early rise and meditation). Nowadays, most of the elder people in Nepal are influenced by the Yoga technique of Ramdev. It will be more beneficial if some modification of Yoga for brain exercise 5-10 min/day, makes their memory long term. My personal opinion also, meditation maintains a halcyon and expeditious mind which is exigent in these morose, truculent and turbulence days.
       I don’t mean, only music and meditation are perfect for refulgent brain but these techniques adorn the regular activity of reading, writing, speaking, memory recalling, and others.

Further reading:  (1) New Scientist (2010), 2780    (2) Science (2010), 330

Emotional Faith and Peace Philosophy, Incident of Laboratory

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Although I have been hearing lots of stolen cases in this area, I had never witnessed. Even in my lab, there were cases of disappearance of a camera, pen drives, etc....before I joined and/or while I was in hometown. After I joined the lab, the miracle of disappearance of goods had continued, and in last two cases, mobiles were grabbed while all lab members were present, but known only after 2-3 hours. When I got the news, I shocked, how could be possible, all of us were in lab? Immediately, I suggested the lab in-charge to observe CCTV camera (focused to lab's main door from outside). I don't have authority to observe. I don't know whether they observed the whole period of time suspected from the last time phone used to the time of known to stolen. But I guess they did not. At that day, might be all lab fellows were in tension, probably except one, who could grab in front of us.

I witnessed this time but the grabber unknown. What was the motivation and psychology behind there and such mischievous happens (like serial killer in the movie), even in this elite place of well educated scholars? I noted in diary, every situation (I was not in lab in previous cases, witnessed only the last two cases; that's why I could not get sufficient information to analyze). I started the miniature analysis with two hypotheses. I got a lot of information from analysis that took about two months. It was matter of retaliatory and revenge of dissension, which was in climax at that time. Belligerent's intention of bellicose and probably other....... But could not get solid proof that's why it was better not to speak any more in between their emotional belief. I am sure, if lab in charge had investigated from the initial first case, it would be possible to get proof. Probably, their emotional faith and belief or may be question of lab's prestige might became obstacles. Also, I had found the misuse of internet from the log file and tracking software. (I had solid proof in that case). But I never made revealed who was/were culprit(s). Instead, I taught in affable manner which file and how to delete to avoid virus. It is still mysterious why lab in-charge did not investigate.

I (and may be lab in-charge also) may be encouraging and bolstering the culprit(s) by not taking any action. However, we have to see in future. But I want peace, adorable, and family environment in the laboratory, whatever might be some fellows have emotional belief and thinking. Peace !   Peace !!    Peace !!!

Make Typing Easy

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By Bishnu Marasini

Sometimes we become irritated and tired when repeatedly typing some lengthy and/or bummer words (For example, we have to type, to get e.g.,) and symbols. Such case happens particularly during thesis, book, etc. writing. Scientific and mathematical symbols writing and their expression is more boring for some people (at least like me who hate typing comparing the other activities in front of computer). Although we might not have noticed, MS office has built facility to overcome this irritation. Just type eg (and space) to get e.g., just type temp (and space) to get temperature. 

1. Click on MS office icon on the upper left corner.
2. Click on word option. 

3. Click/select on proofing
4. Select AutoCorrect Option
5. Select the AutoCorrect Tab
6. (6A) Type the unique shortest form of the word for the desired word in left side and (6B) the desired (correct spelling) on the right side as shown in the figure.


7. Click Replace to store on the database (on MS Word DLL) 
8. Then OK.
9. To insert frequently used symbol (like °C,α, β, etc.) select Math AutoCorrect tab.
10. Don't forget to check on “Use Math AutoCorrect rules outside the math regions".
11. Do/type again as described in 6 and as shown in the figure to get the desired result.

It will be only waste of time if this trick is done in those places (like cyber cafe) where OS is formatted in every week or month.

Switching Completely to Linux Operating System

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By Bishnu Marasini 

       Although my engrossment in electronics as well as better understanding of computer hardware, I have not been working significantly in this field for 10 years (used to do at initial days). Only, as amateur technical support for my colleague is being the use and sharing of my expertise. While, parallel use of both Windows OS and Linux OS more than 10 years, I, now realized to switch completely towards Linux OS because of the following reasons.

To Get rid of Virus: Windows XP is too old to resist virus attack, Windows Vista and Windows 7 also susceptible to attack, the pirated version are even worse. Linux OS might not have pulled hackers’ intention to enervate which may be due to fewer users and free/Open Source Software.
Hardware Compatibility: The latest version of Microsoft like Windows Vista and Windows 7 cannot be installed or are very slow on the older CPU and Motherboard. The latest Linux OS always takes care of older CPU and motherboards but depends on the distro (type) of Linux.
1. Better Understanding of Programming Code and Software Pleothera: Linux is free and Open Source Software and can be modified by anyone and redistribute the OS and we can read and copy every codes associated with it. This feature has been helping me to understand the meaning of code and my experiments in modifying only few terms from the code file and to see the ultimate effects. However, I have not developed any application.
2. Better Security of Files/Pictures/Folders etc. I have very bad experience of corruption of my word (*.doc), excel (*.xls), pdf, pictures (*.jpg) while keeping them under XP OS. Which were damaged and decoded if could be opened. Fortunately, I have not lost them (except few due to backup duration/period cycle) because of monthly backup of data in Linux OS.
3. Easy and Quicker Initial Installation of OS: Linux OS have the feature of complete installation along with all basic drivers e.g., driver of monitor, motherboard, audio drive, printer etc. in a single initial install. All of these drivers would have to be installed after the main Windows OS which ultimately increase installation time.
4. Live CD: Because of live CD it made easier to understand, view features without any change and installation in hard disk. This also helps to restore/copy files and folder accidently deleted even in case of OS failure/crash.
5. Swiftness: I have noticed that opening any application and internet search is very fast in Linux compared to Windows OS. Need for installation of anti-virus software and virus attack might impede the performance of Windows OS.

       Linux is free and becoming user friendly, but still more than 85% people pay to Microsoft/Apple Inc. for the same service because Linux OS still has many limitation.

1. Difficult for Beginner of PC Users: Windows OS is easily understandable and could be one mouse click operation. Also, institute/schools use Windows OS to train basic computer, so they feel easy to use it in future days. However, some distros like Fedora, Ubuntu, OpenSuse, etc. have been progressing a lot in graphical user interface (GUI) so that it would be like Windows OS. They have improved in GNOME, KDE, Xfce, etc. desktop environment.
2. Some Software and Games are not for Linux: Most of the daily required Software like MSOffice, ChemDraw, NamePro, SoftMax, ACD, Adobe Photoshop, Dreamweaver, etc. are only for Windows and can’t be installed in Linux. An adapter-like (emulator) software known as “Wine” facilitates to install these software in the Linux OS. But Wine has not exhibited satisfactory result in complete installation of most of the above applications. Also, it (Wine) opens the gate and vulnerability of virus to Linux root.
3. Connection of Instruments to PC: Most instruments such as ELISA Reader, Microscope, PCR, etc., and even some printer can’t be connected to PC of Linux OS or if connected,  their full capacity enervated. A Distro “Scientific Linux” derived from Fedora and RHEL, "Scibuntu (UbuntuScience)" derived from Ubuntu may become better OS in future days not only to support such kind of scientific equipments but also better view of molecule’s, Protein’s, and DNA’s 3D structures in Linux OS.
4. System Crash: As this OS is free and supported and built by community; some of its application and whole OS vulnerable to crash and should be debugged. The Distro “Debian” is found to be most stable but it is usually found to be outdated in comparison to other Linux Distro.

       At last, our smaller and smaller contribution like reporting of bug found in crash e.g., my report (https://bugzilla.redhat.com/show_bug.cgi?id=613592), sharing of scientific knowledge helps the volunteer engineer/developer to make Linux as better OS in future days. Also, we’ll not be accused of using pirated software used as lured by easiness and better performance; without paying in these days.

       I am currently using Fedora 12/13 as it is updated in every six months and latest repository and application of Linux is available via Fedora than other distro.

Identification of Beta-lactamase Inhibitor; a Strategy for Drug Development against Antibiotics Resistant Bacteria

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Introduction:                                                                             By Bishnu Marasini

       The most threatening to human health is due to bacterial infection and intensive research has been addressing to treat these maladies since the known history. The infectious bacteria are microscopic, unicellular prokaryotes and different than mammalian eukaryotic cells. The outer layer of the bacterial cell consists of cell wall which is not found in mammalian cell and can be taken as target for development of bactericidal agents. The finding of clear zone of inhibition of bacterial culture around the growth of Penicillium notatum in the experiment of Alexander Fleming in 1928 was the positive indication to get rid of such threat.

       Nowadays almost all bacterial infection can be cured using antibiotics. The world consumes tons of antibiotics per year and half of them are beta-lactam type e.g. penicillin, amoxicillin, cephalosporin, cephalexin, cefixime, ceftriaxome, monobactam, carbapenem, methicillin etc. Beta-lactam antibiotics have broad spectrum activity, economical friendly on production, good safety profile, have clinical efficacy. It is also target specific for prokaryotic cells, little side effects except some allergic reaction. So, it has gained wide popularity.

       One of the components of bacterial cell wall is peptidoglycan which is cross linked polymer of repeatedly units of N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM). The final step in cell wall biosynthesis is transamidation reaction catalyzed by the enzyme cell wall transamidase (CWT) also called as penicillin binding protein (PBP). This enzyme helps to cross link the polymer of NAG and NAM. The highly strained and reactive beta-lactam ring of the antibiotics reacts and binds irreversibly with the serine hydroxyl group of PBP (shown in figure 1) which inactivates the enzyme and ultimately death of bacteria (Frère et al, 1984; Tipper and Strominger, 1965).

Figure1: Binding of β-lactam Ring with Penicillin Binding Protein

       However, beta-lactam antibiotics are becoming ineffective against pathogenic bacteria. The most common reason is due to the production of beta-lactamase enzyme (EC 3.5.2.6) which catalyze the hydrolysis of the antibiotics i.e., formation of carboxyl group degrading beta-lactam ring (Shown in figure 2). Hydrolyzed antibiotics lose its activity or binding affinity towards the PBP hence no effect against bacteria. Hydrolysis of beta-lactam is rapid by beta-lactamase than binding of beta-lactam to PBP (Bush 1988). 

Figure 2: Degradation of β-lactam ring by β-lactamase enzyme

       The beta-lactamse (penicillinase) was reported just few years after the first antibiotic discovered (Abraham and Chain, 1940). Although penicillin is the oldest antibiotic and most of the organisms acquired resistant, it is first therapeutic choice in some diseases like syphilis. Beta-lactamse enzyme is an extra cellular enzyme in Gram-positive bacteria and found in periplasmic membrane in Gram-negative bacteria (Bowden and Georgiou, 1990; Dyke and Richmond, 1967). More than 200 types of beta-lactamse have been found (Bush et al, 1995). The difference among them is only the catalytic efficacy and turn over rate range from 0.004 to 1,200 molecules per second by 1 molecule of enzyme. Among them two types i.e. penicillinase and cephalosporinase type has a potent influence on the profile of the beta-lactam resistant antibiotics. Class A beta-lactamse has high affinity towards penicillin G but low affinity towards cephalosporin while class C beta-lactamse has opposite. Class B beta-lactamse hydrolyze the antibiotics by binding with the co-factor zinc (Zn) and class A, C and D hydrolyze by binding through serine residue of it to beta-lactam ring (Sawai et al, 1981). Beta-lactamase became widespread via the mechanism of plasmid exchange/insert among the pathogens (Sykes and Richmond, 1970). The rapid spread and evolution of these enzymes have seriously threatened the present antimicrobial arsenal.

       Two strategies have been developed to combat the problem of resistant. The first approach has been the synthesis/production of beta-lactamase resistant antibiotics e.g. penicillinase resistant beta-lactam antibiotics, nafcillin, oxacillin, ceftriaxone, cefoxitime, aztreonam, imipenem etc. But after few exposure to pathogens these antibiotics also become susceptible to extended spectrum beta-lactamase (ESBL) produced by multi-drug resistant (MDR) pathogens.

       The second approach is to use beta-lactamase inhibitors coupled with beta-lactam antibiotics. These enzyme inhibitors function to permanently inactivate the beta-lactamase in the periplasmic space so that the partner antibiotics can reach its target, penicillin binding protein (PBP). Broad spectrum beta-lactam antibiotics plus beta-lactamase inhibitors combination have been found good safety records and clinical efficacies (Munoz et al, 1996). Augmentin, the production of GlaxoSmithKline which is composed of amoxicillin and clavulanate in 2:1; Timentin (ticarcillin and clavulanate); Sultamicillin (ampicillin and sulbactam) are examples of beta-lactamase inhibitors in combination with beta-lactam used clinically. Clavulanate exhibited clinical efficacy than others and used as standard inhibitor. However, clavulanate was not found so effective against class C beta-lactamase (cephalorinase type) (Bush K, 1989). It also exhibited side effects on the long term of use like liver function destruction, gastrointestinal toxicity etc. (Ioannidis et al, 2002). Also it contains beta-lactam ring it and may be susceptible to beta-lactamase enzyme in upcoming days as broad spectrum beta-lactam antibiotics which were resistant to beta-lactamase, now become susceptible.

World AIDS Day

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Recent Development in HIV Therapy (By Bishnu Marasini)

Human immunodeficiency virus (HIV), a lentivirus discovered in 1983 belongs to family Retroviridiae which is responsible for acquired immunodeficiency syndrome (AIDS), needs arduous work to eliminate. It contains two copies of +ssRNA which codes for 9 genes (~9 KB) is bound tightly to reverse transcriptase integrase and nucleocapsid proteins (p6 and p7), which protects RNA preventing digestion by nuclease. this nocleocapsid is surrounded by viral protein, p17 which also cover Vif, Vpr, Nef and viral protease. The envelope of virus contains some of the host cell membrane which is taken out during bulging out from infedted host cell. So, it contains glycoprotein gp120 and gp41 making envelope's spike. This spike structure is important to understand the replication cycle of the virus and drug development strategy (Schubert and Mcclure, 2005).

Due to error prone and rapid replication and hence immediate drug resistance, no successful single drug and neither immunization could be prepared against HIV. Although, some drugs are available are not sufficient to prevent epidemics, no better tolerated, convenient and cheap drugs are available. That’s why combination of drugs against different targets as well as development of new agents have been an exigent in recent days. Majority of these include reverse transcriptase, integrase, protease inhibitors, viral entry blockers, coating of CD4, CCR5, CXCR4, genetic therapy, immunotherapy (IL-7, IFN-α, IFN-γ) etc.

Reverse transcriptase (RT)

The two sub-units p66 (560 amino acids) and p51 (440 amino acids) together which make asymmetric heterodimer of RT. It acts as both DNA polymerage which copy RNA and as RNase H which degrades RNA only if the RNA is a part of an RNA/DNA duplex. This is very potent target for HIV therapy and nearly half of the discovered drug till date is based on its inhibition. Among them, Nucleoside Reverse Transcriptase Inhibitor (NRTI) and Non Nucleoside Reverse Transcriptase Inhibitor (NNRTI) have been catagorised. NRTIs are are structural analogues of the substrate of DNA lacking 3'-OH groups misleading to chain termination during replication. NRTI includes zidovudine, lamivudine, stavudine, didanosine, zalcifabine, abacavir, emtricitabine, tenofovir are already popular in HIV treatment. In addition, racivir, apricitabine, dexelvucitabine, elvucitabine, alovudine, amdoxovir etc. are in the current clinical development stage.
NNRITs are non-competitive inhibitors of RT binds to the pocket other than the active sites and change confirmation and/or inactivate the enzyme. NNRTI includes nevirapine, delavirdine (1^st generation), efavirenz (2^nd generation), rilpivirine. In addition, combination of these NRTI and NNRTIs has been widely searched for seeking of therapy e.g., Truvada (tenofovir/emtricitabine), Combivir (lamivudine and zidovudine), trizivir, dapivirine (Phase III).

RNAse H inhibitors include BBNH (N-(4-tert-Butylbenzoyl)-2-hydroxynaphthaldehyde hydrazone), DHBNH (dihydroxy benzoyl naphthyl hydrazone), CPHM (4-chlorophenylhydrazone of mesoxalic acid),  Diketo Acid( 4-[5-(Benzoylamino)thien-2-yl]-2,4-dioxobutanoic Acid), N-hydroxyimides, hydroxytropolone etc.

HIV-1 Protease Inhibitors

As already mentioned, HIV contains protease (aspertyl) which cleaves the group specific antigen (Gag) and Gag polymerage (Pol) precursor protein to structural capsid protein (p17, p24, p7 and p1) and functional protein (p11) reverse transcriptase (p66 and p51) and integrase (p32). All of these proteins activated after cleaving by viral protease, so, it has been a potent target for HIV-1 therapy. These includes saquinavir, totanavir, indinavir, nelfinavir, amprenavir, lopinavir, fosamprenavir etc. Side effects such as, lipodistrophy and dosing effect although seen in previous protease inhibitors, better one are atanazvir, brecanavir, darunavir, tipranavir, etc. are extensively under research and in the clinical trial phase which has not exhibited severe side effects as previous drugs.

HIV Integrase Inhibitors

HIV integrase transfer the viral genomic dsDNA into nucleus of host and insert into the host chromosome maintaining its stability, efficient expression and replication. If this enzyme is inhibited then replication and transcription of virus is blocked ultimately reducing viral load in the host body. Inhibitors of HIV integrase can be combined with other inhibitors for best effectiveness. These are efavirenz, raltegravir, elvitegravir etc.

HIV Maturation Inhibitors

At the late stage of the HIV proliferation, capsid precursor p25 (CA-SP1) is converted to mature capsid protein p24 (CA). This conversion can be blocked as HIV therapy. Bevirimat (3-O-(3',3'-dimethylsuccinyl)- betulinic acid) prevent the conversion of p25 to p24 capsid.

Viral Entry Inhibition

The outer spike of virus get attached to the T-cell and macrophase through the receptor and co-receptor (specially CD4, CCR5, CXCR4) present in the cell. Then nucleocapsid is integrated into host cells after attachment and fusion. The inhibition/blocking/coating of these receptor makes virus difficult to fuse with cell and entry. Mobozil, maraviroc, vicriviroc, aplaviroc etc. are the CCR5 and/or CXCR4 antagonist found as HIV therapeutics. However, aplaviroc found to be responsible in increasing liver enzyme and total billirubin. Enfuvirtide, a peptide inhibits the fusion of viral envelope with the host.

Gene Therapy

Although, most of the HIV infected person couldn't afford genetic therapy, significant HIV-infected patients live in setting where they not only afford but also contains sufficient infrastructure to support genetic therapy. Using of anti-sense, ribozymes, optamers, interference (RNAi), proteins (expressed), intrabodies, intrakin, zinc finger nuclease etc. are the the recent strategy for HIV therapy. Ribozymes against the gene tat, rev, and viral U5 has been in the clinical trial stage. Anti-sense RNA transgens pair with HIV RNA making non-functional duplex. Anti-U5 region anti-sensee RNA, envanti-sense RNA is being explored. Homology dependent control of gene activity is triggered by small-double stranded (sds) RNA molecules which is an RNAi regulatory mechanism. This has been applied in viral gene including gag, pol, nef, vif, env, vpr and LTR and showing exhibiting sign in cell line and potentially in HIV therapy in human beings. Another finding is the insertion of gene that express protein resembling mutant form of HIV Rev-protein (M10). It inhibits packing of virus and can be utilized by using retroviral or lentiviral vectors as HIV therapy.

Immunotherapy/ T-Cell Gene Therapy

It has been found that introducing CD28 co-stimulated T-cell reduce the viral infection. Also, genetic change in T-cells that express modified CD4+ significantly lower the virus load. In recent experiment CD4+ lymphocytes, genetically modified to express either protein Rev-M10 or a marking vector with no antiviral payload or both or to express an anti-sense TAR (Trans activating response region) element exhibited good antiviral effects. Gene expression pattern is designed such that it is associated with the acquisition of T-cell memory might be used to reprogram HIV specific T-cells to have T_CM (long lived control memory T cell qualities. 

Others
Passive administration of interleukin (IL-2, IL-7) etc. and antibody specific against spike gp120 and gp41 of viral envelope, and other viral proteins. These not only eliminate/reduce virus load but also increase the number of CD4+ T-cells. IL-7 also protects CD4 and CD8 T-cells against apoptosis induced by HIV. Use of snake venom which contains phospholipase A2 (PLA2) protects human primary blood leukocytes from replication of HIV-1 strain, it also block viral entry into cells.

Conclusion
More than 25 drugs of HIV have been approved by FDA within the 20 years of time after first drug discovery. The combination of different specific target against HIV such as integrase inhibitors, reverse transcriptase inhibitors CCR5 inhibitors etc. can be administered as rescue therapy. Although the side effect, cost, availability, resistance acquired by virus is challenging the drug discovery realm. Research priority is being emphasized to vanquish this virus by human being. New better drugs of higher potency, less toxicity, lower risk of drug resistance development etc. are being developed in parallel with the shift point in calender, indicating good hope that the compliance of scientists but also politicians, Samaritans to stymie HIV.

References:

1. Capitini CM, Chisti AA, Mackall CL (2009) Modulating T-cell homeostasis with IL-7: preclinical and clinical studies (Review), Journal of Internal Medicine, 266: 141-153.
2. Luke W. Meredith, Haran Sivakumaran, Lee Major, Andreas Suhrbier, David Harrich (2009) Potent Inhibition of HIV-1 Replication by a Tat Mutant, PLoS ONE, 4 (11): e7769.
3. Olga Latinovic, Janaki Kuruppu, Charles Davis, Nhut Le and Alonso Heredia (2009) Pharmacotherapy of HIV-1 Infection: Focus on CCR5 Antagonist Maraviroc (Review), Clinical Medicine: Therapeutics, 1: 1497-1510.
4. Paul E. Sax, Camlin Tierney, Ann C. Collier et al, (2009) Abacavir–Lamivudine versus Tenofovir-Emtricitabine for Initial HIV-1 Therapy , New England Journal of Medicine, 361; 2230-2240.
5. Stefan G. Sarafianos, Bruno Marchand, Kalyan Das, Daniel M. Himmel, Michael A. Parniak, Stephen H. Hughes and Eddy Arnold (2009) Structure and Function of HIV-1 Reverse Transcriptase: Molecular Mechanisms of Polymerization and Inhibition (Review), Journal of Molecular Biology, 385: 693-713.
6. Ulirich Schubert and Myra Mcclure (2005), Topley and Wilson's Microbiology and Microbial Infection, Virology Vol 2, 10^th edition, (Brian WJ Mahay and Volker Ter Meuleu: editors) Edward Arnold Ltd and ASM Press, page no. 1323-1345.

Bishnu Marasini