Quick Facts of IL-1R

• Interleukin-1 receptor (IL-1R) is a cytokine receptor which binds interleukin 1 (IL-1) which is a cytokine.

• There are two types of IL-1 receptor, termed type I and type II receptors, each with three extracellular immunoglobulin (Ig)-like domains but limited sequence similarity (28%) and different pharmacological characteristics.

• IL-1R contains three Ig domains and, together with the highly homologous IL-1R accessory protein (IL-1RAcP), forms a receptor complex for IL-1 alpha, IL-1 beta  and IL−1 receptor antagonist (IL-1RA). Of the three Ig-like domains, domains 1 and 2 are tightly linked, while domain 3 is completely separate and connected by a flexible linker.

• Both the receptors exist in transmembrane (TM) and soluble forms: the soluble IL-1 receptor is thought to be post-translationally derived from cleavage of the extracellular portion of the membrane receptors.

• Both of them bind to the Interleukin-1 alpha, interleukin-1 beta and Interleukin-1RA which are cytokines that participate in the regulation of immune responses, inflammatory reactions, and haematopoiesis. Interleukin-1 (IL-1) exerts pleiotropic effects on a variety of tissues through binding to its receptor. interleukin-1 (IL-1R) play an important role in innate immunity by regulating the activity of distinct transcription factors such as nuclear factor-kappaB(NF-kappaB).

• IL1RB is the beta subunit of the receptor and is known also as IL1R2. The human gene encoding the beta subunit was cloned by McMahan et al (1991). In the nomenclature of CD antigens, this receptor has been given the designation CD121b.

• IL1R2 is structurally incapable of signalling and functions as a decoy receptor, binding and inhibiting the effect of IL1. IL1R2 can reduce the number of signalling complexes consisting of IL1R1, IL1RAcP, and IL1, by binding to IL1RAcP and thus has the ability to modulate the responsiveness of cells to IL1 . The type I receptor is primarily responsible for transmitting the inflammatory effects of IL-1 while type II receptors may act as a suppressor of IL-1 activity by competing for IL-1 binding.

• Also opposing the effects of IL-1 is the IL-1RA.The IL-1RA binds IL1 and transduces IL1 signals in cooperation with the co-receptor IL1RAcP to initiate an inflammatory response. In the nomenclature of CD antigens, this receptor has been given the designation CD121a. The human gene encoding the alpha subunit was been cloned by Sims et al (1989).

• All the IL-1 receptors appear to be well conserved in evolution, and map to the same chromosomal location.

• Cells may produce soluble variants of the IL1 receptors (designated sIL1R1, sIL1R2), which can compete with membrane-bound receptors for ligand binding. They can act as molecular sinks and scavengers for free ligand and can play a regulatory role by modulating ligand availability.

• IL-1 Family Receptors:

The IL-1R family consists of members that are characterized by the presence of extracellular immunoglobulin-like (Ig) domains and by an intracellular TIR domain.They are:

-IL-1ra/IL-1F3
-IL-1 Rrp2/IL-1 R6
-IL-1 RI
-IL-18 R alpha/IL-1 R5
-IL-1 RII
-IL-18 R beta/IL-1 R7
-IL-1 RAcP/IL-1 R3
-SIGIRR
-IL-1 RAPL1/IL-1 R8
-ST2/IL-1 R4
-IL-1 RAPL2/IL-1 R9

• The IL-18 receptor (IL-18R), following binding to IL-18, forms a complex with IL-18RAcP to initiate downstream signalling.

• IL1 receptor-related protein-2 (IL-1Rrp2) is the receptor for the agonists IL-1F6, IL-1F8, and IL-1F9, which also uses IL-1RAcP as a second chain. Thus, IL-1RAcP appears to be promiscuous since, in addition to IL-1RI and IL-1Rrp2, it also associates with ST2, which has recently been shown to bind IL-33.

• IL-1R2 and SIGIRR are two inhibitory receptors, the former lacks the Toll/IL-1 receptor (TIR)- domain whereas the latter contains a single Ig domain for the extracellular segment.

• The only members that still remain without any identified function in this subfamily are IL-1RAPL and TIGIRR.

• The adaptor molecules are: the Myeloid differentiation factor 88 (MyD88) and the MyD88-adaptor-like (MAL, also known as TIRAP).

• TIRAP is the TIR domain-containing adaptor protein inducing interferon-alpha.

• MyD88 has a modular structure consisting of an N-terminal death domain (DD) separated by a short linker region from the C-terminal TIR domain.

• The IL-1 receptors and TLRs (Toll-like Receptors) share a common TIR motif in their cytoplasmic domain. While IL-1 receptors respond to traditional IL-1 family ligands, the TLRs elicit inflammatory responses via the recognition of pathogen-associated molecular patterns (PAMPs) such as bacterial proteins, nucleic acids, and cell wall components.

• The TIR domain is responsible for the propagation of the signal within the cell through interaction with a complex signalling cascade. The presence of an intracellular TIR domain is the hallmark of TLR/IL-1R super family consisting of IL-1R subfamily and the TIR-domain-containing adaptor proteins.

• The IL-1 Ligands & IL-1R/TLR Family plays critical roles in inflammation and host defence. These molecules play important roles in both innate and adaptive immunity.

• MyD88 is an important signalling adaptor for both TLR and IL-1R family members. Resident skin cells utilize IL-1R/MyD88 signalling to promote neutrophil recruitment.

• A novel IL-1RI co-receptor, TILRR, links with the signalling receptor complex and enhances recruitment of the MyD88 adapter, controls induction of the Ras GTPase, and amplifies activation of NF-kappaB and inflammatory genes.

• One of the other adaptors involved are TRIF–related adaptor molecule (TRAM) where TRIF is TIR-domain-containing adapter-inducing interferon-β. TRAM contains a TIR domain in the C-terminal region and functions exclusively in the TLR4 pathway. TRAM interacts with TIR-domain-containing adapter-inducing interferon-β (TRIF) and the sterile alpha- and armadillo-motif containing protein (SARM). These adaptors bridge the TLR/IL-1R receptors to the intracellular molecules that transduce their signals into a biological response and play a central role in innate immunity.

• SARM contains a TIR domain at C-terminus, two “sterile a” motif (SAM) protein-protein interactions domains, and an Armadillo repeat motif (ARM).It functions as an inhibitor of TRIF-dependent TLR signalling.

• Another adaptor like toll-interleukin 1 receptor (TIR) domain containing adaptor protein (TIRAP) is required to act as a bridge for MyD88 in TLR2 and TLR4 signalling, while TRIF is used in TLR3 signalling and, in association with TRAM, in TLR4 signalling.

• Based on the type of adaptor molecules involved, the TLR/IL-1R-induced pathways can be sub-grouped in two classes: MyD88-dependent and MyD88-independent responses.

• In the MyD88-dependent pathway, MyD88 associates with IL-1R-associated kinases like IRAK4, IRAK1 and/or IRAK2. IRAK4 in turn phosphorylates IRAK1 and IRAK2 and promotes their association with TNF receptor associated factor-6 (TRAF6), which serves as a platform to recruit the TGF-beta activated kinase-1 (TAK1).

• Once activated, TAK1 activates the IKK complex, composed of IKK alpha, IKK beta , and NEMO (IKK gamma), which catalyzes phosphorylation and subsequent degradation of IkappaB rendering NF-kappaB free to translocate from the cytosol to the nucleus and activate NF-kappaB-dependent genes.

• TLR/IL-1R receptors associate with MyD88 through homotypic interactions between their respective TIR domains. This interaction then allows MyD88 to recruit members of the interleukin-1 receptor-associated kinase (IRAK) family (IRAK1, IRAK2, and IRAK4) through homotypic interactions between their respective Death Domains (DDs).

• The MyD88-dependent TLR/IL-1R signalling plays a vital role early in life, but becomes less important for survival during ageing. This is likely consequent to activation and/or maturation of TLR-independent innate immunity. Moreover, these findings seem to suggest that innate immunity is more important upon the very first encounter with a pathogen. Once adaptive immunity is generated, however, resistance to infection becomes quite efficient even in the absence of crucial functional components of TLR signalling.

• Once activated by their respective ligands, IL-1R, IL-18R, and TLRs engage with one or more adaptor proteins. These adaptors, namely, MyD88, MAL/TIRAP, TRIF, and TRAM are recruited, in various combinations, to the cytoplasmic domains of the receptors through homophilic interactions between Toll/IL-1 receptor (TIR) domains present in each receptor and each adaptor.

• TLR, IL-1R and TNF-R signalling to NF-kappaB converge on a common IkappaB kinase complex that phosphorylates the NF-kappaB inhibitory protein IkappaB.

• An aberrant activation of TLR/IL-1R signalling can promote the onset of inflammatory and autoimmune diseases. The development of therapeutic strategies for the control of their function have potential to cure inflammatory and immune disorders such as sepsis syndrome, asthma, atherosclerosis, Alzheimer’s disease, rheumatoid arthritis (RA).

• Pharmaceutical modulation of TLR/IL-1R signalling pathways by inhibitors, such as decoy peptides and synthetic mimetics that interfere with protein-protein interactions between signalling molecules of the TLR/IL-1R super family, might yield clinical benefits in the treatment of inflammatory and autoimmune diseases.

• The TIR domain of TLR/IL-1R proteins is a putatively suitable target. In particular, the BB-loop region may be regarded as a critical functional interface of TIR domain for its critical role in proper signalling. BB-Loop Decoy Peptides are short amino acid sequences of a protein that are expected to mimic its interaction surface and to prevent interaction of the prototype proteins with their partners.

• For e.g. A TIRAP decoy peptide consisting of the 14 amino acid-long sequence in the BB-loop (LQLRDAAPGGAIVS), fused to the Drosophila antennapedia homeodomain to facilitate the intracellular delivery, specifically blocked TLR4-induced activation of NF-kappaB without affecting the TIRAP-independent TLR9 response. In vivo administration of TIRAP inhibitory peptide counteracted the lung inflammatory response in healthy C57BL/6 mice.

• BB-loop heptapeptides derived from MyD88 and IL-18R inhibited homomeric interaction of MyD88 TIR domain or full-length MyD88 in vitro e.g. cell permeable derivative of the MyD88 BB-loop decoy heptapeptide (RDVLPGT).

• Toshchakov and colleagues performed systematic investigations of decoy cell permeable peptides containing TIR domain BB-loop sequences derived from the adaptor proteins MyD88, TIRAP, TRAM, and TRIF as well as the receptors TLR1, 2, 4, and 6. These decoy peptides were all able to inhibit, with varying activity, the TLR signalling pathways.

• Bartfai and colleagues, by focusing on TIR-domain interactions between IL-1RI and MyD88, synthesized a low-molecular-weight molecule mimetic, hydrocinnamoyl-L-valyl pyrrolidine.

• One of the most effective compounds, termed ST2825, inhibited homomeric interaction of MyD88 TIR domains. This effect was specific for TIR domains and did not affect interaction of MyD88 DD.

Although much emphasis has been placed on the development of NF-kappaB inhibitors, generic inhibition of NF-kappaB may lead to undesired side effects. Hence, a challenging objective is to develop drugs like above that block its effects in specific pathways, while leaving its physiological functions in other contexts largely intact. A promising research is going on in this line ...So watch out for this space...

Gandhi and Me

What is your understanding of Mahatma Gandhi and his message in contemporary global scenario?

A debate on the relevancy of Gandhi in today’s time has become a routine affair on every Mahatma Gandhi Jayanti. Actually it should be other way round- Can we face the challenge of Gandhi's ideals and ideas? For some people Gandhi’s teaching is still relevant today whereas some think that India & the world at large has changed so drastically that there is no role of Gandhi in it. No matter what exactly the truth is, the biggest truth of all is, there is some kind of charisma in him which simply fails to fade. The great Scientist Albert Einstein once said about Gandhi: “I believe that Gandhi’s views were the most enlightened of all the political men in our time. We should strive to do things in his spirit: not to use violence in fighting for our cause, but by non-participation in anything you believe is evil”. The more I read about Gandhi, the more I become humble to the greatness of him who was seeking nothing for himself but was willing to die in order that others may live. The above sentiments are depicted rightly in his words “There are many causes that I am prepared to die for but no causes that I am prepared to kill for."

The name of Mahatma Gandhi, today, transcends the bounds of race, religion, and nation- states, and has emerged as the Prophetic Voice of the twenty-first century. Gandhi is remembered for his passionate adherence to the practice of Nonviolence and his supreme humanism. After the Great Buddha and Jesus, he once again demonstrated that Non-violence could also be an effective instrument of social change.

I think that Gandhi’s value can successfully demonstrate to a World, weary with wars and destruction that adherence to Truth and Non-violence is not meant for individual behaviour alone but can be applied in global affairs too. The science of war leads one to dictatorship, pure and simple. The science of non-violence alone can lead one to pure democracy. Power based on love is thousand times more effective and permanent than power derived from fear of punishment. It is a blasphemy to say non-violence can be practiced only by individuals and never by nations which are composed of individuals. The nearest approach to purest anarchy would be a democracy based on non-violence.

A society organised and run on the basis of complete non-violence should expect that even non-violence be practised in police force. Police ranks should be composed of believers in non-violence. The people will instinctively render them every help and through mutual cooperation they will easily deal with the ever decreasing disturbances. Violent quarrels between labour and capital and strikes will be few and far between in a non-violent state because the influence of the non-violent majority will be great as to respect the principle elements in society.
Similarly, there will be no room for communal disturbances. A non-violent army acts unlike armed men, as well in times of peace as in times of disturbances. Theirs will be the duty of bringing warring communities together, carrying peace propaganda, engaging in activities that would bring and keep them in touch with every single person in their parish or division. Such an army should be ready to cope with any emergency, and in order to still the frenzy of mobs should risk their lives in numbers sufficient for that purpose. Satyagraha (truth-force) brigades can be organised in every village and every block of buildings in the cities. If the non-violent society is attacked from without, there are two ways open to non-violence. To yield possession, but non-cooperate with the aggressor and prefer death to submission. The second way would be non-violent resistance by the people who have been trained in the non-violent way. A nation or group which has made non-violence its final policy cannot be subjected to slavery even by the atom bomb. The level of non-violence in that nation, if that even happily comes to pass, will naturally have risen so high as to command universal respect.

The adoption of satyagraha and nonviolent non-cooperation will oblige the elected political representatives to honestly execute the wishes of the poor and oppressed millions in the rural areas and effectively stop those programs which are not in the interests of the entire polity. In situations where the representatives do not act according to the wishes of the people, Gandhi said 'we can protest and teach people to resist and make it clear to the Government that it cannot look us in this manner.

India today faces the onslaught of multinational investment and globalization in every sector of its economy. Will the new economic policy relieve the hunger of or provide remunerative jobs to the millions living in India? I think the answer to this question is to reconstruct a more harmonious, poverty-free, nonviolent, and self-reliant society based on the ethical and moral principles with which Mahatma Gandhi experimented. Business gurus in India are talking about Mahatma Gandhi as new role model .The Father of the Nation is now being held up as the master strategist, an exemplary leader, and someone whose ideas and tactics corporate India can emulate. The key business thinkers are preaching how corporate India needs to revisit Gandhi's ideas and apply the lessons learnt from him to their leadership styles. Gandhi is being held as a 'strategist. I think that Gandhi’s ideas are of particular relevance to India at this juncture, as it struggles to find ways to inch closer to the 8-10 per cent gross domestic product growth rate necessary to become an economic superpower. Gandhi reinvented the rules of the game to deal with a situation where all the available existing methods had failed. He broke tradition. He understood that you cannot fight the British with force. So he decided to change the game in a fundamentally different way. He unleashed the power of ordinary people, inspired women and men in the country to fight under a unifying goal. Resource constraint did not bother him. He aimed at a common agenda: Poorna Swaraj (Complete Freedom). That was the motivation. Drawing lessons from this, India needs to fundamentally change the way it can grow.

Gandhi's leadership style is being termed as 'follower-centric' and one that took into account existing conditions before determining the strategy. Gandhi advocated having leadership styles that were dependent on the circumstances. When Gandhi was in South Africa, he launched his protests in a suit and a tie. But when he came back to India, he thought of khadi and launched non-violent protests on a greater scale. I believe that Gandhi's style of leadership as applied to corporate India would involve making even the lowest person in the organization believe in it and the significance of his contribution towards it. In business, empowerment is all about making sure everyone is connected to the organization's goals. Gandhi has a way of doing that: making sure that everyone in the cause is connected to the goal. An understanding of these qualities about him is what is happening now in corporate India. Apart from the implications of Gandhi’s values only in relation to the Business sector, the Gandhian vision is a means to rejuvenate the entire nation and all its other important sectors. For e.g., local initiatives can foster the production of goods in cottage industries for primary consumption based on the principles of need and consequently exchange. In such a positive and caring environment resolution of disputes through harmonious reconciliation of competing interests and appeals to the rich and elite to respond to their dharma is possible. These steps will recreate the fervour, which once ignited the nation, for authentic swaraj. If India can revert to rechanneling its massive human resources towards these endeavours through a commitment to the Gandhian path it can resolve its crisis. The poor women, children, and men of this nation can return to the Gandhian message of self-reliance. By forming local, self-governing, and democratic political organizations it is possible to non-violently resist oppression and exploitation both by the state and market forces.

Self-imposed curbs on one's wants and production for one's needs can be achieved by discipline and selflessness. Devoting oneself first to cultivate the land for basic nutrition and only secondarily for exchange value is a must. Realization that self-help and bread labour are useful methods to frontally attack the vicious circle of poverty is imperative. Creation of democratic cooperatives for managing and allocating human and non-human resources in the spirit of trusteeship is requisite.

Gandhi had a dream for India. Realizing this dream has become a nightmare. Today, we are living in a constant adjustment to changing conditions, which require a different kind of discipline. Now it rests on our shoulders, yours and mine to see that the democratic values in our country remains intact and that social justice, equity, gender equality is achieved for all .Rights should follow duties If we are able to achieve this, we shall be helping to reinstate Mahatma Gandhi's dream, I firmly believe it can be done. Gandhi's unfinished task is the biggest challenge before the youth.

Gandhi had great faith in the ultimate success of his mission, because he had infinite faith in the individual's capacity to change. He firmly held that the human nature is capable of radical reorientation; all one needs is a will to explore his own true self. This explains why Gandhi, all through his life was striving to take humanity on to the path of spiritual and moral growth. The progress of civilization, as it has evolved through the ages, id proof that human nature is a developing entity, capable of change for the better. The key to making Gandhi's vision a reality and practising his values is to persistently subvert selfish worldly pursuits with ethical livelihood. This is the immediate struggle every Indian, on an individual and collective basis, has to non-violently and passionately wage.

Mahatma Gandhi was one of the leading volunteers the country has ever produced. Have you ever done any volunteer work? If yes, please outline your efforts and the impact it may have made?

Nature provides. Not always though, especially when there seeps in interference from the human element. This is particularly true of the Melghat forest area in Amravati district of Maharashtra where, between 1992 and 1997, an estimated 5,000 children died due to malnutrition. When the media picked up this shocking story, it generated a wave of criticism directed at the government and its inability to provide for the tribals who have inhabited the forests for centuries. But that is where it ended. No solutions were found. There was nothing concrete in the wake of lip sympathy. Until a group of curious social workers from Pune decided to penetrate into Melghat on a fact-finding mission.
That led to the initiation of the setting up of “Melghat Mitra”, a group which works exclusively for the betterment of the Korkus, which is what the tribal community in Melghat is known as. Five years since it was established with no funds nor an NGO status, Melghat Mitra has emerged as the only body of volunteers who have notched up remarkable achievements in this area of 350 villages, most of which are totally cut off from civilisation. In the 3 monsoon months of 2009, Melghat Mitra ran a “Dhadak Mohim” program where nearly 250 volunteers from Maharashtra and elsewhere lived with the people in 12 villages over a period of 10 days.

I got the privilege to join the organisation as a volunteer in the first batch of July 2009. Besides helping the local government health machinery to deliver their services, we tried to understand the problems and lives of the Korku tribals in Melghat. This program gave us an insight into the complex and multi-faceted problem of malnutrition and helped us to look at the problem from different perspectives. I believe that malnutrition needs to be addressed at its roots by basically ensuring the sustainable livelihood mechanisms for the Korku families. In addition, access to basic health and education services will also have to be ensured. Our strategy was to develop the capacities of the people to solve their own problems rather than make them dependent on us. Therefore, we do not burden the people with our programs but help people in their own initiatives. We continue to raise our funds through the public, strongly believing that such an activity should run entirely through public support, not only in order to ensure accountability and transparency, but also to ensure that the problem of malnutrition in India is understood and owned by the people of our country. I believe that it is only with collective efforts of the common man and of every single citizen that we can address the deep-rooted poverty of our Korku friend’s and others in similar situation.

Our campaign was called by us as the 'We won't let a single child die campaign'. The children who died till now fall in UNICEF's grade 4 category of weight/age ratio, which indicates severe malnutrition. Many of them didn't even have the strength to stand on their own. According to the authorities, the children die because the parents do not take them to a doctor. When a child dies the authorities enter it in their records as a case of diarrhoea or measles. Truth, however, paints an entirely different picture. We have sited through our observation, many reasons for the prevalence of malnutrition in the area. Teenage mothers, large families, lack of medical care and superstition have led to these deaths. The Korku belief that childbirth will be difficult if a woman eats well during the last trimester has led to underweight babies. Besides, the pregnant women must return to work in the fields immediately after they give birth, and therefore cannot nurse their infants for long. The government dole of Rs. 800 to pregnant women has proved counter-productive. The idea of the dole is to limit the size of the family and provide the best possible care to the nursing mother and new-borns. However, most Korku women consider it an incentive to bear more children. Even a mother of 16 children is availing of the dole. Racked by ignorance and poverty, the Korku tribesmen are finding life a painful experience. The death of Melghat's children, infact, is a manifestation of a deeper malaise in the Korku tribe. A visitor to the area will marvel at the fact that the agricultural produce of Melghat is worth Rs 10 crore. But, the tribals have no security of food for the next day. Benami (Property law) holdings are huge and moneylenders hold sway. There is also a relationship between education and the problem of malnutrition. The Korkus do not send their children to school because they need more farm hands. So while boys along with their mother and father go to the farms and girls keep watch on their siblings. There was a primary school in our village run by the zilla parishad with the barest of teaching aids. Most of the schools here have only one room and one teacher, and all the children would sit in the same class to be taught by the same teacher. From standard IV, they would have to enrol in a residential ashram in nearby town, which is why there was a high dropout rate. Added to this was the fact that the inhospitability of the region did not attract too many teachers.I along with my group started abhyas wargas(study classes) and created a force of Boko Mitras (a child is called Boko in the Korku language and Mitra means Friends) who encourage children to attend classes, and ensure that learning is fun and not routine.

My experience in melghat was more than mere doing social work it was one of kind experience .The experience of living among the tribal people of India was journey of self-discovery. The Korkus there even though of their condition are as much happy if not less than any well fed and well equiped city person. This has helped to be more grateful to god and taught to count my blessings rather than cribbing for the things that I don’t have. I hope that the efforts I have put in through Melghat Mitra have brought some positive changes in life of Korkus. I think the project has worked because we were never an NGO seeking to bring about drastic reforms. We went as friends and we remain so.

If one loves animals, then seeing an ad on television depicting animal cruelty can tug at the heart and make the anger boil. However, these ads are on television for one purpose; to make people more aware of the plight of animals and perhaps to convince more people to become active in organizations that are against animal cruelty. Seeing one of the similar ads on the TV stirred me to the core and I thought to join an organization for animal rights to channel my anger positively.
The BSPCA (Bombay Society for the Prevention of Cruelty to Animals) in Mumbai is a charitable organization in existence since 1874. Its purpose is to prevent cruelty to animals and provide help and relief to all animals in Mumbai city. The animal hospital works 24 hours a day and treats an average of about 400 animals per day which includes different species of animals.

The BSPCA is effectively controlling cruelties to animals in Mumbai by employing SPCA Inspectors, social workers and by way of spreading education and awareness programmes. Volunteers are essential part of the hospital team for successfully running these programmes. As a Volunteer since 2 years I got opportunities such as to be a Foster mom or dad for litters of puppies ,Dog walking by-weekdays and weekend ,Grooming for dogs and horses, Fundraising ,Dog kennel assistant-cleaning kennels, feeling water bowls ,to be Emergency help and rescue correspondent ,Data entry operator, to help and participate in the events like Marathon etc. Most cruelty perpetrated on animals is needless and can be avoided with just a little thoughtfulness and sensitivity. There has to be awareness, accompanied by kindness and concern towards all God's creatures. I am glad that I can do my bit for the animals that share our world through BSPCA.

Mahatma Gandhi spearheaded a lot of efforts for social reconstruction and worked for the betterment of disadvantaged. How do you see your education at London Met helping you to follow this leadership?

Around two decades after the first clinical evidence of Acquired Immunodeficiency Syndrome was reported, AIDS has become the most devastating disease that human kind has ever faced. Since the epidemic began, more than 30 million people have been infected with Human Immunodeficiency Virus (HIV). AIDS threatens every fabric of society, increasingly targeting the poor and underprivileged. The pandemic is out of control, we have no effective antiviral agent and no immediate prospect of a vaccine. India being the world's fourth largest population suffering from AIDS, I can feel the extreme need to do research in HIV. Currently investigators are conducting research on various areas of HIV especially its infection, pathogenesis, development and testing of preventive HIV vaccines, prevention strategies, and new therapeutic treatments for HIV infection and AIDS-associated opportunistic infections. This research is identifying new and more effective targets for drugs and vaccines. The desire to become a part of this war against HIV has motivated me to opt for a career in biomedical research in the field of HIV and its therapeutics.

I feel that the knowledge I have gained is infinitesimal and fragmentary. I realize that I am still languishing on the shores and yet to venture into the vast realm of Biomedical sciences. So I chose to go for Masters in the subject so that I can improve my understanding and knowledge related to HIV and AIDS. It’ll not only give me insight to wider perspectives but also guide me in achieving my goal.

The Gandhian method of non-violence is relevant more than ever before in contemporary global scenario. Give us one or two examples of how you have embodied these attitudes in your life.

On Nov 26 last year, 10 Pakistani terrorists sneaked into this mega polis Mumbai by the Arabian Sea, landing by rubber dinghy and unleashed mayhem for three days in this city. Their killing spree and the bloody saga ended only when security forces killed all but one of them - Mohammed Ajmal Amir Kasab was captured during the attack. The 60 hours of terror left 166 people dead. I lost my dear friend in the same. The pain was excruciating and used to surge after seeing her parents losing their only child. Of cores my first reaction was that of sheer anger and helplessness towards the callous terrorist. But soon I realised it was useless. Instead I participated in a candle-light vigil, a police parade, an all-religion prayer meet at the Gateway of India and a memorial service at Chabad House where people from all walks of life came together to pay tribute to the victims and heroes of the 26/11 terror attacks. These peace march were ofcores in memory of those who lost their lives in the mayhem but also a strong indication to terrorist that we were down but not out. As an alert and active citizen I take it up on my selves and tell others to do their bit to maintain vigilance and help the authorities to make the city safer by reporting unclaimed items, suspicious strangers or activities in the vicinity.

I participated in Annual National Service Camps organized by National Service Scheme (N.S.S) in S.I.E.S. College in 2004 and 2005. The Camps were set in villages in Maharashtra which were suffering from alcoholism. During our stay in the village we discovered that the government officials itself are culprits of increasing alcoholism in most of these areas. But I and my groups didn’t confront them directly. We made skits regarding awareness of bad effects of alcoholism and invited those officials along with villagers for the same. Thus I think it was a peaceful and eventually more effective way of tackling that situation.

NF-κB : A Future Drug Target

NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a transcription factor that started its life as a B cell-specific nuclear protein, but has matured to become one of the most extensively studied transcriptional regulators, found to control many pathophysiological processes. Its role ranges from its transcriptional regulatory functions to its participation in diverse processes, including inflammation, immunity, mucosal homeostasis and cancer. NF-kB regulates the expression of over 200 genes that are involved in a variety of functions. It is basically a protein complex found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens.

NF-κB plays a key role in regulating the immune response to infection. It regulates the expression of cytokines, inducible nitric oxide synthase (iNOS), cyclo-oxgenase 2 (COX-2), growth factors, inhibitors of apoptosis and effector enzymes in response to ligation of many receptors involved in immunity including T-cell receptors (TCRs), B-cell receptors (BCRs) and members of the Toll-like receptor/IL-1 receptor super family. It also takes part in the development and the activity of a number of tissues including the central nervous system. Moreover, pathological dysregulation of NF-κB is linked to inflammatory and autoimmune diseases as well as cancer. Activation of the NF-κB/Rel transcription family, by nuclear translocation of cytoplasmic complexes, plays a central role in inflammation through its ability to induce transcription of proinflammatory genes. This pathway is activated upon appropriate cellular stimulation, most often by signals related to pathogens or stress.

In the below link, we will discuss the the regulation of NF-κB activity by IκB proteins and IκB kinase (IKK), specificity of various NF-κB proteins, their role in inflammatory disease, and the development of therapeutic strategies aimed at inhibition of NF-κB.

NF-κB A Future Drug Target.pdf