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News & Views Issue 18 November 2017


EDITORIAL Welcome to the final issue of 2017, a year that saw many new initiatives by the India Alliance aimed at promoting academic research leadership, women in science, clinical and interdisciplinary research, public engagement with science and international collaborations along with some groundbreaking research by India Alliance Fellows. To begin with, we would like extend heartiest congratulations to our fellowship committee member Prof. Sanghamitra Bandyopadhyay, Director, Indian Statistical Institute, Kolkata for receiving the Infosys Prize 2017 in Engineering and Computer Science. We are also happy to share that BM Birla Science Prize for 2016 has been bagged by IA Fellows, Dr. Arun Shukla (IIT Kanpur) and Dr. Subba Reddy Maddika (CDFD Hyderabad). Congratulations to them! Updates on the Fellowship front- we are presently not accepting preliminary applications for any of our Fellowship schemes. However, applications already submitted to various schemes are currently under review. We recently concluded interviews for our Senior and Intermediate Fellowships (SIF) and Clinical and Public Health Research Fellowships (CPH), results of which will be announced on our website shortly. The next call for applications for CPH and SIF will announced on 2 January 2018 and 15 January 2018, respectively. Check our website for regular updates. In this issue, we bring to you a fascinating mix of recently published research of our Fellows in the Research Highlights section. Dr. Arun Shukla and his team at IIT Kanpur continue to decipher structure and function of an important cell membrane protein family, G-Protein Coupled Receptor (GPCR), an important drug target and have now developed synthetic proteins to fine tune their function. Their recently published work has important implications for drug discovery. Recently published research from Dr. Sanjeev Shukla’s group at IISER, Bhopal, has provided new links between epigenetic processes and glucose metabolism in breast cancer progression that can exploited for developing novel cancer treatment strategies. Dr. Kundan Sengupta’s (IISER Pune) recent research sheds light on how the shape and function of the nucleus inside a cell is regulated by proteins called Lamins. This research has important implications for cancer drug discovery. Dr. Guruprasad Medigeshi at THSTI Faridabad was part of a team of international scientists who have developed a rapid diagnostic test that can distinguish between Zika and Dengue viruses. This test could have a significant impact on disease diagnosis and controlling the spread of infection diseases, specially in vulnerable populations. Lymphocytes are immune cells, which play a critical role in the recognition as well as clearance of microbial pathogens. Dr. Soumen Basak and his team at NII, New Delhi, have uncovered a novel inflammatory mechanism that transiently prevents the trafficking of lymphocytes into lymph nodes. They believe that this temporary blocking of immune cells to the site of inflammation can have both good and bad effects on the immune system. Dr. Mahak Sharma (IISER Mohali) in collaboration with India Alliance Fellow Dr. Amit Tuli (IMTECH Chandigarh) demonstrate how Salmonella bacteria, responsible for causing intestinal inflammation and diarrhea in humans, cleverly exploits the host cell’s machinery to tether itself and replicate ensuring its survival inside the host cell. Damage or injury to the nerve cells can have debilitating effects on human life, such as our ability to walk, smell and see. Dr. Anindya Ghosh-Roy and his team at NBRC Manesar have discovered, in a roundworm model, that lost neuronal function can be restored after injury.

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The physical state of cell’s outer membrane not only affects its function but has shown to be altered under stressful conditions. Dr. Bidisha Sinha at IISER Kolkata and her team used a non-invasive technique to measure and map fluctuations in the cell membrane Some of these research stories were also covered in the popular media, links of which are included in this section. This newsletter also includes interview of our Intermediate Fellow Dr. Rashmi Rodrigues at St. John’s National Academy of Health Sciences, Bangalore and profiles of our new Fellows. In light of the recent Nobel Prize announcements, IA Fellows, Dr. Arun Shukla (IIT Kanpur) and Dr. Sveta Chakraborty (IISc Bangalore) describe the significance of the research awarded for Chemistry and Medicine/Physiology, respectively, in this issue- “For cry(o)ing out loud” & “Tick Tock goes the body clock”. The first Developing Indian Physician Scientist (DIPS) workshop was held in Delhi from 23-26 November at CSIR-IGIB, New Delhi. We are presently accepting applications for the DIPS workshop in Hyderabad (2-5 March 2018). Read this issue or visit our website to find out more about these workshops. On the Pubic Engagement front, we are pleased to announce a new public engagement project the “Actor Doctor Theatre project” that aims to foster cross-disciplinary exploration of health and will initiate conversations on important public health issues that India is facing today. This project is being spearheaded by the Darpana Academy of Performing Arts in Ahmedabad with support from the India Alliance. Find out more about this project in this issue. More than ever before it has become important for scientists around the world to work collaboratively to tackle global health challenges. The India Alliance joined the global campaign “Together Science Can” to promote and celebrate international collaboration in science. Launched on 28 September, Together Science Can encourages researchers around the world to join together to protect the future of vital collaboration. More information on this has been included in this newsletter or you can visit www.togethersciencecan.org. Under the “Together Science Can” theme we feature two guest contributions - Maximising collaborative research between India and the UK and Purdue University’s Strategic Focus on Both India and Life Sciences- both these reports emphasize the need for researchers and institutions to take collaborative action to solve problems that can impact human health and well being. The India Alliance and the U.S. Embassy organized “Women in Science- a listening session” on 16 November 2017 at ICGEB, New Delhi, in which both policy makers and women in academia came together to engage in constructive dialogue about opportunities for supporting the advancement of women in science nationally and internationally. A detailed report and recommendations from this session will be made available online shortly. As always, our heartfelt gratitude to all those who have contributed to this newsletter. Special thanks to our Intermediate Fellow at THSTI Faridabad, Dr. Guruprasad Medigeshi for sharing the cover image which shows the dipsticks used for Zika and Dengue diagnosis (photo by Nikolas Alberra). Please write to us if you have suggestions for how we can make these newsletters a more informative and enjoyable read for you next year as well. Find archives of our past newsletters here. Sarah Hyder Iqbal, PhD Public Engagement Officer Wellcome Trust/DBT India Alliance November 2017


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India Alliance Fellowships

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New India Alliance Fellows

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India Alliance Fellows’ Research Highlights:

Recently published research of

Dr. Arun Shukla (IIT Kanpur), Dr. Sanjeev Shukla (IISER Bhopal), Dr Kundan Sengupta (IISER Pune), Dr. Guruprasad Medigeshi (THSTI Faridabad), Dr. Soumen Basak (NII, New Delhi), Dr. Mahak Sharma (IISER Mohali), Dr Anindya Ghosh-Roy, Dr. Bidisha Sinha (IISER Kolkata)

12 India Alliance Fellow in Spotlight Interview with Dr. Rashmi Rodrigues, St. John’s National Academy of Health Sciences, Bangalore

14 For cry(o)ing out loud by Dr Arun Shukla (IIT Kanpur) Tick Tock goes the body clock by Dr Sveta Chakraborty (IISc Bangalore) 2017 Nobel Prizes in Chemistry and Medicine/Physiology

16 India Alliance workshops Developing Indian Physician Scientist (DIPS) workshop, Hyderabad EMBO Research Leadership Course, Delhi & Hyderabad

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Public Engagement Actor and Doctor – Public Health Theatre Festival

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Together Science Can Global campaign to promote international collaborations

20 Guest contribution Maximising collaborative research between India and the UK George Institute for Global Health, UK

21 Guest contribution Purdue University’s Strategic Focus on Both India and Life Sciences By Kaethe Beck & Heidi Arola, Purdue University

22 India I EMBO Symposia 23 Women in Science – A Listening Session 24 Other announcements Postdoctoral position available at IISER Bhopal & ILS Bhubaneswar

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INDIA ALLIANCE

FELLOWSHIPS Clinical and Public Health Research Fellowships Next call for applications: 2 January 2018 Preliminary application deadline : 07 February 2018 Eligibility

successful in building a track record of pursuing a cutting edge research and wish to establish their own independent clinical/public health research program in India. Suitable for applicants with 4-7 years of relevant experience.

Eligibility limit covers the entire range of Clinical and Public Health Research Fellowship schemes • No age or Nationality restrictions. • The candidates need not be resident in India while applying but should be willing to establish an independent research career in India. • Clinicians and Public health researchers do not require a PhD to apply. • This competition is open for clinicians and public health researchers with up to 15 years of post-MD/MS/MPH/PhD or equivalent clinical / public health research experience. • Applicants are advised to choose the most appropriate scheme suitable for them based on their qualification, research experience, career trajectory and track record. Please refer to the guidance notes, provisions and mandate of the scheme for assessing your eligibility on the website. The Office reserves the right to advice on the suitability of the scheme accordingly. Eligibility guidance notes: Early Career Fellowship: For those applicants who have shown promise to pursue research and wish to further their efforts to build a research career under the supervision of a Fellowship supervisor. Suitable for applicants in the final year PhD/MD/MS/MPH or have up to 4 years of relevant experience

Intermediate Fellowship: For those applicants who have been

Senior Fellowship: For those applicants who have demonstrated their potential to lead an independent research program and want to expand it further to undertake pioneering research. Suitable for applicants with 7-15 years of relevant experience. Provisions: The 5 year Fellowship support provides • interested clinicians the opportunity to pursue their research goals in combination with their clinical duties. • competitive personal support • generous research support with flexibility to accommodate requirements of clinical and public health research. • Flexibility to request additional support staff • Support training cost and research sabbatical • Funds for International training and travel Application process: Application forms are available on the India Alliance online application System (IASys) Please visit our website for further information on the remit, provisions and application process. Write to us at info@wellcomedbt.org

Senior and Intermediate Fellowships in Biomedical Research Next call for applications: 15 January 2018 Preliminary application deadline : 21 February 2018 Senior and Intermediate Fellowships are available across the full spectrum of biomedical research from fundamental molecular and cellular studies through clinical and public health research*. Interdisciplinary projects are also welcome. Eligibility: • No age or nationality restrictions. The applicant need not be resident in India while applying but should be willing to relocate to and work in India. • A salaried position or commitment towards a salaried position at the Host Institution is not required. • Applicant can have a PhD in any discipline of science. • This competition is open for basic science/veterinary researchers between 4 -15 years of post-PhD research experience. • Applicants are advised to choose the most appropriate scheme suitable for them based on their qualification, research experience, career trajectory and track record. Please refer to the guidance notes, provisions and mandate of the scheme for deciding on the scheme you wish to compete for. The Office reserves the right to advise on the suitability of the scheme accordingly. Eligibility guidance notes: Senior Fellowship: For researchers who have demonstrated their potential to lead an independent research program and want to expand it further to undertake pioneering research. Suitable for applicants with 7-15 years of post-PhD research experience.

research and wish to establish their own independent research program in India. Suitable for applicants with 4-7 years of post-PhD research experience. Provisions: The 5 year Fellowship support provides • • •

competitive personal salary support generous and flexible funds for research funds to develop international collaborations

Requirements: The following are essential for the application. • • •

A research proposal that is based on a hypothesis and seeks to answer an original biomedical research question A not-for-profit Host Institution in India that will administer the Fellowship for the full duration of the award A sponsor at the Host Institution, who can guarantee space and resources for the duration of the award

Application process: After the call for application has been made, you can complete the online application form available on the India Alliance online application System (IASys) Please visit our website for further information on the remit, provisions and application process. Write to us at info@wellcomedbt.org

Intermediate Fellowship: For postdoctoral researchers who have been successful in building a track record of pursuing a cutting edge

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* We encourage Clinicians and Public Health researchers to apply in the separate Clinical and Public Health competition (see below)


NEW

INDIA ALLIANCE FELLOWS

EARLY CAREER FELLOWS 2017

nutrient limitation is a key driver of community development (Biofilms) in fungi, little is known about the fundamental metabolic driving principles that control this behavior. My aim is to understand how these fungal communities develop from a metabolism perspective, in particular, understanding the molecules and metabolic processes that drive the development of these communities.

Hospital-associated ESKAPE pathogens: Unraveling novel regulatory layers controlling virulence and persistence

I will be using a combination of genetics based techniques, microscopy and quantitative mass spectrometry to address this question. I will initially use Saccharomyces cerevisiae (Baker’s Yeast) as my model system to address some of these questions and subsequently transition to studying communities formed by pathogenic fungi including Candida albicans and Candida glabrata. This knowledge about the conserved metabolic pathways that drive the development of these biofilm communities could potentially aid us in the development of novel therapeutics that would target biofilm associated diseases caused by fungi.

Dr. Shankar Manoharan Vellore Institute of Technology, Vellore WEBSITE

INTERMEDIATE FELLOWS 2016

Clinical and Public Health Research Fellowships The success of Klebsiella pneumoniae (KPN) as a nosocomial pathogen depends on a host of virulence factors that render it resistant to environmental and host-imposed stresses. Adding to its high virulence and persistence, KPN is gaining resistance to last-resort antibiotics. So, it is becoming difficult to treat antibiotic resistant KPN infections using current antibiotics. Therefore, there is a pressing need to identify new drug targets in KPN. The regulatory networks that control the expression of stress responsive genes and virulence factors in KPN are attractive targets for antimicrobial drug design. Consequently, transcriptional control of virulence gene expression by two-component systems and transcriptional regulators in KPN has been investigated before. On the contrary, post-transcriptional control of gene expression in KPN is not well understood. This research intends to elucidate the regulatory mechanisms by which the small-RNAs post-transcriptionally control the virulence, stress tolerance ability and fitness in KPN. The knowledge generated from this project, in the long term will provide insights into previously unknown regulatory mechanisms operational in KPN, which in turn will allow development of novel and reliable therapeutics.

Project THETA: Towards Health Equity and Transformative Action in tribal health Dr. Prashanth Nuggehalli Srinivas Institute of Public Health, Bengaluru WEBSITE

Metabolic Regulation of Fungal Morphogenesis

India's tribal population lives largely in and around thickly forested areas, which are often difficult-to-reach. Most areas with high tribal populations also have poor health and nutrition indicators. However, the poor population health outcomes in tribal communities cannot be explained by geography alone. Social determinants of health, especially various social disadvantages compound the problem of access and utilization of health services and achieving good health and nutritional status. In the interest of achieving equitable health and universal health coverage, we need to better understand the reasons for poor health among tribal populations and generate scientific explanations for the drivers of health inequalities in tribal communities. This will help design and implement evidencebased and context-specific interventions to address health inequalities of tribal populations. In this research project, we will describe and analyse the extent and patterns of health inequalities among forest-dwelling tribal communities in three major tribal regions; explain the underlying reasons for health inequity among tribal communities through a contextualized and empirically validated theory; and design and pilot an intervention to address health inequalities by tribal communities.

Dr. Sriram Varahan Institute for Stem Cell Biology and Regenerative Medicine (inStem), Bangalore WEBSITE

Unicellular organisms including fungi have the ability to reversibly switch (Morphogenesis) to a community associated lifestyle under stressful conditions like nutrient limitation. This community lifestyle allows them to survive and persist under these unfavorable conditions. Interestingly, this reversible switching also allows some of the pathogenic fungi to invade and cause persistent infections in a host. Although it is well established that

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NEW

INDIA ALLIANCE FELLOWS

Longitudinal assessment of metabolomic changes during pregnancy on foetal growth

RESEARCH TRAINING FELLOW 2016 Clinical and Public Health Research Fellowships

Studying potential benefits of an add-on non-invasive focal brain stimulation technique in Schizophrenia

Dr. Vipin Gupta University of Delhi WEBSITE

Dr. Sowmya Selvaraj National Institute of Mental Health And Neurosciences, Bangalore

Pregnancy is the first window of exposures in human life which is dominated by metabolic changes for meeting the raised physiological needs of foetal growth and development. Metabolic adjustments are required for opening the provisions of additional energy sources to support labour and lactation. The system-wide understanding of metabolism during gestation demands the use of holistic approach of metabolomics for high-throughput identification and measurement of levels of metabolites.

WEBSITE

Schizophrenia is a chronic debilitating disorder with working memory (WM) deficit as one of the core cognitive deficits leading to functional impairment. WM deficits are also associated with reduced left dorsolateral prefrontal cortex activation. Transcranial direct current stimulation (tDCS), a novel non-invasive focal brain stimulation technique using a low intensity direct current has shown to improve cognitive deficits especially WM deficits in schizophrenia. Brain derived neurotropic factor (BDNF) has found to have correlation with cognitive deficits and influencing tDCS modulated neuroplasticity. High definition tDCS (HD- tDCS) is found to have more focalized neuro-modulation and potentially greater benefits.

The current research work will assess the longitudinal quantitative changes in metabolism during the course of pregnancy in relation to maternal gestational characteristics. Further, the influence of maternal metabolic changes in pregnancy on foetal growth and biological traits of offspring at birth will also be examined. This study will be conducted in collaboration with Sardar Patel Medical College, Bikaner, Rajasthan. We will extensively phenotype at least 1000 mothers during pregnancy for cardiometabolic traits at each follow-up along with the measurements of foetal growth and offspring size at birth.

In this background, the current study proposes to explore potential benefits of HD- tDCS for WM deficits in schizophrenia patients with the following objectives: a) To evaluate the neurobiological correlates of the effect of add-on HD-tDCS in schizophrenia patients with deficient working memory; b) To examine the neurobiological correlates (functional MRI activation as well as BDNF gene variation and expression) of WM deficit in schizophrenia.

EARLY CAREER FELLOW 2016

Clinical and Public Health Research Fellowships

Atman: An adaptation and evaluation of an intervention for self-harm in youth

The potential translational implications of the study include: Understanding neurobiology of WM deficits in schizophrenia; Novel neurobiological correlates of clinical response to HD-tDCS in schizophrenia patients with WM deficits; Development of personalized neuromodulation for treating schizophrenia in future.

Dr. Shilpa Aggarwal Public Health Foundation of India, Gurgaon WEBSITE

The rates of suicide in India have shifted with economic development with a rising rate of suicide evident in young men and women. Suicide has overtaken maternal causes globally as a major cause of death in young women. Self-harm is the strongest antecedent to suicide. My study is related to modifying and evaluating an intervention to reduce self-harm in youth in India.

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INDIA ALLIANCE FELLOWS’

RESEARCH HIGHLIGHTS Synthetic antibodies to fine tune function of a cell membrane protein family, GProtein Coupled Receptor (GPCR), an important drug target Dr. Arun Shukla, Intermediate Fellow Indian Institute of Technology (IIT) Kanpur

G protein-coupled receptors (GPCRs), a family of proteins embedded in the plasma membrane of the cells, regulate a broad range of physiological processes such as mood, memory, feeding and immune response. About half of the currently sold medicines including those prescribed for controlling the high blood pressure, treating heart failure, and to manage severe pain, work by activating or inactivating different receptors in the GPCR family. A small class of scaffolding proteins, referred to as β-arrestins, critically govern the trafficking patterns, signaling and life-span of GPCRs via universally conserved cellular mechanisms. For example, β-arrestins drive GPCRs from the cell surface to cell interior upon activation, and it serves as one of the mechanisms to determine the temporal signaling response of these receptors. This particular function of β-arrestins depends on their ability to cross-talk with another cellular protein, called clathrin which is a key component of protein trafficking in the cell. We have now generated synthetic proteins, antibody fragments to be precise, which can disrupt the β-arrestin-clathrin interaction, and thereby act as inhibitors of GPCR trafficking from the plasma membrane to endosomal vesicles, a process known as endocytosis

or internalization. Importantly, these antibody fragments are highly selective for β-arrestin-clathrin interaction, and they do not interfere with other β-arrestin functions such as GPCR signaling. As GPCR trafficking patterns and underlying mechanisms are typically very well conserved, these antibody fragments based endocytosis inhibitors appear to be generic across the GPCR family. Considering that some GPCR mutants are internalized even in the absence of their ligand stimulation, a situation that leads to pathophysiological conditions such as nephrogenic diabetes and retinitis pigmentosa, our antibody fragment based inhibitors have novel therapeutic potential. Moreover, the conceptual framework of this study should be applicable to other signaling systems as well, and it highlights the broad implications of our experimental strategy. A synthetic intrabody-based selective and generic inhibitor of GPCR endocytosis. Ghosh E, Srivastava A, Baidya M, Kumari P, Dwivedi H, Nidhi K, Ranjan R, Dogra S, Koide A, Yadav PN, Sidhu SS, Koide S, and Shukla AK. Nature Nanotechnology, October 2017

Novel links between epigenetic processes and glucose metabolism in breast cancer progression Dr. Sanjeev Shukla, Intermediate Fellow

Indian Institute of Science Education and Research (IISER) Bhopal We have identified a novel epigenetic mechanism of cancerspecific gene modification, which contributes to the growth of breast cancer cells by promoting the Warburg effect, increased glucose metabolism in cancer cells which helps them survive. This new information will help us develop better and more specific therapeutics to treat breast cancer.

In the recent times, cancer epigenetics has gained a lot of attention due to the involvement of epigenetic modifications in the initiation and progression of cancer. These epigenetic changes regulate how cells read the genes but do not affect the DNA sequence and is also considered to be reversible. Deregulation of these epigenetic processes have been shown to result in many diseases, including cancer. Following processes are considered as epigenetic

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INDIA ALLIANCE FELLOWS’

RESEARCH HIGHLIGHTS modifications: DNA methylation, histone modification and noncoding RNA (ncRNA)-associated gene silencing. Since epigenetic modifications are reversible, they are an attractive target for cancer therapy. Though epigenetic modifications are associated with changes in gene expression, their role in the regulation of alternative splicing in the cancer cells is not well understood. Alternative splicing is a process by which one gene can generate multiple mRNA or protein isoforms. These alternatively spliced isoforms may differ in their structure and function and may play an important role in cancer-formation or tumorigenesis. Identification of epigenetic regulators of cancer-specific splicing will enable us to therapeutically target aberrant splicing and provide a new approach to cancer therapy.

In our recent report in Proceedings of the National Academy of Sciences (PNAS), we have demonstrated a new mechanism of DNA methylation-mediated regulation of alternative splicing by BORIS (Brother Of The Regulator Of Imprinted Sites), which can contribute to breast cancer tumorigenesis by favoring the Warburg effect. BORIS is a cancer-testis gene which is expressed in germ cells but not in the somatic cells. Interestingly, BORIS gets overexpressed in cancer cells making it an important target for cancer treatment. The cancer cells thrive on glucose by converting it to lactate at the end of glycolysis. The phenomenon is known as aerobic glycolysis or Warburg effect and promotes the growth of the cancer cells. The alternative spliced protein isoform Pyruvate kinase M2 (PKM2) contributes to the Warburg effect by promoting aerobic glycolysis whereas PKM1 isoform promotes oxidative phosphorylation, which is a part of normal glucose metabolism. The PKM gene contains two mutually exclusive exons, exon 9 and 10 which are alternatively included in the final transcript to give rise to PKM1 and PKM2 isoform respectively. In this study, we demonstrate the increased PKM2 isoform expression in breast cancer, which

correlates with higher DNA methylation at PKM exon 10 in breast cancer cells as compared to the normal cells. The alternative splicing and DNA methylation are both known to be altered in the cancer cells but whether and how they are connected is not clear. Here, we describe for the first time that the differential intragenic DNA methylation in breast cancer cells is associated with cancer-specific mRNA splicing. This study provides a novel functional link between epigenetics, alternative splicing, Warburg effect and growth of breast cancer cells. Interestingly, we show that how BORIS/DNA methylation contributes to the Warburg effect by regulating alternative splicing and inhibiting DNA methylation or down-regulation of BORIS leads to reversal of Warburg effect and growth inhibition of breast cancer cells. Importantly, our results show that in addition to PKM splicing, BORIS also regulates alternative splicing of several genes in a DNA methylation-dependent manner. Collectively, we have described a new mechanism based on BORIS binding to explain the alternative splicing events regulated by DNA methylation in breast cancer. Furthermore, this study provides the mechanism to switch the PKM splicing from cancer-specific to normal isoform by controlling the upstream DNA methylation or BORIS, which may provide a route for therapeutic management of breast cancer in future. Intragenic DNA methylation and BORIS mediated cancer-specific splicing contributes to Warburg effect. Singh S, Narayanan SP, Biswas S, Gupta A, Ahuja A, Yadav S, Panday RK, Samaiya A, Sharan SK, Shukla S. Proceedings of the National Academy of Sciences (PNAS). October 2018 Media report - IISER Bhopal employs new strategies to fight breast cancer. The Hindu

New role for the nuclear proteins, Lamins and its implications for cancer drug discovery Dr. Kundan Sengupta, Intermediate Fellow

Indian Institute of Science Education and Research (IISER) Pune

Our recently published study in Molecular Cell Biology suggests a new role for the nuclear protein, Lamin, which is responsible for maintaining the shape and function of the nucleus. The nucleus houses our DNA and is the control centre of our cells. Inside the nucleus is a roundish entity - the nucleolus, which makes a cousin of DNA, ribosomal Ribonucleic Acid (rRNA), an essential part of molecular machines inside the cells, referred to as ribosomes. These ribosomes make proteins that we are all made up of, such as the keratin proteins in our hair and nails. Our research group is interested in understanding what controls the shape of the nucleolus, as changes in nucleolar shape or numbers typically increase rRNA levels. Normal cells have 2 or 3 nucleoli, while cancer cells may have even 10 or more. What maintains nucleolar numbers in normal cells and how is this control cleverly hijacked in cancer cells resulting in multiple nucleoli? Since cancer cells multiply in an uncontrolled manner, they need more protein for their survival and therefore extra nucleoli enable them to survive and multiply rampantly. Lamins are proteins that maintain shape and impart strength to the

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nucleus. In our recently published report we asked the question- do Lamins also control shape and function of the nucleolus. Peering deep into cells using a super resolution microscope, revealed that Lamins in addition to their location at the border of the nucleus, are also located right near the boundary of the nucleolus. Using a molecular approach, we reduced the levels of one of the three Lamins to less than ~30% in cells and much to our surprise, the nucleolus collapsed into a single, large irregular blob! Interestingly, restoring Lamins to their normal levels, brought back the two round and discrete nucleoli. Further, lowering Lamins, tripled the levels of ribosomal RNA. In summary, our study for the first time suggests that Lamins in addition to the nucleus, also control the shape and function of the nucleolus. It remains to be understood in the not so distant future, if restoring or correcting the levels and function of Lamins, would allow us to reverse and hopefully even partially undo the damage and large-scale destruction that cancer cells unleash on the human body. Lamin B2 modulates nucleolar morphology, dynamics and function. Sen Gupta A & Sengupta K. Molecular Cellular Biology. October 2017


INDIA ALLIANCE FELLOWS’

RESEARCH HIGHLIGHTS

A rapid diagnostic test that can distinguish between Zika and Dengue viruses Dr. Guruprasad Medigeshi, Intermediate Fellow

Translational Health Science and Technology Institute (THSTI), Faridabad India alone contributes to around 35% of global dengue cases. Four dengue virus (DENV) serotypes elicit poor cross-protective responses in humans. Antibody-dependent enhancement has been recognized to play a major role in secondary dengue infections leading to severe disease. Recent reports indicate that prior exposure to DENV may also be a risk factor for enhanced zika virus (ZIKV) infection due to cross-reactive antibodies. With the emergence of ZIKV, which is closely related to DENV, there is an increasing need to ramp up diagnostic capabilities to differentiate between different serotypes of DENV and also between DENV and ZIKV. Point-of-care (POC) diagnostic tests based on immunochromatographic techniques utilizing antibodies conjugated to gold nanoparticles are both economical and do not require sophisticated laboratory equipment. Currently POC tests are not available that differentiate between DENV serotypes or between DENV and ZIKV.

recognizing unique epitopes on DENV or ZIKV were also used to differentiate between these two viruses in the rapid POC test. The rapid diagnostic test showed a sensitivities of 76, 89, 100 and 100% for the four DENV serotypes respectively and a specificities of 89, 98, 100 and 96%. The pan-dengue test had a sensitivity and a specificity of 88 and 100% respectively and 81% and 86% respectively for ZIKV. Thus, we have developed the first rapid diagnostic test that can be implemented as a POC test to diagnose dengue infection, differentiate between the four DENV serotypes and also between DENV and ZIKV. We believe this test could impact current epidemiologic surveillance and patient care strategies for both DENV and ZIKV infection worldwide. Rapid antigen tests for dengue virus serotypes and Zika virus in patient serum. Bosch et al. Science Translational Medicine. October 2017

The non-structural protein, NS1, of DENV and ZIKV is a secretory protein which has been used as a target antigen in rapid diagnostic tests. As part of a multi-institutional collaborative team led by Dr. Lee Gehrke, we used the NS1 protein of both DENV (all four serotypes) and ZIKV to raise a panel of monoclonal antibodies, which recognized the conserved and unique epitopes on NS1 protein of DENV and ZIKV. Antibody pairs recognizing serotypespecific epitopes or conserved epitopes across all four serotypes in DENV were used to develop a POC test that was serotype specific or pan-dengue specific respectively. In addition, NS1 antibody pairs

Media report: A rapid test to diagnose Zika and dengue. The Hindu Image above: Dipsticks are dropped into a tube containing 0.03 cc of patient serum and a small volume of gold nanoparticle-antibody suspension. If two dots are seen in 15 minutes, the test is positive. The dipsticks can be assembled for under $1.00 in materials (photo by Nikolas Alberra).

Novel inflammatory mechanism that transiently prevents the trafficking of immune cells, lymphocytes, into lymph nodes Dr. Soumen Basak, Intermediate Fellow

National Institute of Immunology (NII), New Delhi Recent research from our group that employed a combination of biochemical, genetic, immunological and mathematical modeling tools, reveals an inhibitory molecular pathway inside the cell, involving inflammatory proteins, that transiently inhibits the invasion of immune cells at the site of infection.

culminate into appropriate adaptive immune responses against pathogens. But do we need the continued influx of lymphocytes in an otherwise inflamed SLO, which is hosting rapid expansion of the already antigen-activated pool of lymphocytes? Our collaborative study that was recently published in the EMBO journal reveals that the proinflammatory protein, TNF, produced during immune activation, temporarily prevents the further influx of lymphocytes into inflamed SLOs of immunized mice. TNF disrupted lymphocyte trafficking by downregulating homeostatic chemokines. As such, the expression of these chemokines requires partial protein breakdown of the NF-kappaB signal transducer protein, p100 into p52 by the noncanonical NF-kappaB pathway.

Lymphocytes are immune cells, which play a critical role in the recognition as well as clearance of microbial pathogens. The recognition of pathogen-derived antigens occurs in the secondary lymphoid organs (SLO) that are strategically located throughout the body. As one can imagine, lymphocytes are required to enter continuously in these SLOs, a process facilitated by homeostatic chemokines, for surveillance. Once these lymphocytes encounter antigens in SLOs, they undergo activation and rapid expansion that

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INDIA ALLIANCE FELLOWS’

RESEARCH HIGHLIGHTS Our work demonstrates that TNF obstructs processing of p100 into p52 by noncanonical signaling for downregulating homeostatic chemokines in inflamed SLOs. Is this transient inhibition mechanism beneficial or does it exemplify the Achilles’ heel of the immune system? On the one hand, our immune system perhaps evolved this mechanism to ensure that local, available resources are entirely used for supporting the expansion of already activated immune cells in inflamed SLOs. But transient disruption of lymphocyte trafficking in inflamed SLOs may have detrimental consequences as well. It is likely to generate vulnerability in an individual fighting against a

primary infection to a subsequent assault by a different pathogen.

Further understanding of this immune-modulatory mechanism may provide for therapeutic calibration of physiological immune responses. A TNF‐p100 pathway subverts noncanonical NF-κB signaling in inflamed secondary lymphoid organs. Tapas Mukherjee, Budhaditya Chatterjee, Atika Dhar, Sachendra S Bais, Meenakshi Chawla, Payel Roy, Anna George, Vineeta Bal, Satyajit Rath, Soumen Basak. The EMBO Journal. October 2017

Salmonella bacteria exploits host cell’s machinery to tether itself and replicate Dr. Mahak Sharma, Intermediate Fellow

Indian Institute of Science Education and Research (IISER) Mohali Recently published research from our group shows that diseasecausing bacteria, Salmonella enterica serovar typhimurium (hereafter Salmonella) ingeniously uses the mammalian cell’s (host) membrane transport machinery to attach itself and replicate, ensuring its survival inside the host cell. Salmonella is a gram-negative facultative intracellular pathogen that causes gastroenteritis associated with intestinal inflammation and diarrhea in humans and a typhoid-like disease in mice. While the gastroenteritis is usually self-limiting, systemic infection of non-typhoidal S. enterica in immuno-compromised patients or in infants and aged population can result in a life-threatening outcome. Mammalian cells have efficient transport machinery involving the organelles, endosomes and lysosomes that are responsible for transporting molecules (such as proteins, nutrients etc.) from the plasma membrane, sorting them and finally degrading/consuming them. Salmonella replicates inside host cells that have the capability of engulfing solid particles (phagocytosis) or in other cells without this property in a unique membrane-bound compartment known as the Salmonella-containing vacuole or SCV. To establish its replicative function, Salmonella redirects membranes and nutrients from the host cell’s recycling and sorting compartments to the SCV by establishing an interconnected network of tubules, also known as Salmonella-induced filaments (SIFs) forming a continuum with the SCVs. How Salmonella ensures a constant supply of endocytic cargo to the vacuole for its survival and replication remained unexplored.

Notably, Salmonella invasion into the host cell and its replication inside the SCV is facilitated by bacterial effector proteins translocated into the fluid portion (cytosol) of the host cell by its two secretion systems. Our recent work published in PLOS pathogens uncovers a strategy evolved by Salmonella wherein it secretes a bacterial effector protein known as SifA into the host cytosol that recruits component of host vesicle fusion machineryHOPS complex to SCVs and SIFs. We found that Salmonella effector SifA in complex with its binding partner, SKIP, interacts with HOPS and mediates recruitment of this tethering factor to SCV compartments. HOPS complex promotes docking of the late endocytic compartments at the SCV membranes eventually leading to their fusion. Depletion of HOPS subunits both in cultured mammalian cell lines as well as in mouse model inhibits Salmonella replication, likely due to reduced access to host membranes and nutrients by the vacuolar bacteria. Our findings suggest that Salmonella exploits the host’s endosomal and lysosomal membrane fusion machinery for access to host membrane and nutrients, ensuring its own intracellular survival and replication. Salmonella exploits the host endolysosomal tethering factor HOPS complex to promote its intravacuolar replication. Aastha Sindhwani, Subhash B. Arya, Harmeet Kaur, Divya Jagga, Amit Tuli and Mahak Sharma. PLoS Pathogens. October 2017

Media report: Indian scientists decipher how Salmonella survives in human cells. Down To Earth, Hindu Business Line

Lost neuronal function can be restored after injury in a roundworm model Dr. Anindya Ghosh-Roy, Intermediate Fellow

National Brain Research Centre (NBRC), Gurgaon Damage to our nerve cells or neurons, due to an accident or physical stress can severely affect many aspects of normal life, for example our ability to walk, smell and see. It is observed that in adulthood the long nerve processes of injured neurons, known as axons, face a great deal of challenges in surviving and finding their way to reach the right partner neuron. Therefore, injured neurons are unable to transmit nerve signals properly and our ability to

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recover from this functional loss is mostly partial and this ability decays with age. In experimental models of nerve regeneration, in some neurons, it is noticed that after injury, axonal fragments can rejoin by selffusion.


INDIA ALLIANCE FELLOWS’

RESEARCH HIGHLIGHTS study also identified a regulatory mechanism controlling this process.

To study the behavioral consequence of neuronal breakage, our collaborators had to first find a way to cut axonal processes located deep inside the worm's body. They used two femotosecond lasers simultaneously, one to locate and the other to cut the neurons of their interest. It is important to study neuronal regeneration at functional level because the significance of regrowth lies in its behavioral recovery. Although it is not clear whether axonal fusion would help recover the lost function after large injury, which breaks many axons in our nerve bundles, this phenomenon might come into action after spontaneous breakage of axonal process during day-to-day stress induced injury. Nevertheless, it stimulates many research questions to study molecular mechanism of axonal fusion using various model organisms.

The nematode C. elegans with GFP labeled touch neurons. Axons in tail region were severed with laser and imaged one day later. We show that when the injured axonal fragments recognize each other and rejoin (worm shown above) the lost function is restored. However, when the proximal stump fails to join the distal fragment (worm shown below) the function remains impaired.. Credit : Harjot Kaur & Anindya Ghosh Roy

The research team also included researchers from the Tata Institute of Fundamental Research (TIFR) , Mumbai and Bruker India Scientific Pvt Limited.

This phenomenon is termed as axonal fusion. A group of students from our laboratory at the National Brain Research Centre, Manesar, found that this process of axonal fusion restores lost function after injury. In our laboratory, we are using Caenorhabditis elegans (C. elegans), a non-parasitic roundworm, to study neuronal response to injury. C. elegans sensory neurons are responsible for touch sensation. We found that fusion between proximal and distal fragments of injured neuron promotes recovery of function. This

let-7 miRNA controls CED-7 homotypic adhesion and EFF-1– mediated axonal self-fusion to restore touch sensation following injury. Atrayee Basu, Shirshendu Dey, Dharmendra Puri, Nilanjana Das Saha, Vidur Sabharwal, Pankajam Thyagarajan, Prerna Srivastava, Sandhya Padmanabhan Koushika, and Anindya GhoshRoy. PNAS. November 2017 Media coverage: NBRC researchers uncover how damaged neurons recover function. The Hindu

Non-invasive technique to map fluctuations in the cell membrane Dr. Bidisha Sinha, Senior Fellow

Indian Institute of Science Education and Research (IISER) Kolkata Cells at their boundaries have a plasma membrane (PM) and an underlying layer of a special filamentous protein network called the actin cortex. These provide structural rigidity and deformability to cells while also serving as a platform where cell-cell interactions occur, electrical signals are relayed and foreign entities park before invading the cell. The question we have addressed in our recently published paper is what kind of undulations are present in the PM, how do they evolve in time and how are they controlled by the metabolic state and actin cortex. It is important to address this because fluctuations of PM are incessant, present in all cells and can define how the membrane functions. However, at the bottom of cells, these fluctuations are tiny and cannot be measured by normal light microscopy.

We used interference reflection microscopy to measure and map local deformations and create movies of these maps. We then studied the differences in fluctuations across localities inside a single cell and the various cellular factors controlling it (see the image). We found that even though live cells fluctuate more than dead cells, the actin cortex works extensively to keep the PM smoothened out and reduces the fluctuations. We also report nonuniform deformation across single cells originating from transient localized peaks in deformation. Finally, we compare the features of these fluctuations with a theoretical model and extract information like how tense the membrane might be, how easy is it to bend, how pressed it is by the surrounding. This work is unique in the sense that it did not need any labelling and yet extracts details about the physical state of the membrane. The physical state of the membrane not only affects its functions but is also altered when cells are stressed. We, therefore, hope to extend this work in both directions – to understand more about mechanisms of membrane functioning and to test out if this method is useful in quantifying cellular health. Interference based mapping of cell membrane fluctuations reveal their active regulation and transient heterogeneities. Biswas, Arikta; Alex, Amal and Sinha, Bidisha. 2017. Biophysical Journal, October 2017

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INDIA ALLIANCE

FELLOW IN SPOTLIGHT Dr. Rashmi Rodrigues Intermediate Fellow St. John’s National Academy of Health Sciences, Bangalore

Please tell us what you are working on and what impact do you hope it will have. I am currently working with developing mobile phone applications that help people with tuberculosis take their medications better. Tuberculosis is a major public health problem requiring at least 6 months of treatment with up to 4 kinds of medications, daily. Medication side effects, prolonged duration of treatment, costs and the feeling of being cured early during treatment might make patients stop their treatment. This only worsens the condition making the disease recur with vengeance. Partially treated forms of tuberculosis can become immune to routine treatment requiring complex combinations of medicines for even longer periods (up to 18 months). It is therefore essential to ensure that patients do not miss their medications. Until recently, tuberculosis patients visited public hospitals on alternate days and swallowed their medications in front of a treatment provider. Now with daily treatment makes this is difficult. Video observed treatment, an alternative, enables patients replace hospital visits with videos of themselves swallowing medicines (video selfies). This is done via a mobile phone application (see images on the next page). In addition the application has the potential to provide health reinforcements and progress reports making it interactive. What do you see as some of the challenges of mobile-based health interventions? I have worked with mobile-based health interventions for the past 8 years. In the early days, the concept was laughed at- mobile phones for healthcare was considered silly. Now, not very many years later, “mHealth” as it is now known is popular within the healthcare sector. While healthcare professionals have now embraced the technology, the true challenge lies with the beneficiaries. Often, enthusiasm about a mobile phone healthcare applications is short-lived. For example, how many of us continue playing a mobile phone game for over a year? This phenomenon, called intervention fatigue, is not uncommon with mobile health applications. It is therefore, important to ensure that the healthcare applications we develop keep beneficiaries engaged for the entire duration that they are required. Finally the information technology (IT), sector. It as difficult for a physician to understand the anatomy of a mobile application as it is

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for an IT professional to understand human anatomy. Miscommunications, therefore not uncommon, are a strain on resources and stress for the researcher. It takes time and patience to see your dream coming to life as a mobile phone application. Any learnings from the field that challenged or changed any longheld notion? The concept “one size fits all” – this simply doesn't work with mobile phone interventions. Unlike a pill or medication that comes in standard doses, technology has to be both interactive and personalised. Culture, literacy, phone ownership, employment conditions and the disease we target influence patient behaviour and health seeking. Interventions from the developed countries or even other developing countries may not be acceptable in our setting. The technology has to be dynamic, flexible and adjustable to the need of beneficiary it targets. How was the transition from being a clinician to a public health researcher? Any challenges you faced as a women researcher? I took to research early in my career. It provided me a kind of refuge at a stressful time in life. It ensured that I was self sufficient and minimised the stress that came with attending medical emergencies. The concepts, methodological and statistical approaches and the suspense that comes a research query intrigued me 17 years ago and continue to... ‘Woman’, ‘researcher’ and ‘woman researcher’ all have their own challenges. Overall, I must admit that the environment I work in is very supportive. However, research is not as popular amongst clinicians in India as it is in in the western world. In India, a person whose priority is research is therefore considered ‘different’. This alone is a huge challenge. It is important therefore to know your goals, especially for a woman who may have to balance research with several other responsibilities. However, I strongly believe that any woman “can be anything she wants to be”. Is there a research area other than yours that interests you deeply? Prior to working with mobile phone healthcare applications and infectious disease I worked with maternal and child health. Strategies that reduce maternal and child mortality therefore of special interest me. More recently, however, I have been thinking in terms of physical activity and its impact on health (physical and especially mental) and quality of life outcomes.


INDIA ALLIANCE FELLOW IN SPOTLIGHT

Dr. Rashmi Rodrigues

How has Wellcome Trust/DBT India Alliance funding helped you and your research? The India Alliance funding has given me independence as a researcher. I now have adequate resources to pursue quality research along with excellent guidance. The support available for personal development, beyond research, is phenomenal! Any advice from your personal experience for clinicians hoping to make the same transition? Clinicians hoping to make a transition to research should first define their priorities and importantly the time they can commit to research. Achieving the right balance between their clinical and

research careers that gives personal satisfaction is important. In the end, we measure our success against our own goals and not someone else's. What keeps you going everyday? The belief that my work generates evidence for policy and practice even if it may be a small drop in the mighty ocean keeps me going. I strongly believe that the evidence I generate is valuable irrespective of whether it is positive or negative‌

Find out more about Dr. Rashmi Rodrigues’s research here.

Rashmi recently ran the Airtel half marathon in support of Medecins Sans Frontiers (MSF), MSF, an organization that strives to take healthcare to the underserved in difficult circumstances! http://icfn.in/ADHM/fundraiser/rashmirodrigues/

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2017 NOBEL PRIZE IN CHEMISTRY

For cry(o)ing out loud Cryo-EM: From blobology to a Nobel Prize Dr. Arun K. Shukla IIT Kanpur

As we often say, seeing is believing! In biology, this is often accomplished by microscopy techniques which allow us, for example, to see live cells, visualize cellular organelles like mitochondria and nucleus, localize key macromolecules such as DNA and proteins inside living cells, and follow stimulusdependent traveling itinerary of signaling proteins, to name just a few. Electron microscopy (EM), a form of microscopy that uses highenergy electron beams to illuminate the samples for visualization, has been around for several decades, and it has allowed us to visualize the details of many types of biological samples, albeit at low resolution. The term “resolution” here refers to how clearly one can see the fine details of an object; higher the resolution, better we see the intricate details. Cryo-electron microscopy (cryo-EM), where the specimen (i.e. sample to be visualized) is rapidly frozen and imaged at ultra-low temperatures, is being used for the last three decades. However, due to its limitation in terms of resolution it has typically been in the shadow of another biophysical method referred to as X-ray crystallography. It is a biophysical method that uses X-ray diffraction pattern from three-dimensionally organized array of molecules referred to as crystals to extract the atomic-level details of molecules i.e. one can “see” how two atoms interact with each other. At times, cryo-EM is even referred to as “blobology” owing to low resolution because until recently, it has typically yielded overall envelope or crude architecture of samples, and not the intricate structural details. X-ray crystallography has been the first choice to extract atomic and molecular details of biomolecules. A series of technical advances in the last few years have now allowed the cryo-EM to crash the long-standing resolution barrier to achieve near-atomic resolution and hence all the buzz around it and the much-deserved Nobel Prize in Chemistry this year. These technical advances include for example, better sources of electron beams to illuminate the sample, incorporating low-drift microscope stages, better detectors and cameras for capturing the images and significant improvement in computing power.

An illustration to explain the resolution revolution by cryo-EM happened in the past few years. Until 2013, cryo-EM was able to typically reveal only an overall architecture/envelope of biological samples but as of now, it can reveal the near-atomic level of details (and, atomic level details in at least some cases). Credit: Martin Högbom, The Royal Swedish Academy of Science.

Today, cryo-EM allows us to observe very fine structural details, for example, of viruses, molecular machines present inside cells and

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even individual proteins. It also helps us to see how and where small chemical compounds including drug molecules bind to their target proteins. What is even more exciting is that we can do the reverse, that is, using the details yielded by cryo-EM structures, we can predict potential drugs that have high likelihood of binding to our target proteins and regulating its functions, a process referred to as rational drug design that was earlier possible only by X-ray crystallography.

Moreover, as Prof. Joachim Frank, one of the Nobel Prize Awardees for cryo-EM this year, pointed out in his recent lecture at IIT Kanpur, cryo-EM now has the potential to allow us to directly visualize different steps of biological processes by capturing the molecular machines at different points of action. Although it was perceived for quite some time that cryo-EM will be recognized for a Nobel Prize, one can argue that the recent resolution revolution helped it cross the finish line. In fact, it is also reflected in the Nobel citation which reads “for developing cryoelectron microscopy for the high-resolution structure determination of biomolecules in solution”. Needless to say, the three awardees, Profs. Jacques Dubochet, Joachim Frank and Richard Henderson made seminal contributions to bring cryo-EM to where it is today, and the entire structural biology community raises a toast to them. Every time we are able to see something that was not seen earlier, and that too using relatively simpler tools and techniques than previously available, we are one step closer to better understand the mysteries of life. Cryo-EM is one such revolutionary development. Any technology or methodology is constantly evolving, and cryo-EM is no exception. For example, the ease and speed of preparing the sample to be visualized using for cryo-EM can be improved, more automatization of data collection and analysis (e.g. making sense of images of the biomolecules that are captured using cryo-EM) can be incorporated, and further developments are needed to make this technique more usable for smaller proteins. In fact, there are several research groups already working towards addressing these rate-limiting steps in achieving the full potential of cryo-EM. A more practical challenge, particularly in the Indian scenario, is high cost associated with the experimental set-up of cryo-EM and availability of well-trained human resource for the efficient and optimal usage of the equipment. It is not as if the Indian scientific community took note of cryo-EM only after the Nobel Prize was announced; there have been a few laboratories in the country actively using cryo-EM for obtaining structural details of biological samples over the years. What has allowed us to gain momentum, however, is that several young researchers with extensive expertise and hands-on experience with cryo-EM have returned to India in the past few years. Together, we are trying to popularize cryo-EM with the funding agencies; in other words, convince them to invest in this set-up based on its proven potential. A National Facility with a state-of the-art, highend cryo-EM set-up has now been established in the Bangalore Bio-Cluster, and it is likely to open for users in the country very soon. However, one facility is not sufficient to cater to the high number of users in India. There are several Indian researchers who are either relying on early generation cryo-EM set-ups available in the country or trying to get access through external collaborations abroad. Moreover, there is a growing list of emerging/potential users i.e. researchers who are either seriously considering or would become serious users provided the set-up is available. Obviously, there is no match to having multiple high-end facilities in the country in order for us gain maximum mileage out of this cutting edge method going forward.


2017 NOBEL PRIZE IN CHEMISTRY

For cry(o)ing out loud Cryo-EM: From blobology to a Nobel Prize The funding agencies should note that the impact of our investment in cryo-EM can not be suitably judged five or ten years down the road unless there is plenty of uninterrupted availability of cryo-EM time for the broad structural biology community in the country.

globally, at least in some research domains. Structural biology can certainly be one.

The research landscape in India is changing rapidly, and an ecosystem is starting to take shape where excellent research outcomes are not localized anymore. We have the momentum going forward, and as a community, if we dare to dream about getting a call from Stockholm in future, we have to dominate

Dr Arun K Shukla is India Alliance Intermediate Fellow based at IIT Kanpur. Arun uses various biophysical, molecular and biochemical techniques to elucidate the structure and function of important drug targets, G-protein coupled receptors, GPCRs.

Additional reading - Cryo-electron Microscopy – photographing molecules as they are

2017 NOBEL PRIZE IN PHYSIOLOGY/MEDICINE

Tick tock goes the body clock Dr. Sveta Chakrabarti IISc Bangalore

When the alarm goes off to help us get out of bed, the most important signal for our bodies to start the day is the morning sun. Each of us has an internal timer called a biological clock that tells every organ when it is the time to get up, eat, be active and then go to sleep again. The movement of the earth around the sun has led to the evolution of such a timer that is ancient and ubiquitous in all organisms. Any misalignment of this internal clock to the external environment may lead to benign ailments such as jet lag to more severe outcomes like sleeping disorders and depression. Moreover, the efficacy of drugs and their metabolism is highly dependent on the time of administration during the day, and so a deep understanding of the intrinsic rhythm of each organ will be required to improve the action of drugs on them. The first molecular understanding of the functioning of this clock primarily came from the studies using the model organism the fruit fly, Drosophila melanogaster. Jeffrey Hall, Michael Rosbash and Michael Young used Drosophila and its power of genetics to uncover the machinery of the circadian clock and were jointly awarded the Nobel Prize in Medicine this year. The seminal work of these three researchers included the cloning of the pacemaker gene called 'period' in 1984, which was initially identified in a genetic screen more than a decade before by Ron Konopka and Seymour Benzer. The work of Drs Hall, Rosbash and Young showed that the 'period' mRNA and protein levels cycles and oscillates over the day, synchronizing each cell of the body to the day-night rhythm. It is not surprising that the monumental discovery of the circadian rhythm was made in the fruit fly as this simple organism has already won five other Nobel Prizes for the discovery of heredity to innate immunity. Its low cost of maintenance, and the conservation

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of its genetic makeup and behaviour to us humans have made it an ideal organism to work on for more than a 100 years. Hence, the crucial fourth awardee in the Nobel should rightly be the fruit fly. In India, fly genetics has a long history starting with SP Raychaudhuri who began research on Drosophila genetics at Calcutta University in 1941 and later continued his work at the Banaras Hindu University (BHU) until his retirement. Other notable pioneers in fly genetics and their behaviour in India include Obaid Siddiqi, Veronica Rodrigues, K Vijay Raghavan and Gaiti Hasan from the National Centre for Biological Sciences (NCBS). In the field of chronobiology, VK Sharma and Amitabh Joshi at the Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR) work on the impact of circadian rhythm to behaviours such as pupariation (formation of the outer coat of a pupa) and eclosion (emerging from the pupal coat) since the late 1990s. They study such response of Drosophila melanogaster at the population level. Basic science is the key to discover fundamental principles of life and diseases, and thus such research is critical to pave the way for curing diseases and drug discovery. The last few years have witnessed an increase in cuts to funding for basic research that will have an impact on essential discoveries like the circadian rhythm. We hope that with the announcement of this years’ Nobel Prize, the policymakers will realize the contribution of fundamental science to public health, society and overall socioeconomic structure at the global scale. Dr Sveta Chakraborty is India Alliance Early Career Fellow based at IISc Bangalore. Sveta employs Drosophila to investigate mechanisms underlying wound healing, immunity and survival.


INDIA ALLIANCE WORKSHOPS

Rapid developments in biomedicine and information technology is ushering in a new age of medicine. Artificial intelligence, genome editing, tissue engineering, are just a few of the frontier fields that are changing the practice of medicine. The Developing Indian Physician Scientists (DIPS) workshops aim to ignite scientific curiosity in young doctors, while promoting an understanding of the frontiers of medicine and related sciences. The workshops will provide training in quantitative methods and research methodology, and an opportunity to young clinicians to discuss the relevance of biomedical research and career options. Eminent physician- scientists will make up the workshop faculty.

Application deadline: January 2, 2018 Online application form for the Hyderabad workshop can be found here. Please write to us at workshops@wellcomedbt.org should you have any questions regarding these workshops or visit our website for more information. We would appreciate if you could display the workshop flier on your notice board and/or share this information with anyone who might be interested in participating at these workshops.

Workshop will be restricted to 40 participants.

Organizers Prof. Rakesh Aggarwal, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow Dr. Anurag Agrawal, CSIR-Institute of Genomics and Integrative Biology, New Delhi

Eligibility: To apply for participation in the workshop, applicant must be

an MBBS (final professional) and/or MD student training in an Indian medical institution.

prepared to pay refundable advance of INR 2500 (MBBS) or INR 5000 (MD) which will be refunded after the workshop to those who have attended the complete workshop.

prepared to make their own travel arrangements. Accommodation (double occupancy) and meals will be provided by the organisers at no charge.

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Supported and facilitated by Wellcome Trust/DBT India Alliance is an initiative funded equally by the Wellcome Trust, UK and Department of Biotechnology, India, aimed at promoting basic biomedical, clinical and public health research in India through funding and engagement.


INDIA ALLIANCE WORKSHOPS

Benefits

Application deadline: 20 January 2018

•Introduce key academic leadership concepts; •Develop further individual leadership styles; •Convey key communication skills; •Learn how to effectively select the right staff; •Expand support network for leadership issues in academia.

Complete the Online Application form here http://bit.do/leadershipcourse Please write to us at workshops@wellcomedbt.org should you have any questions regarding this course or visit our website for more information.

The four-day EMBO Research Leadership Course will cover topics including:

We would appreciate if you could display the course flier on your notice board and/or share this information with anyone who might be interested in attending this course.

•leadership skills; •communication skills; •team development; •conflict solving strategies; •effective problem solving; •staff selection.

Workshop provided by Gesellschaft zur Förderung der Lebenswissenschaften (GFLW), Germany, aims to foster science and research by organising scientific events and financing courses and workshops for scientists. It delivers the EMBO Laboratory Leadership Courses on behalf of EMBO.

Practical exercises, in the form of role-play and discussion groups, provide hands-on experience. The principle of this course is – "As much theory as necessary and as much practice as possible".

Supported and facilitated by Wellcome Trust/DBT India Alliance is an initiative funded equally by the Wellcome Trust, UK and Department of Biotechnology, India, aimed at promoting basic biomedical, clinical and public health research in India through funding and engagement. European Molecular Biology Organisation is a professional organization of life scientists in Europe. Its goal is to promote research in life science and enable international exchange between scientists.

To apply for participation in the Course, the applicant must be •Assistant or Associate Professor (or equivalent) in Life Sciences. •Prepared to pay refundable advance of INR 10,000, if selected for the course. This fee will be refunded after the workshop to those who have attended the complete workshop. •Prepared to make their own travel and pay for their accommodation arranged by India Alliance in a 3-star hotel or equivalent.

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INDIA ALLIANCE PUBLIC ENGAGEMENT

Click on the poster for more information on this project.

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The Wellcome Trust/DBT India Alliance joins the global campaign “Together Science Can” to promote and celebrate international collaboration in science. Launched on 28 September, Together Science Can encourages researchers around the world to join together to protect the future of vital collaboration. Collaboration across borders makes science work better and faster. Solving complex problems such as epidemics, the growing burden of dementia, and climate change relies on the best ideas, wherever they come from. But world events threaten the environments within which collaboration thrives, creating an uncertain future for researchers. Together Science Can unites researchers and institutes from across the world and the full spectrum of sciences to mobilise political and social support for global scientific collaboration. It’s a partnership between Wellcome Trust (UK), Wellcome Trust/DBT India Alliance, Royal Society, Helmholtz Association, Max Planck Society, “la Caixa” Foundation, Novo Nordisk Foundation, Wallenberg Foundations, J&J Innovation, Global Health Technologies Coalition and African Academy of Sciences/Accelerating Excellence in Science in Africa. The campaign calls on researchers to come together with colleagues in their labs or across their organisations and join hands in a gesture that signifies partnership. Dedicated Together Science Can Instagram and Twitter pages will celebrate and champion these partnerships, showcasing the stories that are helping to tackle major global challenges.

a network that can speak up for science during key global events. "India Alliance has joined this campaign because we believe that science is collaborative, participatory and makes most sense when it solves real problems for real people. We have also joined this to give leadership opportunities to our researchers. Only enlightened leadership will take forward science, and through it, development both locally and globally." Dr Shahid Jameel, CEO, Wellcome Trust/DBT India Alliance. Dr Jeremy Farrar, Director of Wellcome, said: “Together science can tackle some of the biggest global challenges of our time. But creating barriers betrays the foundations of science, which should be about the exchange of ideas across borders, and we must speak up to prevent this. We can do so much more when we work together, and that includes influencing the decisions that affect scientific progress.” To find out more about Together Science Can visit the website: https://togethersciencecan.org/ Together Science Can can be found on social media using #TogetherScienceCan, or on: •Instagram: @togethersciencecan •Twitter: @togetherscican •Facebook: Together Science Can

Researchers and supporters are also encouraged to sign up via the campaign website (togethersciencecan.org), creating

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If you have ideas, issues and/or stories that you would like to highlight through this campaign, please get in touch with us at public.engagement@wellcomedbt.org


GUEST CONTRIBUTION

Maximising collaborative research between India and the UK: Needs and opportunities in light of India’s new national health policy This article was originally posted on George Institute for Global Health UK website The event also included a panel discussion on ‘India-UK research: Opportunities, challenges and lessons’, which featured - in addition to Dr. Jameel - Professor Dame Caroline Watkins, Professor of Stroke and Older People’s Care at the University of Central Lancashire; Professor Kara Hanson, Professor of Health Systems Economics at the London School of Hygiene and Tropical Medicine; Professor Ajit Lalvani, Chair of Infectious Diseases at Imperial College London; and Professor Maarten De Vos, Director of the Oxford Centre for Affordable Healthcare Technology at the University of Oxford. The discussion was chaired by Professor Vivekanand Jha, Executive Director of The George Institute for Global Health India.

A keynote speech by Dr. Shahid Jameel, Chief Executive Officer of the Wellcome Trust/DBT India Alliance, began a wide-ranging and engaging discussion on research collaboration at an event on 27 October 2017 organised by The George Institute for Global Health UK, the Oxford-India Health Research Network and the OxfordIndia Centre for Sustainable Development at Somerville College, Oxford. Dr. Jameel described the backdrop to India’s new national health policy, which was launched by the government earlier this year. He also gave a comprehensive overview of the policy itself, which recognizes the key role of health research and the need to increase international collaboration. Dr. Jameel gave examples of where this may be important, such as work around the diagnosis and management of tuberculosis, and research into zoonosis (disease which can be transmitted to humans from animals).

The panel discussed what the key needs will be for India-UK research in the medium to long-term, given the expectations of governments and funding bodies, and provided advice on building a successful research career and establishing cross-country research collaborations. The need for a multidisciplinary approach and the likely impact of Brexit were also covered, along with the specific legal and ethical issues that need to be considered with India-UK research. In addition to the panel discussion and keynote speech, the event featured a number of short presentations and Q&As about ongoing or recent research collaborations between India and the UK. These covered a wide range of research, including: The George Institute’s SMARThealth Pregnancy project in Andhra Pradesh; the relationship between rural-to-urban migration and HIV in north India; a relational approach to agency for mapping pathways into and out of poverty; and empowering children to take charge of their nutrition. Download the agenda for a full list of presenters and the subjects covered (PDF 692KB).

L-R : Professor Vivekanand Jha, Dr Shahid Jameel, Professor Maarten De Vos, Professor Ajit Lalvani, Professor Kara Hanson, Professor Dame Caroline Watkins

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GUEST CONTRIBUTION

Purdue University’s Strategic Focus on Both India and Life Sciences Kaethe Beck & Heidi Arola, Purdue University Purdue University in West Lafayette, Indiana, is well known as an engineering and agriculture school, and rightfully so; years of strategic efforts have cemented the reputation. Perhaps less obvious, but equally impressive, is the university’s strength in the Life Sciences—including in areas such as structural biology, analytical chemistry, sensory systems, and drug discovery, to name a few. At the same time, Purdue has designated India as a country of strategic importance to the university and is focused on deepening its engagement across the board with Indian students, alumni, researchers, institutions, corporations, and government entities.

Recognizing the university’s promise for leadership in the Life Sciences, Purdue President Mitch Daniels announced a significant financial investment of $250 million in 2015, which included support for the development of two new Life Science pillars of excellence: the Purdue Institute for Inflammation, Immunology, and Infectious Disease (PI4D), led by renowned virologist Dr. Richard Kuhn, and the Purdue Institute of Integrative Neuroscience, led by Dr. Donna Fekete, a hearing scientist specializing in molecular level inner-ear development. These institutes enhanced the existing Purdue Life Science community consisting of the Regenstrief Center for Healthcare Engineering, the Center for Cancer Research (a U.S. National Cancer Institute designated Cancer Center), the Institute for Plant Sciences, and the Institute for Drug Discovery. While each institute/center at Purdue occupies its own discrete space, there are common themes and technologies shared among them—most notably robust data science and analytics capacity, imaging capabilities and technologies developed at Purdue, and convergent modeling approaches. Purdue is routinely ranked as a top ten agriculture school and the Purdue Institute for Plant Sciences has coalesced the university’s existing expertise and taken research in the field to a new level. Since its inception in 2013, the Institute has hired 10 new faculty and launched a corn and soybean innovation center that encompasses more than 25,000 square feet and includes a field prototyping facility. Further, Purdue is at the forefront of determining the future of digital agriculture with its development of novel sensors and new algorithms that are pushing the boundaries of optimization for healthier plants, and in turn, healthier people. One of the next steps in this continued pursuit is the upcoming completion of a Controlled Environment Phenotyping Facility in early 2018. This new facility will allow highly controlled growth conditions that cannot easily be tested in actual farms; researchers will be able to study a range of environmental and atmospheric conditions, watering techniques, plant nutrition and soils, and effects of chemicals application. The Life Science Institutes have ushered some early successes in their short tenure. For example, In 2016, Dr. Richard Kuhn, Director of the Purdue Institute of Inflammation, Immunology and Infectious Disease, and Dr. Michael Rossmann, perhaps best known for inventing the Molecular Replacement Method which has been used to determine the structures of more than half of the 100,000+ structures deposited within the international Protein Data Bank, resolved the structure of the immature Zika virus at high resolution using a specialized detector. PhD student Devika Sirohi, from Meerut, India, played an integral role in this groundbreaking discovery. Their work is critical to understanding how the virus can replicate and spread.

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Doctoral student Devika Sirohi works with Michael Rossmann and Richard Kuhn at Purdue to reveal the structure of the Zika virus. (Purdue University photo)

Devika is just one of the many talented Indian graduate students and faculty of Indian origin making significant contributions to their fields at Purdue. As of fall semester 2017, 1068 Indian graduate students and 933 undergraduates (the largest number of UGs at any U.S. institution) call Purdue home. Parallel to its strategic focus on Life Sciences, Purdue is building a singular, sustained, and strategic country partnership with India. Despite having students and faculty from, and activities in, more than 125 countries, Purdue has selected just two countries—India and Colombia—as countries of strategic importance.

The Purdue-India partnership is overseen by Executive Vice President for Research and Partnerships Suresh Garimella, an IIT Madras distinguished alumnus awardee, who has established dedicated staff to help steward partnership activities. One highlight this year was a new Memorandum of Understanding between Purdue and India’s Science and Engineering Research Board (SERB) that paves the way for 25 visiting PhD students from Indian institutions to spend a year as visiting research scholars at Purdue as well as the development of joint virtual research centers between Purdue and Indian institutions. The 4th Annual IndiaPurdue Collaborative Lecture Series in honor of Professor CNR Rao is also just around the corner. The January 8-12, 2018 series will be headlined by Founding Director of the Purdue Institute for Drug Discovery and Ralph C. Corley Distinguished Professor of Chemistry Professor Phil Low, who will speak on “New Targeted Therapies for Cancer, Autoimmune, and Infectious Diseases." More details on the lectures will be available on the Purdue-India Website as arrangements are finalized. Professor Low is tentatively scheduled to give public lectures in Bangalore, Chennai and Mumbai that week. With its strategic focus on both Life Sciences as a research and education domain, and India as a nation, Purdue can be expected to be a lifetime partner with the Indian Life Sciences research community. Related links: Purdue selected to partner with India’s Science and Engineering Research Board Daniels launches international engagement campaign, announces alumni initiatives during trip to India, Taiwan


Next call for applications : February 2018 (tentatively)

About India I EMBO Symposia

following expert advice and review.

The Wellcome Trust/DBT India Alliance and European Molecular Biology Organization (EMBO) will jointly fund up to three meetings per year in India. The meetings should address discovery and innovation through an interdisciplinary approach, with the speakers and participants discussing important global challenges in the context of the life sciences.

Application process

The meetings should be small, with 10 – 15 highly acclaimed international speakers and 50 – 75 participants, allowing early to mid career scientists to interact with leading international experts during a period of three days. Proceedings from the meeting should be drafted as a position paper to advise the India Alliance regarding this area of research. The paper should in particular outline if and how research covered by the meeting could be beneficial to India. India Alliance may consider increasing funding for research in that area following expert advice and review. Benefits • The maximum funding available for an India | EMBO Symposia is 60,000 euros. • EMBO also supports the organizers and meeting in the following ways: • EMBO creates a dedicated meeting webpage, including registration and abstract submission forms. • EMBO provides a poster and advertising in selected print and social media channels. • Organizers can apply for funds for an EMBO Young Investigator lecture, EMBO Science Policy lecture and EMBO Women in Science lecture. Eligibility • India | EMBO Symposia must take place in India, but scientists from anywhere in the world are eligible to apply, independent of their nationality. • India | EMBO Symposia must cover frontier, pioneering and interdisciplinary areas of life sciences that are underserved in India, and include speakers with interdisciplinary expertise. Furthermore, the application should include a list of (mostly) confirmed speakers. • For detailed information on the eligibility criteria, including the format of the meeting, please consult the application guidelines (pdf). Please note: After the meeting, the organizers must provide a position paper on the theme that includes a plan to catalyze research in that area in India. India Alliance may consider funding research in that area

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• Applicants will be asked to complete an online and an offline application form. • All incoming applications are screened to ensure eligibility requirements are met. • The decision on which proposals receive funding will be jointly made by the EMBO Course Committee and the India Alliance Meetings Committee in May and October. • All applicants will be informed of the outcome of their application by email shortly after the committee meetings in September Required documentation

Applicants will be asked to provide: • A list of organizers • Proposed title and topic of the meeting • Reasons for holding a meeting on the proposed topic • Information on any competing or similar meetings held in the current, proposed or following year • Proposed date and location • List of proposed speakers/instructors • Draft programme • Participant selection criteria and number of participants • Proposal for the position paper • Information on the practical component of the meeting (if applicable) • Draft budget Selection process

The selection process involves the following steps: • All incoming applications are screened to ensure eligibility requirements are met. • The decision on which proposals receive funding is jointly made by the EMBO Course Committee and the India Alliance Meetings Committee in May and October. • All applicants are informed of the outcome of their application by email shortly after the committee meetings. For detailed information on the application process, key dates, format of the meeting and required documentation, please consult the application guidelines or visit India | EMBO Symposia website. For any enquiries, please write to workshops@wellcomedbt.org


EVENT

Women in Science- A Listening Session

Photo credit: Stewart E Davis

Over the years, the number of women receiving advanced STEM education and degrees globally has increased, with countries such as Australia, Canada and India awarding nearly half of advanced degrees in science to women. However, despite these advances, women remain underrepresented in the scientific workforce globally. Rates of employment for women in science and technology vary from a low of less than 15% in Japan to highs approaching 40% in the European Union. This issue represents a significant loss of contribution to the economy of most countries and to the global intellectual potential. In particular, there is significant gender inequality in academia, with the percentage of female graduates in science far outnumbering the number of women faculty in these fields. Gender inequality in science has been a topic of discussion among regulatory bodies, government entities, and international agencies for many years. While there is growing recognition that gender inequality in science should be mitigated, there are few solutions proposed that directly affect the desire and ability of women to remain in the scientific and technical workforce. Two recent articles in Nature Jobs and Indian Express by India Alliance Fellow Dr. Farah Ishtiaq and India Alliance staff members, Dr. Shahid Jameel (CEO) and Dr. Bela Desai (Grants Adviser) highlighted some of the problems faced by women scientists in India and offered possible strategies to support and retain more women in research. Life of Science, a media platform focused on covering women scientists in India, also regularly brings to the fore challenges faced by women in science through interviews with women researchers from across the country.

In order to continue these deliberations and to better understand the landscape facing women in science in academia in India, the India Alliance and the U.S. Embassy organised a listening session on 16 November 2017 at ICGEB, New Delhi, in which both policy makers and women in academia came together to engage in constructive dialogue about opportunities for supporting the advancement of women in science nationally and internationally. Dr. Ellen Carpenter, program director at the National

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Science Foundation, in the Division of Undergraduate Education and U.S. Embassy Science Fellow moderated the session. We hope this session was the first of many more such meetings that will help to define the needs and objectives of women in the science workforce in India, and will help to define strategies to maintain and expand the role of women in science. A detailed report and recommendations from this meeting will be made available online shortly. Media report- Curbing gender bias in science DailyO


OTHER ANNOUNCEMENTS Postdoctoral position available at IISER Bhopal

Postdoctoral position available at Institute of Life Sciences (ILS), Bhubaneswar

Applications are invited from Indian nationals for the post of Postdoctoral Fellow under the following research project funded by Wellcome Trust/DBT India Alliance.

Institute of Life Sciences (ILS), Bhubaneswar, an autonomous Institute of the Department of Biotechnology, Ministry of Science & Technology, Government of India, invites applications from Indian Nationals for research personnel in the following project.

Title: Hypoxia-mediated expansion of transcriptome due to epigenetic modifications in breast cancer tumorigenesis and chemoresistance

Wellcome Trust/DBT India Alliance sponsored project: “Understanding the role of IRGM-mediated innate immune response in diseases�

This project aims to investigate whether and how hypoxia contributes to the generation of cancer-specific spliced isoforms via epigenetic modifications and whether hypoxia-induced alternative splicing is involved in the tumorigenesis of Triplenegative breast cancer (TNBC).

Principal Investigator: Santosh Chauhan, PhD, Scientist D, ILS Bhubaneswar

Applications are invited for the following post; Post-doctoral Fellow (PDF): 01 Nos.

For more details about our research, please visit our website https://home.iiserb.ac.in/~sanjeevs/

Emoluments: Rs. 36,000 per month + 20% HRA (as per DBT norms and commensurate with years of experience).

Name of the Post: Postdoctoral Fellow, Department of Biological Sciences

Eligibility: Candidates must hold a Ph.D. degree (or should have submitted his/her Ph.D. thesis) in biological sciences. Experience in mammalian cell culture, molecular biology techniques and cell biology techniques is required. Candidates having experience in handling mice and candidates having first author publication in peer-reviewed journal in above subject areas will be given preference.

Duration: One year (extendable up to five years, subject to satisfactory performance and availability of funds) Essential Qualification: Applicants should have a PhD in Life Sciences or related subjects with experience in analysis of nextgeneration sequencing (NGS) data/ computational biology. Age: Maximum age is 32 years for general candidates at the time of application (to be relaxed by 5 years for SC and ST candidates and persons with physical disability) Application Procedure: Interested applicants should email their CV and a 1-page cover letter (describing their past accomplishments, research interests, and career goals) along with names and contact information of three references to sanjeevs@iiserb.ac.in. This position will remain open until filled. Shortlisted candidates will be called for interview by e-mail. No TA/DA will be paid to the candidate for appearing in the interview. The selected candidate will be notified by e-mail and expected to join immediately.

Mode of Selection: The candidates with above mentioned eligibility can write to chauhan2010santosh@gmail.com or schauhan@ils.res.in. Please send your detailed CV and if possible, PhD supervisor reference letter. The shortlisted candidates will be called for formal interview. Work area: Cell Biology, Cancer Biology, Autophagy and Inflammation. For details of work going in the lab, please visit www.autophagylab.com Initial appointment will be for one year, extendable up to 4 years or until termination of the project whichever is earlier. The position is purely temporary and co-terminus with the project.

Contact details Dr. Sanjeev Shukla Assistant Professor & Wellcome Trust/DBT Intermediate Fellow Indian Institute of Science Education and Research (IISER) Bhopal E-mail: sanjeevs@iiserb.ac.in

No TA/DA will be paid for attending the interview. The decision of the Director regarding selection of candidates will be final and no correspondence will be entertained in this regard.

Please send your feedback, suggestions and contributions to public.engagement@wellcomedbt.org Follow us on www.wellcomedbt.org 24.

India Alliance Newsletter I Issue 18 I November 2017  
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