Job opening in ImmunitoAI

We are HIRING – Scientist (Immunology)!!

At immunitoAI, we are solving some very significant problems in Antibody Discovery towards development of Therapeutic Antibodies.

We are in the search of talented individuals who are motivated to solve real-world problems at exceptional speed to take up key positions in the company and be a part of the core-team in a fast-growing start-up.

If you are that Someone and fit into the Job Description below, follow the link below for a detailed Job Description and Application Form https://lnkd.in/gzZQdTx

Position: Scientist – Immunology

Location: Bangalore

Salary: 10-15 LPA CTC

Minimum Qualification: Ph.D in Immunology or related field or M.Sc with min. 4 years’ experience in Immunology or related field

Responsibilities:

  • Research and experiments on antibody expression, purification, binding studies etc.
  • Setting up the mammalian tissue culture facility
  • Learning and Adapting Fast in an early stage start-up
  • End to end responsibility of R&D, Designing of Experiments, Development, Testing and Release of protein products
  • Working in cross-domain team with biochemists and computer scientists

Zinc interaction with membrane modulate SOD1 aggregation in ALS 

Dr. Achinta Sannigrahi’s interview with Bio Patrika hosting “Vigyaan Patrika”, a series of author interviews. Dr. Sannigrahi is currently working as a postdoctoral research associate in the chemical engineering department of the Indian Institute of Science. He did his PhD in structural biology and bioinformatics division of CSIR-Indian Institute of Chemical biology under the supervision of Prof. Krishnananda Chattopadhyay (2014-2020). His PhD research work was based on protein-membrane interactions towards the understanding of molecular mechanisms of different pathogenic and neurodegenerative diseases. Achinta obtained his B.Sc. Degree in chemistry from Burdwan University (2009-2012). After that, he did his M.Sc. in the department of chemistry in IIT Guwahati (2012-2014). He qualified CSIR-UGC national eligibility test (Dec 2013) and GATE (2014) in chemical sciences. During his PhD work, Achinta received the prestigious Biophysical society travel award (2019) and an ICMR travel grant to attend the 63rd biophysical society meeting held in Baltimore, Maryland, USA. After PhD, Achinta received SERB-national postdoctoral fellowship for his postdoctoral work in IISC. Here, Achinta talks about a portion of his PhD work which is recently published in eLife (2021).

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How would you explain your paper’s key results to the non-scientific community?

ALS, also known as Lou Gehrig’s disease after the name of a famous baseball player, is a fatal neurodegenerative disease, which causes nerve cell breakdown leading to progressive paralysis and ultimately death.Presently no cure is available for ALS. Although the aggregation of an enzyme Cu/Zn Superoxide dismutase (SOD1) is believed to be a potential causative factor behind ALS, lack of proper understanding about the disease pathophysiology makes it difficult for the development of a therapeutic solution. This enzyme SOD1 contains two metal cofactors, namely a Cu and a Zn. Here, we found out that, the process of aggregation of SOD1 might have a membrane connection. In addition, we figured out the regions of SOD1 which are responsible for the membrane induced aggregation and potentially the disease. We found out that these regions are residing near the Zn binding center of the enzyme. These locations are necessary for designing potential drug molecules against ALS.

Figure 1: Schematic representation of cofactor derived membrane association model of SOD1 shows that absence of Zn cofactor leads to the membrane binding and aggregation resulting cell death and ALS.

the results would provide a mechanistic understanding of SOD1 aggregation and this process of aggregation can result in the disease pathology of ALS.

What are the possible consequences of these findings for your research area?

Our findings described in this publication may have two important implications. First, the results would provide a mechanistic understanding of SOD1 aggregation and this process of aggregation can result in the disease pathology of ALS. Second, this paper is expected to provide crucial insights, which might be helpful towards the development of a therapeutic solution against this complex disease.

What was the exciting moment (eureka moment) during your research?

It is known that ALS is a sporadic disease. However, SOD1 is known to have more than 140 ALS mutants. While different mutants are known to offer different extents of disease severity (period between onset and death), there was no known correlation between the physical/conformational traits of the mutants’ severity and the (word missing) severity. While we were developing this model, in which the membrane connections and the cofactor Zn were considered the key factors, we observed a correlation could be established between the disease severity and the distance between the mutation position and the Zn binding site. I do not think it was shown before and it was indeed the most exciting moment when we figured that out.

What do you hope to do next?

Our present work is mainly focused on in vitro studies. Our next step will be to test this in in-vitro model in animal and human patient systems, if possible.

Where do you seek scientific inspiration?

I was born and raised in a small place in West Bengal. However, education was always given priority in our upbringing and we were always told to ask questions. I have found that Indian scientists have contributed enormously to the process of scientific development while working under many constraints. I have always told myself that I can also help.

I have been inspired by my supervisor Prof. Krishnananda Chattopadhyay whose relentless participation and encouragement helped me a lot to do my research work in different projects. I have also been inspired by our group members, our collaborators and, the interesting research works, which are being carried out by various scientific folks worldwide.

How do you intend to help Indian science improve?

I am extremely proud of the way Indian science is progressing. However, I think that somehow the translation effort in Indian science is not able to catch up with the progress made by the basic biomedical Indian scientists.

I would continue to work hard to understand the molecular details of human biology using a multidisciplinary approach. After my post-doc in IISc, I would like to take up a faculty position in India and hopefully, the future research work from my group would produce few therapeutic molecules against diseases relevant to national interests.

Reference

Achinta Sannigrahi, Sourav Chowdhury, Bidisha Das, Amrita Banerjee, Animesh Halder, Amaresh Kumar, Mohammed Saleem, Athi N Naganathan, Sanat Karmakar and Krishnananda Chattopadhyay (2021) Metal cofactor zinc and interacting membranes modulate SOD1 conformation-aggregation landscape in an in vitro ALS Model, eLife 2021;10:e61453. DOI: 10.7554/eLife.61453

Dr. Krishnananda Chattopadhyay lab: https://iicb.res.in/faculty/krishnananda-chattopadhyay

Edited by: Ritvi Shah

From Chaos to Order

Mr. Subhankar Kundu’s interview with Bio Patrika hosting “Vigyan Patrika”, a series of author interviews. Subhankar is from Gangarampur, West Bengal. He completed his B.Sc. in Chemistry from Scottish Church College, Kolkata (University of Calcutta, 2014). In 2016, he won a gold medal in his Master’s degree from the National Institute of Technology (NIT) in Rourkela. After which, he joined the Ph.D. program in the Indian Institute of Science Education and Research, Bhopal, under the guidance of Dr. Abhijit Patra. His research work revolves around the development of functional fluorescent materials for intracellular sensing and imaging and exploration of complex molecular self-assembly processes at various length scales. Here, Subhankar talks about his work “Deciphering the evolution of supramolecular nanofibers in solution and solid-state: a combined microscopic and spectroscopic approach” published in Chemical Science.

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How would you explain your paper’s key results to the non-scientific community?

Patterns are nature’s preferred state of being. There are myriad examples of patterns found in nature, ranging from flower petals, snowflakes, seashells, peacock feathers, etc. The arrangement of small bricks in designed pattern can lead to the construction of a building. Similarly, the supramolecular self-association of small molecular building units, a spontaneous natural process, leads to the formation of diverse, complex architectures, thus caterings to nature’s fondness for patterns and arrangements. Self-assembly also plays a vital role in constructing bio-architectures through hydrophobic and hydrophilic interactions in the living systems. For example, the double helix structure of DNA molds via the zipping up of the two long chains of nucleotides connected through hydrogen bonds between the complementary base pairs. Another example is that the aggregation of proteins leads to the formation of amyloid fibrils. 

Based on natural self-assembly processes, researchers have been developing self-assembled micro-and nanoarchitectures like micelles, vesicles, gels, and aggregates using small π-conjugated molecules. Thus, the development of supramolecular self-assembled fluorescent nanostructures with morphology-dependent tunable emission is in high demand due to their promising scope in bioimaging, sensing, switches, nanodevices, and molecular machines. However, deciphering the evolution of molecular self-assembly leading to the one-dimensional nanostructures from a solution is still intriguing, albeit challenging. The morphology of the molecular aggregates can be visualized using electron microscopy in the solid-state. On the other hand, their optical properties are mostly studied in the dispersion state. Nevertheless, asserting a correlation between the morphology and the emission property in the dispersion is often rudimentary and needs a careful relook. 

In our recently published work (Chem. Sci., 2021), we demonstrated an intriguing case of molecular self-assembly that led to the formation of nanofibers employing small organic molecule, TPAn (Figure 1). A morphological transformation from spherical nanoparticles to nanofibers has been elucidated through the variation of the composition of binary mixture. The case of nanofiber formation was quite similar to that of amyloid fibril due to the protein aggregation. The dispersion of TPAn showed the morphology of a three-dimensional network of nanofibers in the solvent-evaporated samples observed through electron microscopy. In contrast, fluorescence correlation spectroscopy (FCS) results implied the formation of smaller-sized anisotropic nanoaggregates in the dispersion, which could further agglomerate, leading to the formation of the network of nanofibers through solvent evaporation. The reversible morphological transformation between a network of nanofibers and spherical nanoaggregates in the presence of external stimuli was probed by a combined spectroscopic and microscopic approach using steady-state absorption, emission, and FCS analysis coupled with electron microscopy, which showed the role of pyridinic N-centers governing the self-assembly process. TPAn was found to be specific targeting agent for lipid droplets in HeLa cells. Hence, the fate of TPAn was explored in the complex and heterogeneous medium, like HeLa cells, revealing the contrasting optical responses in lipid droplets compared to that in the bulk solution and molecular aggregates. The spectroscopic investigations inside the cells implied that the internalization of TPAn inside the HeLa cells occurred as a molecular form; however, it behaved like noncovalent aggregates due to the hydrophobic interactions with lipid droplets (Figure 1).

Figure 1. Schematic illustration depicting the molecular self-assembly from nature to laboratory

What are the possible consequences of these findings for your research area?

In the published work, we aimed to understand the growth of supramolecular nanofibers from solution through nanoparticles in both solid and dispersion states. Apart from that, we also tried to connect the missing link between the analytical tools, which are often used to understand the self-assembly process in solid and dispersion states. The general idea provided in this study to relate the size, shape and emission properties of fluorescent molecular aggregates in heterogeneous media will open up an exciting avenue to elucidate the complex self-assembly processes in biological systems.

properties of fluorescent molecular aggregates in heterogeneous media will open up an exciting avenue to elucidate the complex self-assembly processes in biological systems.

What was the exciting moment (eureka moment) during your research?

It is tough to point out a particular moment; because, I was equally excited during the overall journey of this work. From the beginning of understanding the fluorescence correlation spectroscopy (FCS) to handling a highly sophisticated instrument (PicoQuant, MicroTime 200), and doing fluorescence lifetime imaging (FLIM) study, fitting and analysis of FCS data, etc., I was excited a lot, and these were the eureka moments for me.

What do you hope to do next?

The in-depth understanding of single-molecule spectroscopy helped us to streamline several of our works. In the next project, we are planning to probe the growth and kinetics of hierarchical porous structure formation through FCS and FLIM analyses.

Where do you seek scientific inspiration?

I believe that no one can inspire you better than yourself and your work. Many peoples around me, directly and indirectly, supported and helped me a lot during this journey. However, the scientific inspiration in my case always came from learning various instruments, analyzing the experimental data, and most importantly, handling the problems that were out of my comfort zone. 

How do you intend to help Indian science improve?

Indian science needs a lot of improvements to stand along with the other countries. Most importantly, there should be a strong association between the science in the classroom and the science in the laboratory. Secondly, science should be smoothly translated from laboratory to industry. In terms of propagating scientific temperament, the education in schools should be imparted that inculcate the habit of questioning among the students. On research front that include the field I worked on. Hence, I would like to take the challenge and explore the single-molecule spectroscopy toward its applications in industrial research and environmental remediation to a greater extent which will eventually enrich the content of Indian science.  

Reference

S. Kundu, A. Chowdhury, S. Nandi, K. Bhattacharyya and A. Patra, Deciphering the evolution of supramolecular nanofibers in solution and solid-state: a combined microscopic and spectroscopic approach, Chem. Sci., 2021,12, 5874-5882.

Email: subhankar16@iiserb.ac.in

Dr. Abhijit Patra lab: http://home.iiserb.ac.in/~abhijit/

Edited by: Ashwani Kumar and Ritvi Shah

Research Analyst, Prescient Advisory, Prescient Analytics

About You

Have you decided that biopharmaceutical data research and analytics is for you? Are you looking to build commercial and content expertise across a range of disease areas? Prescient is looking for post-graduates and early-career analysts to join our growing Advisory unit within our Prescient Analytics team in India as a Research Analyst. Do you have:

  • An analytical and creative mindset for conducting well-synthesised research and converting it into meaningful analysis?
  • Knowledge of development and commercialisation aspects of the biopharmaceutical industry, especially in the US and EU?
  • Experience supporting highly complex biosimilars, oncology or immunology data research and analytics?
  • The ability to communicate with impact, both verbally and in writing, and the ability to operate effectively as part of a global team?
  • Attention to detail, efficient time-management skills, professionalism and a strong work ethic? 

If so, consider turning your expertise into a valuable career at Prescient.

 About Prescient Analytics

Prescient Analytics is an integral and strategic part of Prescient’s client offering. The team consists of disease, functional and market experts responsible for ensuring that the depth, breadth and timeliness of our secondary data analytics is best in class. The team plays a critical role in supporting our Advisory business globally to help with analytics and research for complex cases and client development.

 About the Opportunity

As a Research Analyst, Prescient Advisory, your time will be divided as follows:

  • 80% on conducting secondary research and analytics
  • 10% on building and maintaining knowledge assets
  • 10% on communicating and articulating research approach

You will be part of a fast-growing PE-backed business that allows high-performing employees to make an impact and contribute to growing the business. You will have the chance to channel your advanced degree into supporting the development and commercialisation of portfolios, assets and brands by integrating therapeutic, clinical and commercial expertise to ensure that clients are able to make confident decisions.

About The Role

You will be responsible for supporting data gathering, analysis and insight creation across a range of disease areas. You will engage in thought partnership with the Advisory team and work to formulate /test hypotheses, solve complex problems, and communicate approach and output.

The Research Analyst position requires an understanding of the evolving biopharmaceutical market and trends. Knowledge of drug development and commercialisation is also required.

  • Reporting: You will report to a Senior Research Manager within Prescient’s India office.

Key Responsibilities

  1. Analysis and Reporting: Analyse and synthesise findings, and develop insights and implications, to create deliverables that deliver a linear, evidence-based story on the topics in focus
  2. Secondary Data Analytics: Source, analyse and report published information, be it scientific, clinical, commercial, corporate or regulatory
  3. Task Management: Plan and execute data research and analysis under the guidance of other members of the Analytics team
  4. Maintenance of Knowledge Assets: Build data repositories linked to specific therapeutic areas, market dynamics and regulatory dynamics
  5. Internal Client Management: Collaborate with members of other Prescient business teams to ensure that clients experience best-in-class insights
  6. Subject Matter Expertise: Develop subject matter expertise across relevant disease areas

Required Experience and Skills

  • One or more of the following degrees in the life sciences: MTech (biotechnology or related areas); MPharm; MSc/MBA combination
  • 1-3 years of professional experience focused on pharmaceuticals (experience in oncology, immunology or biosimilars preferred)
  • Confident communication skills to work effectively with global colleagues and contribute to deliverables by working effectively both collaboratively and independently
  • Analytical skills with the ability to collect, organise and disseminate significant amounts of information with attention to detail and accuracy
  • Ability to contribute value-added insights to available information by assessing data
  • Understanding of drug development and commercialisation processes
  • Proficiency in the use of Microsoft Office applications, especially PowerPoint and Excel
  • Fluency in English

What We Offer

  • Competitive package and remuneration linked to performance
  • High-growth, entrepreneurial environment where you can create significant business value and forge your own path
  • Platform for accelerated professional development and career growth with significant levels of responsibility and accountability
  • Opportunity to be mentored by seasoned industry professionals and become expert in cutting-edge therapies

About Prescient Healthcare Group

Prescient is a pharma services firm specializing in dynamic decision support and product and portfolio strategy. We partner with our clients to turn science into value by helping them understand the potential of their molecules, shaping their strategic plans and allowing their decision making to be the biggest differentiating factor in the success of their products. When companies partner with Prescient, the molecules in their hands have a greater potential for success than the same science in the hands of their competitors.

Founded in 2007, Prescient is a global firm with six offices across three continents. Our team of more than 250 experts partners with 23 of the top 25 biopharmaceutical companies, the fastest-growing mid-caps and cutting-edge emerging biotechs, including some of the biggest and most innovative brands. More than 80% of our employees hold advanced life sciences degrees, and our teams deliver an impressive depth of therapeutic, clinical and commercial expertise.

Prescient has been a portfolio company of Bridgepoint Development Capital since 2021 and Baird Capital since 2017. For more information, please visit: www.prescienthg.com

Apply here: https://www.linkedin.com/jobs/view/2440278986

How bacteria efficiently pack their bags?

Dr. Amitesh Anand’s interview with Bio Patrika hosting “Vigyaan Patrika”, a series of author interviews. Dr. Anand, a chemistry graduate, earned his doctorate in Chemical Biology from CSIR-Institute of Genomics and Integrative Biology (IGIB), India. He is currently working on microbial systems and evolutionary biology with Prof. Bernhard Palsson at the University of California San Diego, USA. His research work has made significant contributions towards the understanding of bacterial adaptive features and their stress response pathways. He remains passionate about the microbial lifestyle and continues to explore pathogenic as well as applicative aspects of bacterial systems as a Postdoctoral employee. He is setting up his research group at the Tata Institute of Fundamental Research, Mumbai, India starting June 2021. Here, Dr. Anand talks about ‘how bacteria efficiently pack their bags’ and discusses his paper titled “Restoration of fitness lost due to dysregulation of the pyruvate dehydrogenase complex is triggered by ribosomal binding site modifications” published in Cell Reports (2021).

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How would you explain your paper’s key results to the non-scientific community?

We mostly recognize bacteria as harmful pathogens, however, many of them are advantageous to us. Unlike us, these microorganisms can peculiarly maintain their lives as single-celled organisms. They have to pack various resources required for their growth as well as protection against environmental assaults within the restricted cell size. We can relate the dilemma of bacterial cell packing its resources to a similar situation that all of us experience during remote travel. We can call it a ‘Traveler’s bag packing dilemma’. The defined size of the bag allows us to carry a limited amount of resources. We have to carefully choose how much protective gear like clothes, shoes, etc. can be included so that we have sufficient space left to pack food items. Similarly, bacterial cells also have to carefully utilize their cellular space to pack enzymes and metabolites needed to support growth and protect them from environmental assaults. And, as expected, an imbalance in this resource partitioning compromises their growth potential. In this paper, we have examined the adaptive response of a bacterium to a resource imbalance.

Pyruvate dehydrogenase complex is a large enzyme complex linking glycolysis to the TCA cycle or Krebs cycle in the cell. We deleted the repressor of this enzyme complex from the Escherichia coli genome. As expected, the loss of repression resulted in the increased expression of this giant enzyme complex compromising the efficient packing of cellular volume and decreasing the growth rate of the bacterial strain. But the most interesting part of the study was the finding that the bacterial strain could regain its growth capabilities after about 300 generations of evolution. We have also examined the mechanistic basis of the observed adaptive changes in the strain. The evolved strains re-engineered the Shine-Dalgarno sequence of the Pyruvate dehydrogenase complex to tailor its expression. The details are discussed in the paper.

Figure 1: A schematic showing alternate strategies to regulate expression of the Pyruvate dehydrogenase complex.

this study further emphasizes the importance of examining the distal impact of any cellular perturbation

What are the possible consequences of these findings for your research area?

Majority of the classical microbiological approaches fail to recognize the adaptive plasticity in the microbial physiology that is often manifested over an evolutionary timescale. This is one of the factors behind our limited success against the infectious agents and in realizing the full potential of industrially important strains. While revealing the mechanisms to restore gene expression in the absence of its canonical regulator, this study further emphasizes the importance of examining the distal impact of any cellular perturbation.

What was the exciting moment (eureka moment) during your research?

We were suspecting that a mutation in the Shine-Dalgarno sequence of the Pyruvate dehydrogenase gene could be responsible for the observed growth rate improvements. Therefore, we introduced this mutation in the growth retarded strain using CRISPR-Cas9 system. We were amazed to see the full recapitulation of the adaptive phenotype and this was definitely the eureka moment of the project.

What do you hope to do next?

After spending approximately five very productive years at the University of California San Diego, I am returning to India to set up my research group at the Tata Institute of Fundamental Research, Mumbai. My research group will focus on the fundamental and translational aspects of cellular bioenergetics. I encourage the readers of Bio Patrika to get in touch with me, if they are interested and looking for a research position in my group.

Where do you seek scientific inspiration?

My scientific inspiration comes from almost everywhere. We are born scientists; it is just that some of us lose the scientific temperament over time.

How do you intend to help Indian science improve?

Indian science has a huge potential and provides us with several opportunities. My intention is to create a nurturing environment in my research group and inspire young minds.

Reference

Anand A, Olson CA, Sastry AV, Patel A, Szubin R, Yang L, Feist AM, Palsson BO. Restoration of fitness lost due to dysregulation of the pyruvate dehydrogenase complex is triggered by ribosomal binding site modifications. Cell Rep. 2021 Apr 6;35(1):108961. doi: 10.1016/j.celrep.2021.108961.

Edited by: Neha Varshney

Job opening in Bharat serums and vaccines

Looking for PhD candidates with good understanding of protein analysis and characterisation using physiochemical and/or bioanalytical techniques.

Candidate should have 2-5 year of experience after PhD.

Experience in analytical and bioanalytical development of a Biopharmaceutical product is preferable but not mandatory.

Job location: Mumbai

Please share CV to lomary.singh@bharatserums.com

Mistakes in protein synthesis can lead to phenotypic diversity

Dr. Laasya Samhita’s interview with Bio Patrika hosting “Vigyan Patrika”, a series of author interviews. Dr. Laasya is postdoc and DBT/Wellcome Trust early career fellow with Dr. Deepa Agashe, National Centre for Biological Sciences, Bangalore. As an independent postdoctoral fellow, she works in an Evolutionary Biology laboratory and blends molecular biology with evolution, investigating how errors in protein synthesis can influence bacterial adaptation, and even turn out to be good for the cell. She is also interested in studying antibiotic resistance and exploring its link with translation accuracy. She obtained her PhD from the Indian Institute of Science. During her doctoral research she explored the molecular mysteries of bacterial protein synthesis. After her PhD, Laasya worked as a freelance science writer for a year. In the future, she intends to understand more about the contribution of non-genetic variation to adaptation and evolution. Here, Laasya talks about her work on “The impact of mistranslation on phenotypic variability and fitness” published in Evolution journal.

Listen audio

How would you explain your paper’s key results to the non-scientific community?

Popular media often portrays DNA as the ‘code of life’. Like with any code, decoding is essential to make sense of the underlying information. DNA is decoded into RNA, and finally into protein molecules which perform most of the work in a living cell. Therefore, changes in DNA often result in changes in the coded proteins, altering cellular properties. However, the interesting fact is that proteins can still change without the code (DNA) being disturbed at all. This happens due to the mistakes made during decoding. Even though these mistakes are usually not transmitted across generations, they can still influence how a cell behaves and its fitness in various ways. However, this can only happen if the mistakes are ‘visible’, that is if they result in changing some cellular property. Very often, mistakes in protein synthesis (decoding) are corrected or buffered and never see the light of day, so to speak. The key result of our paper is that, such mistakes in protein sequences (mistranslation) not only alter the mean trait value but also increase the variability of some cellular properties that are important for cellular health. This means that now we have trait values in the population which did not exist previously. For example, consider a classroom with children’s heights ranging from 3 feet to 4 feet, in turn resulting in specific physical height based capabilities. On adding new children, if we expand the children’s height range from 2 feet to 5 feet, new height based capabilities emerge. For example, taller children may be able to reach switches and shelves that the others cannot (new trait values).

Figure 1: Translation errors. Image credit: Dr. Deepa Agashe.

What are the possible consequences of these findings for your research area?

Variability in phenotypes is the raw material for evolution. Now that we know that mistranslation increases phenotypic variability, we can speculate that mistranslation can potentially influence evolution. This is a big step forward because like we discussed earlier, unlike DNA, proteins are not passed on from generation to generation. This means that mistakes at the protein level are usually confined to the single cell or generation in which they occur. However, by altering variability in fitness linked traits, they can still influence which cells will survive to represent the next generation, or which will perform the best.

What was the exciting moment (eureka moment) during your research?

This particular piece of work was complex and involved many twists and turns. There were two or three potential Eureka moments which fizzled out, as happens so often in research! Ultimately though I think the most exciting finding came through Godwin’s single cell observations: the fact that mistranslating cells show wider (more variable) distributions of cell length and division times.

What do you hope to do next?

I look forward to establishing my own research group in India. My plan is to blend basic and applied science in my research, while delving into how non-DNA based changes can impact evolution.

Every successful experiment is a confidence and enthusiasm booster!

Where do you seek scientific inspiration?

Every successful experiment is a confidence and enthusiasm booster! I find that discussions with mentors and colleagues along with quiet walks give me focus, as do occasional breaks from work to do something entirely different.

How do you intend to help Indian science improve?

Indian science has expanded hugely in the last decade, particularly in terms of manpower. I hope to make use of this very skilled and diverse scientific community to establish collaborations and widen my own expertise. Increasing competition and expectations has also driven up levels of stress among students and postdocs. I therefore also hope to function as an empathetic and motivating mentor, and spread the excitement of doing science.

Reference

Samhita, L., K Raval, P., Stephenson, G., Thutupalli, S. and Agashe, D. (2021), The impact of mistranslation on phenotypic variability and fitness. Evolution. https://doi.org/10.1111/evo.14179

Dr. Deepa Agashe lab: https://adaptationlab.in/

Edited by: Pratibha Siwach

Calcium sensor STIM1 regulates gene expression and synaptic connectivity of Purkinje neurons

Sreeja Kumari Dhanya’s interview with Bio Patrika hosting “Vigyan Patrika”, a series of author interviews. Dhanya is a Ph.D. student working under the guidance of Prof. Gaiti Hasan in National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore. She completed her master’s in Medical Biotechnology from Manipal School of Life Sciences (MSLS) at Manipal Academy of Higher Education (MAHE), Manipal. Her doctoral research focuses on understanding the role of STIM1 (Stromal Interaction Molecule), a calcium sensor molecule present in the endoplasmic reticulum (ER) and investigating its role in regulating gene expression, excitability and synaptic connectivity in mouse Purkinje neurons (PNs). Her research has significantly contributed to uncovering novel aspects of intracellular calcium signaling in regulating neuronal functions and physiology in mammalian system. Dhanya, as her long-term goal, envisages exploring signaling mechanisms involved in various neurodegenerative disorders and identifying novel therapeutic insights. Here, Dhanya talks about her work on ‘Purkinje Neurons with Loss of STIM1 Exhibit Age-Dependent Changes in Gene Expression and Synaptic Components’ published in Journal of Neuroscience.

Listen audio

How would you explain your paper’s key results to the non-scientific community?

Calcium in neurons plays an important role in regulating various cellular processes such as neurotransmission, gene expression, etc. Proper control of calcium flux between the cytosol and intracellular calcium stores (endoplasmic reticulum and mitochondria) is required for maintaining normal neuronal functions. Cytosolic calcium levels depend on both the calcium entering from the extracellular space through stimulation of the receptors and those released from the intracellular stores through endoplasmic reticulum (ER) resident calcium channel, the inositol 1,4,5-trisphosphate receptor 1 (IP3R1). Previous studies have reported mutations in IP3R1 are associated with spinocerebellar ataxias 15 and 16 (SCA 15/16) where Purkinje neurons undergo neurodegeneration leading to impaired coordination of vertebrate movements.

Refilling of calcium into the ER is initiated by an ER resident calcium sensor protein, STIM1 through interaction with pore channel Orai and transient receptor potential channel TRPC3 in Purkinje neurons. Previous studies have reported a correlation between loss of STIM1 and metabotropic Glutamate receptor 1 (mGluR1) controlling synaptic transmission and neuronal calcium homeostasis in Purkinje neurons. However, molecular mechanisms involved in affecting synaptic plasticity with loss of STIM1 is not known. To understand how altered intracellular calcium signaling leads to age-dependent deficits in Purkinje neuron function, as observed in neurodegenerative disorders like SCAs, we investigated cellular and molecular changes in the Purkinje neurons of mice with Purkinje neuron- specific knockout of STIM1. We observed that loss of STIM1 in the Purkinje neurons caused motor learning and coordination deficits in mice suggesting the importance of STIM1 in regulating membrane excitability and calcium transients following mGluR1 activation. Loss of STIM1 would reduce calcium levels in ER thereby attenuating intracellular calcium release upon mGluR1 stimulation and loss of STIM1-induced store-operated calcium entry.

Figure 1: Schematic representation of intracellular calcium signaling in Purkinje neurons. Activation of mGluR1 stimulates IP3 mediated calcium release from ER through IP3R and dearth of calcium in ER is sensed by STIM1. Store operated calcium entry is initiated through interaction of STIM1 with Orai and transient receptor potential channel TRPC3. Calcium entered into the cytosol moves to ER through sarcoendoplasmic reticulum calcium transport ATPase (SERCA) [Image created using Biorender (BioRender.com)].

It has been well known that gene expression changes upon reduced store-operated calcium entry in non-excitable cells. We further investigated the transcriptional profile of mature STIM1 knockout Purkinje neurons. Interestingly, we observed that loss of STIM1 in Purkinje neurons significantly altered the expression of genes belonging to key biological pathways such as calcium signaling, synaptic signaling, endocytic recycling and neurite development amongst others. The differential gene expression correlated with altered dendritic patterns and greater climbing fiber-Purkinje neuron synapses in ageing STIM1PKO mice suggesting long-term changes in synapse formation with loss of STIM1 in Purkinje neurons.

Overall, our data provide a novel role of STIM1 in regulating the gene expression profile and synaptic connectivity of Purkinje neurons. These findings are relevant in the context of uncovering the mechanisms by which dysregulated calcium signals impact molecular and cellular pathways involved in multiple neurodegenerative disorders.

Figure 2. Schematic representation showing a novel role of STIM1 mediated calcium signaling in mouse Purkinje neurons [Image created using Biorender (BioRender.com)].

The findings provide evidence for the novel role of STIM1 dependent calcium homeostasis and signaling in regulating the expression of multiple key components of neurite development and synaptic organization in ageing animals.

What are the possible consequences of these findings for your research area?

Dysregulation of intracellular calcium signaling in Purkinje neurons has been proposed as a possible mechanism in the pathogenesis of many neurodegenerative disorders. More specifically, individuals with mutations of the IP3R are associated with SCA 15/16. However, the precise molecular mechanism underlying neuronal dysfunction and motor coordination deficits is poorly understood. Our study elucidates a potential mechanism by which altered intracellular calcium signaling affects neuronal morphology and synaptic connectivity of Purkinje neurons thereby affecting motor behaviour. The findings provide evidence for the novel role of STIM1 dependent calcium homeostasis and signaling in regulating the expression of multiple key components of neurite development and synaptic organization in ageing animals. The outcome opens a path to discovering new therapeutic interventions alleviating the degenerative changes associated with neurodegenerative disorders.

What was the exciting moment (eureka moment) during your research?

The most exciting moments were when we found that the loss of STIM1 affects multiple gene expression across various biological pathways and the transcriptional alterations are age-dependent, evident in older mice. This suggested a possible molecular mechanism acting downstream of the STIM1 and reflected on the various possible biological networks affected on dysregulated intracellular calcium signaling. To our surprise, we also found that the gene expression changes correlated with altered dendritic morphology and greater climbing fiber-Purkinje neuron synapses further indicating the impairment in error encoding during motor learning tasks.

What do you hope to do next?

Our study identifies the functional significance of STIM1 mediated calcium signaling on Purkinje function and synaptic connectivity. My immediate goal is to investigate whether we could rescue the motor deficits and other neuronal dysfunction observed in the STIM1 knockout mice by altering Septin 7 levels exclusively in the Purkinje neurons. The rationale behind this study was influenced by the novel discovery from our lab where Septin 7 which are GTP-binding proteins was found to function as a ‘molecular brake’ on the activation of Orai channels (pore channel present on plasma membrane) in Drosophila neurons and human neural progenitor cells. Partial genetic depletion of dSeptin7 was found to rescue the flight defects in Drosophila with IP3R mutations or STIM knockdown. This indicates store independent opening of dOrai channels and enhancement in the intracellular calcium entry on lowering dSEPT7 levels, thereby compensating for the reduced function of IP3R or STIM in Drosophila neurons. We are interested to further investigate if this negative regulation of Orai by Septin7 is conserved among mammals and to explore the molecular and behaviour modulations in Purkinje neuron-specific STIM1-SEPT7 knockout mouse model.

Where do you seek scientific inspiration?

My scientific inspiration comes from my school days where I was curious to seek answers to scientific problems. I was always fascinated by the discoveries and the innovative way by which each question was addressed. I was curious to understand the complex system of life and rediscover the intricate machinery that works in a programmed manner inside a living organism. The amazing training and guidance that I received at MSLS, Manipal during my Master’s motivated me to explore more into life sciences and gave me immense confidence to pursue research as my career. I am very fortunate to take up my Ph.D. journey under the mentorship of Prof. Gaiti Hasan as her tremendous support and guidance always instigate a drive to develop my scientific thinking and explore more on discovering novel findings.

How do you intend to help Indian science improve?

I believe that young minds at their early stages of education should be motivated to develop the desire for science and develop an interest in scientific reasoning. According to my perspective, students should be made aware of the various opportunities available in India and provide proper guidance to pursue research careers. There should be more efforts to help the young researchers establish their own labs and provide adequate support through various funding agencies. I would certainly go for my post-doctoral research in the field of neuroscience to expand my knowledge, skills and expertise so that I can contribute to the identification of potential targets and collaborate with pharmaceutical domains to develop therapeutic drugs against neurodegeneration.

Reference

Sreeja Kumari Dhanya and Gaiti Hasan. Purkinje Neurons with Loss of STIM1 Exhibit Age-Dependent Changes in Gene Expression and Synaptic Components. Journal of Neuroscience 28 April 2021, 41 (17) 3777-3798; DOI: https://doi.org/10.1523/JNEUROSCI.2401-20.2021

Email: dhanyask@ncbs.res.in

Prof. Gaiti Hasan Lab: https://www.ncbs.res.in/faculty/gaiti

Edited by: Pragya Gupta

COVID-19 management at home

Dr. Ujjwal Rathore, a virologist at the University of California-San Francisco, while being closely involved with coronavirus research has spent a significant amount of time and effort in providing useful advice to multiple members of his family, and others afflicted by COVID-19. In this video (in Hindi), he talks about how to deal with COVID-19 at home, when to seek medical advice and separates facts from fiction. Please watch and share the video widely- science can save lives!
Most cases of COVID (oxygen level 92% or more) can be managed at home with paracetamol (for symptoms such as fevers), adequate hydration, rest and maximum possible isolation from other family/household members. Unfortunately, a number of medicines/therapies being prescribed for COVID in India are NOT effective. These include: antibiotics such as Azithromycin etc., FabiFlu (Favipiravir), Ivermectin and Hydroxychloroquine.

Please also refer to COVID home care tips by IndiaCOVIDSOS (https://www.indiacovidsos.org/home-care). Translations in multiple Indian languages (and Nepali) are also available.

Description above written by Rohini Datta

Video credits: Dr. Ujjwal Rathore

Check Ujjwal YouTube channel: VirusDuniya https://www.youtube.com/watch?v=2-ouF8w-s6s

Profile at https://profiles.ucsf.edu/ujjwal.rathore

Biopatrika Three Minute Vigyan (3MV) Video Competition Winners

Last year Biopatrika opened up the Three Minute Vigyan (3MV) Video competition to allow video submissions, with the only requirement being that the submission had to adhere to time limit of “Three minutes.”

Overall, we got 27 submissions from 26 different participants, representing school, college and industry around the globe. Each of the video was incredible on its own, which made picking winners difficult. After a rigorous judging process, we chose the top 2 in junior category (School students) and top three in Senior category. The video entries have been judged based on the merit of their presentation and quality of communication and not the quality of the content.

Thanks to the judges!

All video entries are uploaded to Biopatrika YouTube channel. Do Like, Share and Subscribe.

Twitter Feed #3MV

Winners in junior category. YouTube entry 12 and 3.

Winners in senior category. YouTube entry 24, 26 and 6.

Prize

1st Prize: Rs. 3000

2nd Prize: Rs. 1500

Third Prize: Rs. 750

School student entries will receive Rs. 200 as token of appreciation.

Prizes will be distributed in the form of Amazon coupon by email.

All participants will receive certificate by email shortly.

Thanks all for your enthusiasm and participation.

Stay home, stay safe.