Every summer La Vida brings you a series of webinars with an aim to enrich you with
knowledge and information about the latest research being conducted by brilliant minds
across the world. Find below the details of upcoming/recent webinars.


SUMMER WEBINAR SERIES 2022

Energetic Phosphates in Cell Signalling - from pyrophosphoinositol to pyrophosphoserine

Inositol pyrophosphates (PP-IPs), such as diphosphoinositol pentakisphosphate (IP7) and bisdiphosphoinositol tetrakisphosphate (IP8), are a class of ubiquitous, energy rich metabolites, whose synthesis is catalysed by two groups of enzymes, IP6 kinases and PP-IP5 kinases. Since the discovery of PP-IPs in the early 1990s, significant progress has been made in uncovering pleiotropic roles for these small molecules in cellular physiology. PP-IPs exert their effect on proteins in two ways – allosteric regulation by direct binding, or posttranslational regulation by serine pyrophosphorylation, a modification unique to PP-IPs. Serine pyrophosphorylation is achieved by Mg 2+ -dependent, but enzyme independent transfer of a β-phosphate moiety from PP-IPs to a prephosphorylated serine residue located in an intrinsically disordered region, amidst acidic amino acid residues. We have demonstrated that serine pyrophosphorylation by PP-IPs regulates diverse cellular processes, including rRNA synthesis, dynein-driven vesicle transport, and protein stability. However, our understanding of the molecular details of this phosphotransfer process from pyrophospho-inositol to generate pyrophospho-serine, is still nascent. Our current knowledge of the importance of protein pyrophosphorylation, and recent advances in understanding the mechanism of this important yet under-appreciated posttranslational modification will be discussed.



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Meeting id - 915 0028 0149

Passcode: 496831

Role of RNA interactions in controlling physiological properties and function of RBP condensates

A large fraction of the human proteome consists of RBPs. These proteins perform diverse functions in cells. Many of these RBPs like FUS, EWSR1, TAF15, TDP43 and hnRNAP1, which are present at high concentrations in the nucleus of the mammalian cells, contain low complexity domains making them prone to undergo liquid-liquid phase separation, a physicochemical process to make micron scale condensates in both the cellular environment and in vitro. In cells, these RBPs are present at concentrations where they can readily phase separate into condensates. We are currently studying how do cells control the formation of RBP condensates at specific times and locations? Additionally, these phase separation prone proteins tend to aggregate and form solid-like assemblies in the cytoplasm in neurodegenerative diseases- Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration, the underlying mechanism for which is unclear. In this talk, Dr. Shovamayee Maharana will present evidence to elucidate the mechanisms which inhibit the spontaneous formation of RBP condensates and solid-like transitions in cells.



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Inherent Conformational Plasticity in dsRBDs enables interaction with topologically distinct RNAs

Many double-stranded RNA-binding domains (dsRBDs) interact with topologically distinct dsRNAs in biological pathways pivotal to viral replication, cancer causation, neurodegeneration, etc. In this study, we hypothesized that the adaptability of dsRBDs is essential to target distinct dsRNA substrates. We employed a model dsRBD and a few toplogocally distinct dsRNAs to test the systematic shape-dependence of RNA on the dsRBD-binding using NMR spectroscopy and molecular modeling. We used NMR line-broadening, microsecond timescale dynamics measurements using relaxation experiments, and atomistic molecular simulations to show a distinct binding pattern for the dsRBD with the topologically distinct dsRNAs, and a role of intrinsic dynamical basis for the substrate promiscuity for dsRBD proteins.



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Deciphering the role of super-enhancers in diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is one of the most aggressive forms of lymphoma with poor response to standard-of-care (R-CHOP) therapy. This poor response and acquired drug resistance to R-CHOP chemotherapy is partially explained by its remarkable heterogeneity. Genomics based studies in the past had been identified recurrently mutated oncogenes in DLBCL e.g., BCL6, KMT2D, CREBBP, EP300 etc. Despite the discovery of such recurrent genomic alterations, there are very limited options available for DLBCL patients’ treatment, which indicate towards the urgency of identifying novel mechanisms of DLBCL tumorigenesis and drug targets. In our recent study, we looked at super-enhancers (SEs) regions and their involvement in DLBCL tumorigenesis and in this talk, Dr. Jeetender Chugh will talk about this study.



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Linking immunity, infection-history, and fitness costs: Lessons learnt from parallelly evolving beetle lines under single vs multiple infections

In nature, hosts can face multiple pathogens simultaneously. While this might warrant activation of different immune mechanisms to counter mixed infections, an expansion of diverse immune arms together can collectively increase the costs of immunity, reducing the rate of adaptation against pathogens. However, a comparative experimental framework is missing. Here, we used several Tribolium beetle lines evolving against either a single or a combination of pathogens with divergent within-host growth dynamics— Fast-growing Bacillus thuringiensis (Bt); Slow-growing Pseudomonas entomophila (Pe); A combination of both (M). Although we began by imposing an equivalent selection pressure (~60% mortality in all lines), resistance could evolve most rapidly against Pe by overexpressing antimicrobial peptides and lysozyme (within 12-generations), whereas resistance against fast-growing Bt did not evolve yet, possibly because beetles could not invest more in fast-acting immunity relevant to Bt-clearance such as cytotoxic phenoloxidase. Expectedly, resistance evolution against M was delayed (~17-generations), perhaps due to increased costs of an extended immune repertoire. Finally, we found a novel cost of immune responses in ancestral lines where they compromised the germline DNA-repair and increased the mutational load in offspring, but evolution with pathogens rapidly reversed this effect by improving germline maintenance to reduce the deleterious mutation transmission.



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Deciphering the Targetable Metabolic Vulnerabilities in Breast Cancer Brain Metastases

HER2+ breast cancer patients presenting with either synchronous (S-BM) or metachronous (MBM) brain metastases have poor survival outcomes. Although relatively rare, HER2+ breast cancer patients with synchronous brain metastases have a median overall survival of around 6 months. In contrast, metachronous brain metastases or relapse are observed in approximately fifty percent of HER2+ breast cancer patients considered disease free after a variable length of time post primary diagnosis and treatment. It is believed that disseminated latent residual cells (Lat) that survive current therapies are responsible for the metastatic relapses or metachronous metastasis. How disseminated tumor cells survive as latent/dormant entities for extended period of time before initiating metachronous metastasis is poorly understood. Moreover, the basis for disparate metastatic fitness among disseminated tumor cells of similar oncotype within a distal organ is unknown and vital for better clinical management. Through phenotypic screen in mice, we have isolated isogenic HER2+ S-BM, Lat and M-BM brain metastatic cells. Employing those isogenic HER2+ breast cancer brain metastasis models, we show metabolic diversity and plasticity within brain-tropic cells determines metastatic fitness. Lactate secreted by aggressive metastatic cells (S-BM and M-BM) or lactate supplementation to mice bearing latent residual disease limits innate immune surveillance and triggers overt metastasis. Attenuating lactate metabolism in S-BM impedes metastasis, while M-BM adapt and survive as latent residual disease. In contrast to S-BM, Lat and M-BM survive in equilibrium with innate immune surveillance, oxidize glutamine and maintain cellular redox homeostasis through the anionic amino acid transporter xCT. Likewise, xCT expression was significantly higher in matched metachronous brain metastatic samples compared to primary tumors from HER2+ breast cancer patients. Genetic or pharmacological blockade of xCT eradicates residual disease and brain metastatic relapse in these preclinical models. In sum, by investigating phenotypically distinct brain-tropic S-BM, Lat and M-BM cells, we uncovered the impact of metabolic diversity and adaptations on metastatic fitness and identified targetable metabolic vulnerabilities.

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SUMMER WEBINAR SERIES 2023

Breaking the bilateral body symmetry: Left-right patterning in mammalian embryo

While the majority of the animal kingdom has a bilaterally symmetric body plan, many groups manifest left-right (LR) asymmetry with respect to the organisation of internal organs. In mammals, the breaking of bilateral symmetry to establish LR pattern occurs in the gastrulating embryos before the organs are formed. Disruptions in this mechanism result in Heterotaxia syndrome, characterized by a range of LR defects. In spite of this importance, several fundamental questions regarding the LR patterning mechanism remain poorly understood. Mouse embryos mutant for Tbx6, encoding a T-box transcription factor, display severe LR defects. Tbx6 is an early developmental gene with a central role in mesoderm germ layer specification and in progenitors generating posterior spinal cord and musculoskeletal tissues. How this key developmental gene functions in the LR patterning mechanism is unclear. Combining loss of function studies using mouse genetics and ChIP-sequencing approach to identify the global transcriptional targets, our research shows that Tbx6 controls LR patterning mechanism at multiple critical regulatory steps. Based on this evidence, we propose that Tbx6 could be a part of the mechanism to induce the LR patterning mechanism in the right time prior to the initiation of organ formation.



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Muscles: How are they formed and maintained in a living system?

Skeletal muscles, the kinds we use our bodies and limbs for, are fascinating organ systems. Their essential locomotory functions make them central to quality of life. Other functions you may not have heard about make them a key node in systemic metabolism. Their intricate yet stereotypical structure links bodily activity with physiology at a molecular level. Deviations result in debilitating diseases, many of which are genetically linked. How do they attain such intricate form and retain function throughout our lives?

A lot of what we know about mammalian muscle maintenance from studying their stem cells in vitro. This reductionist approach yields valuable information about how satellite cells behave in a dish. In this talk I will bring to light what we are finding about skeletal muscle maintenance and homeostasis inside a living system where all relevant cues from the muscle environment come together. This living system is Drosophila. Fruit-fly flight muscles bear striking similarities in structure and function to human muscles. They allow us to modulate molecular function at a cellular and molecular level. We showed the existence of the satellite like cells in Drosophila for the first time and the cues they get from surrounding muscles. We now ask further if they respond to physical signals like mechanical tension and through what signaling pathway.

Further, muscles at a fundamental level are contractile syncytia. Many nuclei coexist and function within the same relatively large cell throughout the animal’s life. We ask if the two ends of the same cell have identical cytological processes active. I’ll be discussing our findings that suggest that a host of molecular differences exist along the length of Drosophila flight muscle cells. We find mRNA for close to a hundred proteins including transcription factors, proteases and ion channels enriched in different regions of the muscle fibre. The differences are critical to the formation and maintenance of muscles. How the activities of so many molecules come together just so that flies can beat their wings at 200 hz over a rotting banana is a new and hugely exciting question with implications for how we view human myodystrophic conditions.



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The tick-tock of the daily clock – neural underpinnings of circadian pacemakers.

We now know that a large number of behaviours and physiological processes occur at specific times of the day and that they are not mere responses to geophysical cycles caused due to the rotation of the earth on its axis. In most metazoans the endogenous mechanisms that make up these timekeeping entities reside in neuronal networks. I will discuss how circadian pacemaker circuits govern body functions and evidence for how disruptions in clockwork function can be detrimental to overall health.



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Diary of a scientific wanderlust - Journey from embryology to disease biology

My undergraduate degree is in Chemistry. I studied Biochemistry during my MSc. I performed PhD research in Molecular Biology - Molecular mechanism of initiation of protein synthesis to be precise. During postdoctoral training, I learned embryology of developing chick limb skeleton. Adult limb skeleton is comprised of multiple elements. However limb skeletal development begins with a single cartilaginous template which is branched (along the long axis) and segmented (perpendicular to the long axis) to give rise to the distinct skeletal elements. Further, while the early limb skeleton is made of pure cartilage, in mature skeleton most of the cartilage is replaced by bone. This cartilage that is replaced by bone is referred to as transient cartilage. Only the cartilage adjoining the plane of segmentation remains as cartilage forever and is varyingly referred to as permanent cartilage or articular cartilage or joint cartilage.



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Drosophila models of genetic and viral-induced microcephaly

Our goal is to understand how genetic mutations and viral infections cause neurological disease. Disease causing genetic mutations are often difficult to pinpoint due to multiple candidates in a single patient. Variants in a particular gene of interest are frequently discovered in one or very few patients, which does not provide sufficient evidence for a definitive diagnosis. Model organisms can facilitate functional analysis of human variants, promoting disease identification and characterization. The fruit fly is particularly suited for this role with quick and highly sophisticated genetic manipulations. Functional testing of human variants using Drosophila can lead to disease diagnoses, identification of molecular pathogenic mechanisms, and testing of therapeutic targets. We focus on microcephaly, a devastating neurodevelopmental condition that affects brain development and is characterized by reduced brain size. We established a discovery platform to identify novel genetic variants that cause microcephaly using information from patient cohorts. Our goal is to use this platform to investigate mechanisms of disease, but also determine how these pathways function in normal development. In addition to genetic mutations, viral infections can also cause similar neurodevelopmental defects. One such example is Zika virus, which is associated with very severe microcephaly. We developed Drosophila as a model to identify phenotypes caused by viral protein expression. We use the expansive set of genetic tools to determine what conserved pathways viral proteins interact with to cause disease.



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Cancer Vaccines: Unveiling Opportunities and Confronting Challenges in Design and Development

Cancer is a leading cause of death worldwide, with an estimated 9.5 million cancer deaths in 2020. In India, cancer is the leading cause of death for women and the second leading cause of death for men. The most common cancers in India are lung cancer, breast cancer, and colorectal cancer. Lung cancer is the leading cause of cancer death for both men and women in India, breast cancer is the leading cause of cancer death for women, and colorectal cancer is the third leading cause of cancer death for both men and women.

Despite the urgent need to develop an effective cancer vaccine, none is currently available. This interactive lecture will explore the challenges of cancer vaccine development, the various strategies currently being used to design cancer vaccines (such as dendritic cell vaccines, oncolytic virus vaccines, peptide vaccines, and nucleic acid vaccines), with a focus on peptide vaccines and the bioinformatics tools that can be used to design them

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SUMMER WEBINAR SERIES 2024

Unraveling Cell-Type Specific Roles of Disease-Associated Mutations in the Noncoding Regulatory Genome

Dr. Shipra Bhatia's talk explores the hidden complexities of the noncoding regulatory genome, focusing on how mutations in these regions contribute to diseases in a cell-type-specific manner. Unlike protein-coding regions, these regulatory sequences play a subtle yet vital role in controlling gene expression. Dr. Bhatia highlights recent advancements in understanding how mutations in these areas influence specific cell types, leading to distinct disease outcomes. Her work emphasizes the importance of studying the noncoding genome to uncover its potential for targeted therapies, opening new avenues for precision medicine.



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Moving Molecules: Trafficking, Development, and Diseases

Dr. Deepa Subramanyam provides an in-depth view of the molecular trafficking mechanisms that are crucial for cellular function, development, and disease progression. Her talk highlights the processes by which molecules are transported within cells and how these pathways regulate critical developmental stages. She also discusses the consequences of disruptions in these systems, linking them to a wide range of diseases. Through her findings, Dr. Subramanyam offers valuable insights into how molecular trafficking not only maintains cellular health but also holds the key to understanding and potentially treating complex diseases.



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Emergent Features of Collective Cell Dynamics: A Mechanobiological Perspective

Dr. Tamal Das from TIFR-H delves into the fascinating world of collective cell dynamics, examining how groups of cells interact and coordinate their movements. His talk focuses on the mechanobiological principles governing these processes, emphasizing the role of physical forces and mechanical signals in shaping cellular behavior. By exploring emergent properties, Dr. Das sheds light on how collective dynamics influence tissue formation, repair, and disease progression, offering a new perspective on the interplay between mechanics and biology.



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Organizing Epithelial Patterns

Dr. Raj Ladher’s talk uncovers the intricacies behind the organization of epithelial cell patterns, which are fundamental to the structure and function of tissues. He explains how cells in epithelial layers achieve precise spatial arrangements and maintain their organization through coordinated signaling and mechanical interactions. His insights reveal the critical role of these patterns in development and disease, emphasizing their significance in maintaining tissue integrity and function.



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Measuring Metabolism Across Scales: Molecular, Spatial, and Temporal Resolution

Dr. Prasad Phapale discusses innovative approaches to understanding metabolism by integrating molecular, spatial, and temporal scales. His talk highlights advancements in metabolic profiling techniques that allow researchers to capture the dynamic and complex nature of cellular metabolism. Dr. Phapale emphasizes the importance of studying metabolic pathways in various contexts, including disease progression and treatment strategies, providing a holistic view of how metabolism operates across multiple scales.



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Harnessing Microbials from a Plant-Associated Bacterium for Sustainable Agriculture

Dr. Gopaljee Jha explores the potential of plant-associated bacteria in revolutionizing sustainable agriculture. His talk focuses on harnessing beneficial microbes to enhance crop productivity, improve soil health, and reduce dependence on chemical fertilizers. By studying the interactions between plants and microbes, Dr. Jha presents novel strategies for developing eco-friendly agricultural practices, showcasing how microbial biotechnology can address global challenges in food security and environmental sustainability.



This webinar has already been conducted. If you want the recording, you can request it using this form.