Institutional Publications
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Item The RNA-binding protein Quaking is essential for cardiac homeostasis and function by regulating Morf4l2 splicing(Elsevier B.V., 2026) Kumari, Sunaina; Shashi; Singh, Sandhya; Swain, Abinash; Prakash, Shakti; Chitkara, Pragya; Sharma, Rakesh Kumar; Agarwal, Pratyush; Kundu, Samprikta; Gaur, Aakash; Kumari, Renu; Sinha, Abhipsa; Chatterjee, Shambhabi; Prasun, Pankaj; Hummel, Oliver; Pant, Bhaskar; Srivastava, Kinshuk Raj; Hübner, Norbert; Datta, Dipak; Mitra, Kalyan; Mishra, Durga Prasad; Guha, Rajdeep; Thum, Thomas; Kumar, Shailesh; Gupta, Shashi KumarBackground: Lower levels of Qki were reported in human and mouse-failing hearts, implicating its involvement in cardiac diseases. However, the molecular and functional effects of its downregulation in adult myocardium remain largely unknown. Objective: We aim to uncover the effects of Qki knockdown in adult hearts. Methods & results: Here we show that AAV9-mediated knockdown of Qki by shRNAs in the hearts of adult BALB/c mice led to cardiac malfunction, atrophy, apoptosis, heart failure, and death within two weeks. Global transcriptomic analysis of Qki knockdown hearts revealed significant dysregulation of 996 alternative splicing events upon Qki knockdown. Mechanistically, we discovered that loss of Qki promotes the exclusion of the third exon of Morf4l2, leading to higher expression of exon three excluded variant (Morf4l2Δex3). Like rodents, the RNA-seq dataset from 108 human hearts revealed a lower splice junction count of MORF4L2 exon three in hearts with low levels of QKI compared to subjects with higher QKI levels. Specific knockdown of Morf4l2Δex3 rescues Qki knockdown-induced cardiac cachexia and improves cardiac function. Moreover, Morf4l2Δex3 was increased in the colon cancer-induced cardiac cachexia mouse model, and its inhibition prevented cardiac cachexia and improved cardiac function. Mechanistically, exon three of Morf4l2 lies in the 5'UTR, and its exclusion leads to higher expression of MORF4L2 upon Qki knockdown due to the lack of a G2-quadruplex. Importantly, MORF4L2 protein sequence and localization were not affected by alternative splicing as exon three lies in the 5'UTR. We found that MORF4L2 is a chromatin-bound protein and regulates H3K27ac. Conclusion: Qki knockdown in the adult heart leads to cardiac cachexia due to the alteration of Morf4l2 splicing. Inhibition of Morf4l2Δex3 inhibits cancer-induced cardiac cachexia, demonstrating it as a potential therapeutic target.Item Identification and downstream analyses of domains amplified in plant genomes: The case of StAR-related lipid transfer (START) domains in rice(Springer Nature Publishing AG, 2021) Mahtha, Sanjeet Kumar; Purama, Ravi Kiran; Kumari, Renu; Yadav, GitanjaliPlant genomes can withstand small- and large-scale duplications, at a far greater success than any other kingdom in the tree of life, resulting in the existence and evolution of gene families, often with over a hundred members! The gene families, in turn, go through subfunctionalization or neofunctionalization, to form protein domains performing unique or grouped functions in context of the original activity. Due to the large number of such cases in the plant kingdom, it has become a routine task for plant biologists to investigate their specific gene family of interest. In this chapter, we provide a simple and standard pipeline for this effort, taking the example of steroidogenic acute regulatory protein (StAR) related lipid transfer (START) domains in rice, as reference. We describe the extraction, processing, and downstream analysis of Oryza sativa var. japonica proteome towards identification and comparative exploration of START domains. This was done by training profile Hidden Markov Models (HMM) of 35 reported START domains in Arabidopsis, which were then used to search potential homologs in rice. Downstream investigations included domain structure analysis, visualization of exon–intron patterns, chromosomal localization of START genes, and phylogenetic studies, followed by identification of cis-regulatory elements and gene regulatory network construction. Additionally, we have also highlighted various alternative tools and techniques that can be used to perform similar analyses, along with salient features.Item Lychee-associated hypoglycaemic encephalopathy: A new disease of children described in India(The National Academy of Sciences, India, 2020) Kumar, Sushil; Kumari, Renu; Pandey, RichaFruits of lychee tree (Litchi sinensis), extensively horticultured in India, China and many other countries, are delicious and possess many nutritious and medicinal properties. In India and other Asian countries, in lychee harvest season, outbreaks have been occurring of rapidly developing hypoglycaemia, encephalopathy, seizures and cerebral oedema in young children when they ingest lychee fruit arils in large numbers on empty stomach. It has been shown that the acute neurological illness is hypoglycaemic encephalopathy, caused by the actions of hypoglycin A (HGA) and methylenecyclopropylglycine (MCPG), the non-protein L-amino acids present in the edible arils of lychee fruits. Both HGA and MCPG phytotoxins are known to disrupt the pathways of β-fatty acid oxidation and gluconeogenesis in human body cells, result in accumulation of many undesirable metabolites of the blocked energy generating pathways, and altogether produced the often fatal hypoglycaemic illness. Here, the related work is summarized and commented upon and prospective genetical interventions in Litchi sinensis to eradicate the problem are outlined. Toxin-deficient lychee genotypes need to be developed by screening of germplasm accessions, and use of conventional and new site-directed mutagenesis technique of plant breeding. Lychee trees that produce super-toxin-rich (× 10 average toxin concentration) fruits are required to be identified and tagged to stop consumption of their fruits. New plantings must use toxin-deficient (low-toxin) lychee genotypes.Item Perspectives of the Artemisia annua dry leaf therapy (ALT) for malaria and of its re-purposement as an affordable cure for artemisinin-treatable illnesses(Indian National Science Academy, 2018) Goel, Richa; Kumari, Raj; Singh, Vijender; Kumari, Renu; Srivastava, Suchi; Kumar, SushilMalarial diseases continue to risk the lives of more than 3 billion people in 97 countries in the world, causing sickness in several million people and death to half a million patients. The preponderate malaria causing apicomplexan protozoan parasite species Plasmodium falciparum and Plasmodium vivax have become genetically resistant to most of the approved antimalarial drugs, including the artemisinin-based combination therapies (ACTs). At this time, there is a vigorous need to make enough efforts to meet the challenge of combating multi-drug resistant malaria by (a) speeding up the trials in progress on relatively more effective, new and mechanistically different antimalarial pharmaceuticals, (b) production of effective vaccines against falciparum and vivax malaria, (c) devising of new ways to use the presently available anti-malarials such as by using three-drugs ACTs and by using the different two-drug and three-drug ACTs sequentially, and (d) induction of Artemisia annua dry leaf therapy (ALT) of recent origin, but of ancient precedent, as an effective treatment for acute and complicated malaria. Here, a perspective type review is presented of the: pre-ALT antimalarial drugs, methodology of their usage and consequences of resistance development; safety, efficacy, affordability, quality maintenance and resilience to resistance development aspects of ALT; and possibilities of ALT re-purposement for treating many infectious-metabolic disorder related- and cancerous-diseases. In conclusion, an urgent need is emphasized for pilot studies and clinical trials on ALT to attest its deployment as anti-malarial and cure for diseases beyond malaria.Item Ebola virus disease: Biology, diagnosis, treatment and prevention of epidemics(Indian National Science Academy, 2017) Kumar, Sushil; Kumari, Renu; Pandey, Richa; Sharma, VishakhaEbola virus disease (EVD) is a highly lethal contagious disease caused by the negative RNA strand Ebola virus. Reservoired in wild forest animals of Africa, Ebola virus infects humans that come in direct contact of diseased animals and outbreaks of EVD result from person to person spread of infection. A recent EVD outbreak in West Africa has killed several thousand persons. Since Ebola infection will persist in animals, EVD epidemics are expected to continue to occur in future. Infected travellers from Africa can initiate/import outbreaks in countries of other continents. This review describes the properties of the Ebola virus and EVD, the ongoing attempts to develop diagnostics, vaccines and medicines for prevention and cure of EVD and the supportive care that saves some EVD patients. Also discussed are measures that can stop and prevent EVD outbreaks. Need for inclusion of EVD in the education, research, drug and medical equipment manufacturing programmes, of the densly populated countries such as India, is emphasised.Item Coevolution mechanisms that adapt viruses to genetic code variations implemented in their hosts(Indian Academy of Sciences, 2016) Kumar, Sushil; Kumari, Renu; Sharma, VishakhaViruses, the preponderant species, are the agents of horizontal gene transfer between cellular organisms, a major means for generation of genetic variability that drives evolution in varying environments. Recent work on virus × host interaction has led to revision of the conventional idea that the genetic code of the virus and host must be same so that the host translational system facilitates efficient, accurate and complete expression of the infecting viral genome. There is evidence now that differences between the genetic codes of viruses and their hosts are not an absolute barrier to virus multiplication. The recent work on mechanisms by which viruses overcome the mismatch in codon usage of host versus theirs is discussed here contextually. Examples of coevolution of viruses and their hosts, in terms of genetic code usage, discussed here agree with the concept that their evolution is reciprocally driven and therefore suggestive of a kind of long-term interdependent symbiotic relationship between them.Item New insight-guided approaches to detect, cure, prevent and eliminate malaria(Springer, 2015) Kumar, Sushil; Kumari, Renu; Pandey, RichaNew challenges posed by the development of resistance against artemisinin-based combination therapies (ACTs) as well as previous first-line therapies, and the continuing absence of vaccine, have given impetus to research in all areas of malaria control. This review portrays the ongoing progress in several directions of malaria research. The variants of RTS,S and apical membrane antigen 1 (AMA1) are being developed and test adapted as multicomponent and multistage malaria control vaccines, while many other vaccine candidates and methodologies to produce antigens are under experimentation. To track and prevent the spread of artemisinin resistance from Southeast Asia to other parts of the world, rolling circle-enhanced enzyme activity detection (REEAD), a time- and cost-effective malaria diagnosis in field conditions, and a DNA marker associated with artemisinin resistance have become available. Novel mosquito repellents and mosquito trapping and killing techniques much more effective than the prevalent ones are undergoing field testing. Mosquito lines stably infected with their symbiotic wild-type or genetically engineered bacteria that kill sympatric malaria parasites are being constructed and field tested for stopping malaria transmission. A complementary approach being pursued is the addition of ivermectin-like drug molecules to ACTs to cure malaria and kill mosquitoes. Experiments are in progress to eradicate malaria mosquito by making it genetically male sterile. High-throughput screening procedures are being developed and used to discover molecules that possess long in vivo half life and are active against liver and blood stages for the fast cure of malaria symptoms caused by simple or relapsing and drug-sensitive and drug-resistant types of varied malaria parasites, can stop gametocytogenesis and sporogony and could be given in one dose. Target-based antimalarial drug designing has begun. Some of the putative next-generation antimalarials that possess in their scaffold structure several of the desired properties of malaria cure and control are exemplified by OZ439, NITD609, ELQ300 and tafenoquine that are already undergoing clinical trials, and decoquinate, usnic acid, torin-2, ferroquine, WEHI-916, MMV396749 and benzothiItem Origin, structure and function of millions of chromosomes present in the macronucleus of unicellular eukaryotic ciliate, Oxytricha trifallax: a model organism for transgenerationally programmed genome rearrangements(Indian Academy of Sciences, 2015) Kumar, Sushil; Kumari, RenuThe unicellular eukaryotic ciliate protists characteristically contain a germline micronucleus (MIC) and a somatic macronucleus (MAC) in their cytoplasm. The MAC, which is crucial for the pursuit of cellular growth and mitotic divisions, is derived from a postzygotic MIC. The transition from MIC to MAC involves extensive editing of the MIC genome, followed by massive amplification of the residual MAC genome. The spirotrichous ciliate, Oxytricha trifallax, has been most extensively deployed as the model system to reveal the mechanism(s) of origin of the architectural complexities of MAC. This has been possible by the application of genome sequencing, synthetic RNA transgenesis and a variety of other genetic techniques. Here, we summarize and discuss the current observations of MAC genome derived from MIC genome, properties of MAC genome structure, function and significance of the novel features described in O. trifallax. The differences in the genome organization of O. trifallax and its relative alveolate species Paramecium tetraurelia and Plasmodium falciparum have been described. Aspects of programmed genome rearrangements, MAC genome structure and function requiring further analyses in different ciliate protest have been pointed out.Item Occurrence of molecularly diverse Bt Cry toxin-resistant mutations in insect pests of Bt+ corn and cotton crops and remedial approaches(Indian Academy of Sciences, 2015) Kumar, Sushil; Kumari, RenuCultivation of Bt + genotypes has dispensed with insecticidal sprays and thereby corn and cotton farmers have hugely benefited worldwide. Recent recordings of genetically diverse Cry-resistance in insect pests of Bt + corn and cotton fields have raised grave concern. Curiously, bulk of Cry-resistant pink bollworms found in certain Bt + cotton fields in India proved homozygous for multiple linked mutations. Besides, dominantly inheritable Cry-resistance and cross resistance between different Cry-proteins have also been noted. To stem evolution of resistance against anti- insect protein-toxins, new nematology research on IPM procedures, complementary to refuge and Cry stacking technologies is imminently needed.Item Genetics of dioecy and causal sex chromosomes in plants(Indian Academy of Sciences, 2014) Kumar, Sushil; Kumari, Renu; Sharma, VishakhaDioecy (separate male and female individuals) ensures outcrossing and is more prevalent in animals than in plants. Although it is common in bryophytes and gymnosperms, only 5% of angiosperms are dioecious. In dioecious higher plants, flowers borne on male and female individuals are, respectively deficient in functional gynoecium and androecium. Dioecy is inherited via three sex chromosome systems: XX/XY, XX/X0 and WZ/ZZ, such that XX or WZ is female and XY, X0 or ZZ are males. The XX/XY system generates the rarer XX/X0 and WZ/ZZ systems. An autosome pair begets XY chromosomes. A recessive loss-of-androecium mutation (ana) creates X chromosome and a dominant gynoecium-suppressing (GYS) mutation creates Y chromosome. The ana/ANA and gys/GYS loci are in the sex-determining region (SDR) of the XY pair. Accumulation of inversions, deleterious mutations and repeat elements, especially transposons, in the SDR of Y suppresses recombination between X and Y in SDR, making Y labile and increasingly degenerate and heteromorphic from X. Continued recombination between X and Y in their pseudoautosomal region located at the ends of chromosomal arms allows survival of the degenerated Y and of the species. Dioecy is presumably a component of the evolutionary cycle for the origin of new species. Inbred hermaphrodite species assume dioecy. Later they suffer degenerate-Y-led population regression. Cross-hybridization between such extinguishing species and heterologous species, followed by genome duplication of segregants from hybrids, give rise to new species.