The human biological clock is composed of several molecular mechanisms which are synchronous with the day-night cycle or circadian rhythm. Disruption in the cycle can lead to chronic metabolic disorders.

Among other things, the circadian rhythm keeps a check on the proliferation of cells in the body. However, when cells become cancerous, they break away from the circadian rhythm and escape from the circadian control system to undergo uncontrolled proliferation.

The processes that promote cancerous growth can hijack the metabolic balance to fuel the rapidly proliferating cancer cells. The dysregulated metabolic balance in cancer cells results in the increased generation of a substance called lactate.  Further, cancer cells produce large quantities of a protein called IL-1β that promotes the growth of tumors. Till now, it was not clear how cancer cells sustain the high rate of production of lactate and IL-1β in conjunction with the cellular circadian rhythm.

The researchers at NBRC have now unraveled the mystery. They have found that cancer cells modify the molecular components of cellular circadian rhythm to create a new regulatory network that produces more lactate and IL-1β. The network has been named as Lactate-Inflammation-Clock (LIC).

In their first set of experiments, the research team used chemicals to activate/inhibit lactate and IL-1β in glioma cells, a type of tumor that occurs in the brain and spinal cord.

They found that, when activated, lactate and IL-1β induce the expression of important circadian proteins called Clock and Bmal1. Further molecular experiments revealed that Clock/Bmal1 transcriptionally activates the expression of LDH-A (Lactate producing enzyme) and IL-1β thus confirming the existence of the LIC regulatory network.

The team found that LIC controls the key pathways of glioma progression such as cell cycle, DNA damage and repair of cytoskeletal architecture and modification of chromatin,which is a complex of DNA and proteins that forms chromosomes within the nucleus of cells.

In further studies, the researchers found that similar LIC regulatory networks were present in stomach and cervical cancer cells as well and that disruption of these networks can interfere with their tumor-promoting signals too.

Speaking to India Science Wire, leader of the team, Ellora Sen, said, “We noted significant correlation of LIC circuit with patient survival and anti-cancer drug sensitivity. Patients with stomach, cervical or brain cancers survived longer when they had lower levels of Clock, Bmal1, LDHA and IL1-β protein. We found that clinically approved EGFR inhibitors such as gefitinib and erlotinib can be utilized for disrupting the LIC regulatory loop in cancer cells”.

She and her team are now working in collaboration with IIT-Mumbai to develop the mathematical model for the LIC regulatory circuit. “The model, when fitted to the patient molecular profile of LIC components, could serve as a framework for a new approach to cancer treatment based on the body clock. It may be called cancer chronotherapy”.

The study team included Pruthvi Gowda, KirtiLathoria, Shalini Sharma, Shruti Patrick and Sonia B. Umdor. The study has been accepted for publication in American Society for Microbiology journal `Molecular and Cellular Biology’.

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keywords: National Brain Research Centre, NBRC, molecular mechanism, cancer, circadian rhythm, metabolic, proliferation, protein, tumour, glioma, brain, spinal cord, DNA, chromosomes, cervical, mathematical model

TB has been associated with mankind since the beginning of human civilization. It is caused by a bacterium called Mycobacterium tuberculosis (M.tb). It travels through the air from one human to another human till it finds its happy home in the lungs. Tuberculosis is a curable disease if treated properly and timely. There is a need for a fast and advanced detection system for the diagnosis of tuberculosis disease, like a smoke detector, that could detect fire and blare alarm before the fire could go out of hand. Identification of important virulent proteinsof M.tb is important for TB care and management program. The arsenal of M.tb is equipped with several such proteins which help the bacterium to avoid and weakenthe host immune-responses. A protein called PPE2 is one such.

Earlier studies by the group of researchers had shown that PPE2 protein works by blocking the production of compounds called reactive nitrogen species (RNS) and reactive oxygen species (ROS) which are some of the key elements of the human immune system.

The new study has taken the work forward by getting new insights that suggest that PPE2 could also be playing an important role in regulating the synthesis of Vitamin B₁₂ in the bacterium. Vitamin B₁₂ plays a fundamental role in bacterial metabolism and gene regulation.The human body cannot synthesize Vitamin B₁₂ and depends upon gut microbiota or external food supplements to meet the daily requirement of Vitamin B₁₂. M.tb, on the other hand, has genes for Vitamin B₁₂ synthesis. The true nature of the Vitamin B₁₂ pathway in the bacterium, however, is still a mystery. The new study gives some insight into this.

A striking feature in M.tb physiology is the presence of a regulatory RNA element or riboswitch in a cluster of genes known as an operonin a functioning unit of its DNA. The cluster has three genes – ppe2, cobq, and cobu. While cobq and cobu genes are already known to be part of the Vitamin B₁₂ biosynthesis process, not much is known about PPE2’s role.

The new study has helped unravel the mystery to some extent. In this study, it has been observed that PPE2 could bind to DNA located beforeoperon ppe2–cobq–cobu suggesting thatPPE2 protein might be playing a role in the regulation of the ppe2-cobq1-cobucluster.

Speaking to India Science Wire, the leader of the team, Dr. Sangita Mukhopadhyay stressed that it was only a first step and more research is needed in the form of a detailed understanding of the underlying mechanism. “Vitamin B₁₂ has a fundamental role in bacterial metabolism and gene regulation and if carefully investigated, ppe2-cobq1-cobu cluster and riboswitch together, may present opportunities to translate the basic knowledge of microbial metabolism into effective therapeutic methods”, she added.

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Keywords: Hyderabad, Centre for DNA Fingerprinting and Diagnostics, CDFD, molecular mechanism, bacterium, immune system, Mycobacterium tuberculosis,M.tb, lung, diagnosis, protein, Vitamin B_12, gut, microbiota,RNA, DNA, genes

The Asian elephant is a charismatic species with a long history of coexistence with humans. Yet works on societies of wild elephants based on long-term observations are rare.

To fill this gap, researchers from Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), a Bengaluru-based autonomous Institute of the Department of Science and Technology, Government of India, studied how male Asian elephants associate among themselves. They used six years of field data on 83 animals from Nagarahole and Bandipur National Parks in Karnataka for this study. They identified the individual elephants using features of their ears, tails, and tusks.

An interesting finding of the study is that adult males spent greater proportions of their time solitarily rather than in mixed-sex or in all-male groups. Old (over 30 years) males were sighted more frequently with their age-peers and less frequently with their younger (15–30 years) counterparts than expected at random in all-male groups.

These findings suggest that male associations among the old males were more intended for them to test their strengths against their age-peers than out of camaraderie.

The young males also did not seem to `disproportionately’ initiate associations with old males unlike in African savannah elephants. It seemed that social learning from older individuals was not important for young Asian male elephants for some reason. Another interesting finding was that all-male groups were rarer and smaller than those seen with African savannah elephants.

However, although in general male associations were weak, most males had a significant-top associate, with whom their association was the strongest.

In a paper published in the journal `Frontiers in Ecology and Environment’, the researchers said that differences in male social organization amongst Asian elephants from that of the related African savannah elephant that occupies a similar niche possibly arise from differences in ecology. “Studies on the foraging ecology of male elephants are required in the future to further understand the differences in social organization between species”, they noted.

The study was conducted by P.Keerthipriya, S.Nandini and T.N.C.Vidya of the Evolutionary and Organismal Biology Unit at Jawaharlal Nehru Centre for Advanced Scientific Research.

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keywords: human-elephant conflict, conservation, management, coexistence, Jawaharlal Nehru Centre for Advanced Scientific Research, JNCASR, Bengaluru, Nagarahole, Bandipur, Karnataka, tusk, solitary, African savannah elephants, social learning, ecology, foraging

The lab had earlier found that the serotonin receptors are sensitive to cholesterol surrounding them. In the new study published in Science Advances, they report a sensor region on human serotonin1A receptor that can detect cholesterol. They looked at specific regions called CRAC motifs in the receptor. These are believed to interact with cholesterol. The researchers carefully replaced specific amino acids in the CRAC motifs of the serotonin1A receptor and identified a particular amino acid responsible for the cholesterol-sensitive function of the receptor.

The researchers collaborated with Dr Jana Selent’s group from Pompeu Fabra University Hospital del Mar Medical Research Institute in Barcelona, Spain to visualize the protein-cholesterol interaction via computer-aided molecular dynamics simulations. This helped them predict how the specific amino acid on CRAC motif enables the receptor to sense changes in cholesterol levels by controlling molecular motion in certain regions of the receptor, says CSIR-CCMB statement.

“These findings are important since cholesterol levels change in our cells with age and in many disease conditions.  We believe our work will help in developing better drugs that keep in mind not just the receptor as the drug target, but also the lipid environment in which the receptor is present”, explained Prof Chattopadhyay.

“Our expertise in structural biology at CCMB is key towards a physical understanding of cells and their functions. This not only adds to the detailed view of living cells but also have immense potential in therapeutics development”, said Dr Vinay Nandicoori, Director, CCMB. (India Science Wire)

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Keywords: Molecular, sensor, serotonin, receptor, cholesterol, Cells, receptor proteins, cell membranes, drug target,physiology CSIR-CCMB, drug designing

Presently, colon cancer gets detected at very late stages. There are two techniques to detect it; either CT colonography and colonoscopy or immunohistochemistry. While CT colonography involves low dose radiation, colonoscopy is an invasive process whereas immunohistochemistry can be subjective and sometimes not reproducible.

A new collaborative study involving four institutes in India and one in France, and led by Dr.SagarSengupta at the National Institute of Immunology (NII),has discovered a new way that could identify the disease even at Stage I, the earliest stage.

Dr.Sengupta’s laboratory works on microRNAs, which are small single-stranded non-coding RNA molecules, silence the expression of many proteins. The microRNAs are known to bind to the messenger RNA molecules that code for the proteins and thereby either inactivate or destroy them.

The new study has discovered that six micro RNAs get upregulated in colon cancer cells and that the levels of these were controlled by a master regulator protein, named CDX2. Importantly, the upregulated microRNAs, which were named `DNA damage sensitive microRNA’s or `DDSM’s, were  found to target a group of cellular proteins  which are essential to  maintain the pristine nature of genetic material within each cell of the body. Experiments involving laboratory mice confirmed that the cells have a greater tendency to form cancers if there is over expression of these microRNAs and consequent loss of these genome stabilizers.

The researchers have tested their findings on publicly available datasets in The Cancer Genome Atlas (TCGA) and also in a cohort of colon cancer patients who had come to All India Institute of Medical Sciences (AIIMS), New Delhi for treatment. Analysis was done with the available data of over 410 patients and the biopsy materials of 54 patients from AIIMS, New Delhi.

They found that the DDSMs were upregulated even in Stage I colon cancer tissues. The upregulation persisted upto the final Stage IV colon cancer. More importantly, increased expression of the DDSMs in cancer patients decreased the probability of their survival.

Speaking to India Science Wire, Dr.Sengupta said, “We believe that the identified DDSMs can serve as an invaluable biomarker for colon cancer early detection process. We now have to determine whether the DDSMs can also be detected in patient blood samples. If that is possible, it would make colon cancer detection as simple as the detection of blood sugar in diabetic patients”.

Apart from NII and AIIMS, New Delhi, Regional Centre for Biotechnology, Faridabad, St. John’s Research Hospital, Bengaluru and University of Strasbourg, France contributed to this study. A report on the work has been published in the Journal of Cell Science.

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keywords:CT colonography, colonoscopy, immunohistochemistry, radiation, invasive process, National Institute of Immunology, NII, microRNAs, protein, cellular, experiment, mice,  genome stabilizers, The Cancer Genome Atlas, TCGA, All India Institute of Medical Sciences, AIIMS, biopsy

A new study at the Population Biology Laboratory at Indian Institutes of Science Education and Research (IISER)- Pune promises to help decipher this and several other similar mysteries.

The scientists at IISER,YashrajChavhan, SarthakMalusare, and SutirthDeyconducted their study on E Coli bacteria. They grewsamples of the bacteria with varying population sizes across different environments and then subjected them to whole-genome, whole-population sequencing analysis. They found that samples with a small population size acquired a certain set of mutations which allow them to survive in a certain environment but not in others.

Samples with large populations also developed these mutations. However, they further developed some certain compensatory mutations that together helped them to survive in multiple environments. It was clear that population size determined the kind of mutations available to the bacteria, which in turn, leads to the type of fitness they acquire.

The group studied about 480 generations of E. coli in four types of steady environments consisting of different carbon sources, namely, galactose, thymidine, maltose and sorbitol, and one fluctuating environment in which the carbon source changed unpredictably amongst the four sources.

The study assumes importance as so far it was understood that the ability of a bacteria to develop multi-drug resistance was based on what was termed as `fitness cost’: when bacteria become fit in one environment, they either lose fitness or fail to increase fitness in other environments. The new study has clarified this by showing that when the environment is fluctuating, large populations can bypass this effect.

However, the research work only shows that large population size can help in fluctuating environments. It is not yet clear as to what is the cut-off size. It willvary from one species to another. It would be interesting to figure them out for different kinds of organisms. The scientists have published a paper in the journal `Ecology Letters’.

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Keywords: public health, bacteria, mysteries, E Coli bacteria, population, environment, whole-genome, sequencing, analysis, mutations, survive, generation, carbon sources, galactose, thymidine, maltose, sorbitol, fitness cost, cut-off size.

“The guidelines provide detailed protocols that include pictorials and frequently asked questionsfor an easier understanding of those collecting samples for COVID testing in wildlife”, said Dr. Vinay K Nandicoori, Director, CSIR-CCMB.

LaCONES started testing animal samples for possible SARS-CoV-2 coronavirus infection in August 2020. The scientists found the first positive samples from Asiatic lions in Nehru Zoological Park, Hyderabad in April 2021. During these days, LaCONES team has tried testing for coronavirus using different kinds of nasal, oropharyngeal, rectal and fecal samples from the animals. LaCONES regularly tests wildlife samples using DNA-based molecular biology tools to solve wildlife cases. These tests are very similar to the ones being used for coronavirus testing.

“We hope that our recommendations help the zoo staff in collecting and packing the samples appropriately before they send them out to animal testing centres, will smoothen the process for the zoos as well as testing centres. Given how difficult it is to get samples from animals, it is all the more important that we make most of the samples we get”, said Dr. Karthikeyan Vasudevan, Scientist-in-charge, LaCONES, CSIR-CCMB.

Keywords: LaCONES, CSIR-CCMB, CSIR, COVID-19,Zoo Animals, Captive Animals, Laboratory for the Conservation of Endangered Species, Centre for Cellular and Molecular Biology,Coronavirus Infection, Central Zoo Authority, Ministry of Environment, Forest and Climate Change

This could pave the path towards understanding the probable role of the virus in neurodegenerative pathologies, especially given the fact that the virus has been detected in brain tissue of the patients suffering from neurological disorders such as Alzheimer’s, Parkinson and multiple Sclerosis.

The EBV can cause cancers like nasopharyngeal carcinoma (a type of head and neck cancer), B-cell (a type of white blood cells) cancer, stomach cancer, Burkett’s lymphoma, Hodgkin’s lymphoma, post-transplant lymphoid disorders, and so on. More than 95% of the adult population is positive for EBV. However, the infection is mostly asymptomatic, and very little is known about the factors which trigger the development of such disease. It was the detection of the virus in patients with neurodegenerative diseases that triggered the search for the mechanism of propagation of the virus.

Scientists’ teams from the Departments of Physics (led by Dr. Rajesh Kumar) and Biosciences and Biomedical Engineering (Dr. Hem Chandra Jha) at IIT Indore along with their collaborator, Dr. Fouzia Siraj, at National Institute of Pathology (ICMR), New Delhi, used Raman Spectroscopy System supported by “Fund For Improvement of S&T Infrastructure (FIST)” scheme of Department of Science and Technology to trace the propagation mechanism of the virus. Research scholars Ms. Deeksha Tiwari, Ms. Shweta Jakhmola, and Mr. Devesh Pathak also contributed to this study published recently in the journal ‘ACS Omega’.

The phenomenon of Raman Scattering, first discovered by Indian Nobel laureate (awarded by Bharat Ratna) Sir C. V. Raman, provides information on the structure of any material based on the vibrations produced in them. Similarly, the light falling on the virus generates vibrations in the biomolecules, depending on the make of the virus. Using RS, the light that is scattered by the virus can be captured and analyzed to understand its structure and behaviour. Interestingly, every virus has a different biomolecular composition and thus generates a unique Raman Spectrum that serves as a fingerprint to its identity.

Dr. Jha’s and Dr. Kumar’s team have elucidated the infection pattern of EBV in the brain cells showing that the virus is also capable of infecting the glial cells (astrocytes and microglia) in the brain. This study noticed a differential pattern of infection progression in different glial cells. Dr. Jha said, “We found that the virus may take different time intervals to establish and spread infection in various types of glial cells of the brain.” Apart from the timeline of infection progression, their team also tried to reveal the biomolecules involved at each step of the virus infection and relate it to various neurological manifestations.

Dr. Rajesh added, “Our study showed that molecules like phospho-inositols (PIP), a type of lipid, glycerol, and cholesterol, are predominantly altered during EBV infection in the brain cells.”

The study, based on spatial and temporal changes in Raman signal, was helpful in advancing the application of Raman Scattering as a technique for rapid and non-invasive detection of virus infection in clinical settings. Since all the techniques available for viral load detection in the brain by far include invasive methods, RS can be a sigh of relief for patients undergoing brain biopsies for diagnostic purposes. Furthermore, it can be helpful in determining the stage of infection based on biomolecular markers and thus aid in early diagnosis.

Cryo-EM has revolutionized structural investigations of macromolecules in recent times. It is a testimonial for a revolutionary technology for structural biologists, chemical biologists, and ligand discovery, which has gained a clear edge over contemporary x-ray crystallography. In light of these advancements, cryo-electron microscopy technique was recognized with the Nobel Prize for the high-resolution structure determination of biomolecules in solution (2017). The revolution in resolution resulted in atomic-level understanding of the Zika virus surface proteins, thus aiding structure-based drug discovery, deciphering of structure of hard-to-crystallize membrane proteins and other macromolecular complexes.

The National Facilities supported by the Science & Engineering Research Board (SERB), an institution under the Department of Science & Technology (DST), would help explore Macromolecular Structures and Complexes” and create research knowledge base and skills for cryo-EM research in India to establish leadership in structural biology, enzymology, ligand/drug discovery.

The establishment of these facilities in all directions of the country–Indian Institute of Technology, Chennai; Indian Institute of Technology, Bombay; Indian Institute of Technology, Kanpur; and Bose Institute, Kolkata would help in scaling up cryo-EM based structural biology research in different corners across the country. These centers are designated as SERB National Facility for Cryo-Electron Microscopy and will work on the identified thrust areas. They will be accessible to all researchers.

Housed with 200kV machines have added advantages like lesser maintenance and can help generate human resources through training, which can also help sustain the facility for longer duration. Each Cryo-EM facility costs about Rs. 28.5 crore for a period of five years and an amount of Rs. 114 crores for research in the critically important research areas.

While IIT Chennai will focus on nano-biointerfaces (e.g. materials–microbes, materials–human tissue), IIT Bombay will execute research on ribosome translation and its implication in disease and antibiotic resistance, neurodegenerative disorders and tackle problems to address solutions to cancer, membrane structure, composition, dynamics & transport. IIT Kanpur will conduct research focused on macromolecular structures and drug discovery with a specific focus on membrane proteins, and Bose Institute, Kolkata will focus on transforming the structure-guided drug discovery and therapeutics research for communicable and non-communicable diseases, allosteric drugs, transcription, and epigenetics.

The first national cryo-EM facility was established at National Centre for Biological Sciences (NCBS) in 2017 and then subsequently in IISc, Bangaluru, and RCB Faridabad. However, it was felt that the existing cryo-EM research facilities in the country are not adequate to leave a mark at the global stage. Historically, Indian scientists have contributed significantly in the area of Prof. GN Ramachandran and Dr. G. Kartha made a remarkable contribution to structural biology, biological, chemical, physical, computational, and theoretical crystallography and materials crystallography. Given significant advances in cryo-EM of large structures, SERB has taken the responsibility that concerted funding should be provided to establish leadership in this area to enable and empower Indian researchers to lead from the front.

The experimentation with these animals needs people with multiple expertise and specialised animal biosafety level 3 laboratories (ABSL3). Realising the importance of these requirements for developing antiviral and vaccine candidates for SARC-COV-2, scientists at the Institute of Life Sciences, Bhubaneswar (an autonomous research institute of Department of Biotechnology, Govt. of India) have established these animal models and a ABSL3 laboratory. This platform at ILS has been established with the support from Biotechnology Industry Research Assistance Council (BIRAC) under Mission COVID Suraksha.

The COVID-19 research team of this institute has recently established and characterised hamster models of SARS-CoV-2 infection by using a local virus isolate cultured and characterised at ILS. The proteomic studies carried out at ILS shows the similarities between SARS-CoV-2 infection in humans and hamsters.This along with analysis of clinical parameters it has been observed that tissue samples show the pathophysiological manifestation of SARS‐CoV‐2 infection similarto that reported earlier in COVID‐19 patients. This provided strong molecular evidence that supports the clinical relevance of this model in COVID-19 research. The findings of this study have recently been published in a prestigious journal, FASEB (Federation of American Societies for Experimental Biology) Journal. ‘The current and perspective users of the ILS platform include NIRRH, Mumbai, IIT Indore, NCBS-InStem, Bangalore; NCL, Pune, CIAB, Mohali etc”