Monday, 2 December 2019

A New Paradigm For Better Drug Discovery Targeting GPCRs

IIT Kanpur based new study suggests beta-arrestins can adopt different shapes when they bind to GPCRs and thereby, mediate distinct downstream functions in cellular and physiological contexts.

Dr. Arun Shukla with research team member at IIT-Kanpur
Researchers from the Indian Institute of Technology- Kanpur have found structural differences between Beta-arrestin Isoforms 1 and 2 upon their interaction with receptors. Beta-arrestin is a cellular protein that acts as universal regulator of GPCRs and this finding may help in designing novel therapeutic targets. 

G-Protein Coupled Receptors (GPCRs), a class of membrane proteins, are the largest clinically relevant family of receptors. They are involved in most of the physiological processes including brain function, regulation of blood pressure, body’s defense mechanism against pathogens, and feeding behavior. Therefore, they are among the most sought after receptors for designing drug targets. 

Beta-arrestin belongs to a small family of arrestin proteins which are important for regulating signal transduction at G-protein-coupled receptors. The two isoforms of beta-arrestins are highly similar in their overall structure and sequence composition, and therefore, they were generally believed to have redundant function. Interestingly, they often facilitate different functions related to GPCR signaling and regulation. However, mechanical basis for such functional differences is not known. 

“We discover that these two different beta-arrestins can adopt different shapes when they bind to GPCRs and thereby, mediate distinct downstream functions in cellular and physiological context,” said Dr. Arun Shukla. “Therefore, these findings may have direct implications for understanding the regulation of GPCRs to design novel therapeutic targets,” he added. 

The results of the study have been published in the journal “Cell Reports”. 

Study suggests nearly half of the medicines that doctors prescribe work by targeting one of the GPCRs in our body. Therefore, it is very important to understand how these receptors work, and how can we leverage this information to design better medicines. 

“Our study integrates a previously missing framework in the paradigm of GPCR targeted therapeutics. As beta-arrestins are sometimes linked with the undesired side-effects of currently prescribed medicines, one can imagine a scenario where our study can provide a handle to minimize the side-effects of GPCR targeted medication,” said the study leader Dr. Shukla. 

This is a multi-institutional collaborative project involving five different laboratories across the globe. Besides Arun Shukla, the research team included Eshan Ghosh, Hemlata Dwivedi, Mithu Baidya, Ashish Srivastava, Punita Kumari, Tomek Stepniewski, Hee Ryung Kim, Mi-Hye Lee, J.V. Gaste, Madhu Chaturvedi, Debarati Roy, Shubhi Pandey, Jagannath Maharana, R. G. Gonzalez, L. M. Luttrell, K. Y. Chung, Somnath Dutta, Jana Selent. 

The study was supported by the Wellcome Trust/DBT India Alliance, Science and Engineering Research Board (SERB), Department of Biotechnology (DBT), and the Indian Institute of Technology, Kanpur. (SciSoup) 

Journal Reference:

Thursday, 19 September 2019

Study Paves The Way For New Approach To Boost Rice Yield

Scientists at the National Institute of Plant Genome Research (NIPGR) have identified a gene that is involved in regulating the size of rice grain.

BY Sunderarajan Padmanabhan Published in India Science Wire

Dr. Jitendra K. Thakur and his research team at NIPGR, New Delhi
Rice productivity in India is low compared to other countries like China and Japan though it has the largest area under rice cultivation. Now scientists at the National Institute of Plant Genome Research (NIPGR) here have identified a gene that is involved in regulating the size of rice grain.

The new development represents a new approach towards developing rice varieties that produce bigger and consequently heavier grains.

The researchers had found in earlier studies that expression of a particular gene, OsMed15a, was higher at different stages of seed development. The observation led them to explore its role further. They scanned 509 different rice genotypes and found that the nucleotide sequences of the OsMed15a gene varied depending on size of grain. OsMed15a was also found to play major role in regulating the expression of three other genes - GW2, GW5 and DR11I- which determine grain size and weight.

“When we suppressed the expression of OsMed15a in transgenic plants using RNAi technology, the seeds became smaller and wider,” explained Dr. Jitendra K. Thakur, lead researcher, while speaking to India Science Wire. For further work, the group is collaborating with Ranchi-based Indian Institute of Agriculture Biotechnology so that grain size could be increased substantially through standard breeding methods.

“This study is important as it establishes OsMed15a as a connecting link between some of the different genes important for grain size/ weight trait in rice. In the next phase, using high throughput ‘omics’ tools, we would be delineating complete network of genes and proteins being connected through OsMed51a,” Dr. Thakur said.

He also noted that the size and shape ofrice grain is not only important for boosting yield but also contribute to the market value of rice. “Indians prefer long and slender rice grains. There are some small grain rice which are full of pleasant aroma. We are trying to introgress long grain allele of OsMed15a in these varieties so that the seeds become longer. We hope that in this way we would be able to produce location-specific long grain aromatic rice”, he added.

The research team included Dr. Swarup K. Parida, Nidhi Dwivedi, Sourobh Maji, Mohd Waseem, Pallabi Thakur and Vinay Kumar. The study results will be published in journal BBA - Gene Regulatory Mechanisms. This work was supported by grants from Science and Engineering Research Board (SERB) and Department of Biotechnology (DBT).

Tuesday, 17 September 2019

IISc Study Sheds Light On How A Midbrain Region Helps Us Pay Attention

Researchers at the Indian Institute of Science (IISc) have identified how a key midbrain region plays a vital role in attention in humans, using advanced imaging and modelling techniques.


(Devarajan Sridharan and Varsha Sreenivasan)

The human brain is regularly bombarded with information. It is through attention that it makes decisions efficiently: it processes relevant information and tunes out distractions. Understanding how attention works in the brain and how it controls behaviour can help scientists understand disorders such as Attention-Deficit Hyperactivity Disorder (ADHD), according to Devarajan Sridharan, Assistant Professor at IISc’s Centre for Neuroscience and his PhD student Varsha Sreenivasan, who recently published their findings in the  journal Proceedings of the National Academy of Sciences.

Attention is widely associated with the outermost layer of the brain tissue called the cerebral cortex, which is also linked to awareness, thoughts, memory, language, and consciousness. It is only recently that scientists began linking a midbrain region called the Superior Colliculus (SC) with attention.

“SC is an evolutionarily conserved midbrain structure that can be found in all vertebrates, including fish, lizards, birds and mammals. It is usually studied for its role in controlling eye movements,” explains Sreenivasan.

To demonstrate its role in attention, scientists had in recent years studied behaviour in monkeys during attention-demanding tasks. They observed that the monkeys were attentive when the SC was stimulated and distracted when this part of the brain was silenced.

But scientists were not sure how exactly SC promotes attention in humans: was it focusing on the target visual stimulus over several others for decisions (increased choice bias) or was it enhancing the visual clarity of the target stimulus (increased visual sensitivity)? Bias- or sensitivity-mediated attention plays out in situations that require rapid and selective decision making, for instance, at a traffic signal.

Consider this example: you are driving on a foggy morning and you stop at a signal. The signal appears green, but you are unsure. As you are in a hurry, your brain decides that it is green and you drive away. In this case, your choice bias towards the green signal is guiding your decision. In an alternate scenario, you see that the fog is lifting gently. You detect a flicker of the green light and you drive away. Here, your visual sensitivity towards the green signal increases, which then helps your decision-making process. While a few recent studies have made the case for SC’s role in controlling choice bias, others have leaned towards visual sensitivity.

To address this debate, in the current study, Sreenivasan and Sridharan conducted two sets of experiments in human participants, using non-invasive techniques. In one, they conducted a behaviour test on 22 participants, where they tracked changes in bias and sensitivity during attention-demanding tasks. In the second experiment, they studied the anatomy of SC in 82 participants, including the 22 tested earlier. Using an imaging technique called diffusion Magnetic Resonance Imaging (dMRI), and a 3D modelling technique called tractography, they tracked white matter fibres in the brain connecting the SC with other regions, including the cortex.

When they compared the results of the two experiments, they found that SC strongly connects with a part of the cerebral cortex called the parietal cortex, which has previously been associated with attention. They also show that the strength of SC-cortex connectivity can predict individuals’ bias, but not sensitivity.

“We also show that choice bias is stronger, on average, towards the right side of our visual field. Interestingly, SC connections in the cortex also mirror this asymmetry for bias, which further underscores the relationship between SC and bias,” explains Sridharan.

In the future, the team plans to study the activity of SC using a different imaging technique called functional MRI (fMRI) that can identify increased blood oxygen levels in areas of the brain that are activated during tasks. Sreenivasan adds, “Through fMRI, we will investigate if SC’s activity correlates with behavioural measures of sensitivity and bias. Our approach can also help understand if SC-cortex connection asymmetries are predictive of certain kinds of attention disorders such as ADHD.”

Journal Reference:
Subcortical connectivity correlates selectively with attention’s effects on spatial choice bias


Friday, 19 July 2019

Indian Scientists Develop Database Of Everyday Chemicals Harmful To Human Health

The chemical substances have been classified in seven broad categories - consumer products, agriculture and farming, industry, medicine and healthcare, pollutants, natural sources and intermediates - and 48 sub-categories.

The research team at IMSc, Chennai
In our daily lives, we get exposed to dozens of chemicals either through products we use or consume as well as through exposure to the environment. Such chemicals are present in consumer products, pesticides and insecticides, cosmetics, drugs, electric fittings, plastic products, electric and electronic devices and so on. Many of them contain substances harmful to human health and have been subjected to research over the years.

Now, Indian scientists have developed a comprehensive database of such chemicals belonging to a particular category known as endocrine disrupting chemicals or EDCs. These chemicals can interfere with hormones in human body, causing adverse health effects related to development, growth, metabolism, reproduction, immunity, and behaviour. The World Health Organisation (WHO) considers them as ‘chemicals of emerging concern.’ EDCs are only a subset of toxic chemicals in our environment that affect the hormonal system.

The database is not a simple listing of chemicals but a comprehensive catalogue of research studies that focused on impact of these chemicals on health. These studies have been done in rodents and humans. The database has been developed by an inter-disciplinary team of researchers at the Chennai-based Institute of Mathematical Sciences (IMSc).

Over 16000 scientific studies about EDCs and evidence of their ability for endocrine disruption were mined. Based on this, 686 potential hormone-disrupting chemicals have been identified with evidence of causing hormonal changes in 1796 research articles specific to humans or rodents. 

The first version of 
Database of Endocrine Disrupting Chemicals and their Toxicity profiles’ (DEDuCT) has been published and it is freely accessible.

The chemical substances have been classified in seven broad categories - consumer products, agriculture and farming, industry, medicine and healthcare, pollutants, natural sources and intermediates - and 48 sub-categories. Almost half of the chemicals listed in the database fall in the ‘consumer products’ category. Of 686 potentially harmful chemicals identified in the database, only 10 are in the Safer Chemicals Ingredients List (SCIL) of the US Environment Protection Agency.

All detailed information such as which EDC causes endocrine disruption, at what dose and if the study has been in animals or humans, is available in a searchable mode. The dose information is critical since some of these chemicals can result in adverse impacts even at very low doses, while in some case it may not be so. One can also get chemical structure, physico-chemcial properties and molecular descriptors of the chemicals.

“We identified EDCs based on published experimental evidence about their ability to cause endocrine disruption, and compiled observed adverse effects along with dosage information. Adverse effects have been classified further into seven systems-level changes. This information will facilitate toxicology research towards understanding the mechanism of endocrine disruption by these chemicals,” explained Areejit Samal, scientist who led the research team in the computational biology group at IMSc, while speaking to India Science Wire.

The information will be useful to regulatory agencies, health authorities and industry. In addition, it can be used for developing machine learning-based predictive tools for EDCs. The database is more comprehensive than other available resources on EDCs and contains extensive information on dose which other databases do not have, researchers said.

Besides toxicology experts and other scientists, the database can also be useful for general public. “This resource can help raise awareness against indiscriminate use of EDCs in daily life. People can browse these chemicals by environmental source in our user-friendly database or can search if chemicals in products they use are EDCs based on our compilation,” added Samal.

The IMSc group has earlier developed an online database of phytochemicals present in Indian herbs that can potentially be developed into drugs.

The research team included Bagavathy Shanmugam Karthikeyan, Janani Ravichandran, Karthikeyan Mohanraj, R.P. Vivek-Ananth, Areejit Samal. A report on the database is to be published in scientific journal Science of the Total Environment.

Monday, 8 July 2019

Indian Scientists Develop 'Black Gold' - A Wonder Material

Scientists at the Mumbai-based Tata Institute of Fundamental Research (TIFR) used gold nanoparticles and by rearranging size and gaps between them developed a new material which has unique properties such as capacity to absorb light and carbon dioxide. 

Prof. Vivek Polshettiwar with research team at TIFR, Mumbai
Indians are fascinated with gold, making India one of the largest consumers of the yellow metal globally. Now Indian scientists have tinkered with the chemistry of the material and turned it into ‘black gold’ which they say can be potentially used for applications ranging from solar energy harvesting to desalinating seawater.

Scientists at the Mumbai-based Tata Institute of Fundamental Research (TIFR) used gold nanoparticles and by rearranging size and gaps between them developed a new material which has unique properties such as capacity to absorb light and carbon dioxide. Gold does not have these properties, therefore ‘black gold’ is being called a new material. In appearance it is black, hence the name ‘black gold.’

The findings have been announced in Chemical Science, a scientific journal published by the Royal Society of Chemistry.

“We have not doped gold nanoparticles with any other material or added other materials. We varied inter-particle distance between gold nanoparticles using a cycle-by-cycle growth approach by optimizing the nucleation-growth step, using dendritic fibrous nanosilica, whose fibers were used as the deposition site for gold nanoparticles,” explained Vivek Polshettiwar, who led the research team, while speaking to India Science Wire.

One of the most fascinating properties of the new material is its ability to absorb the entire visible and near-infrared region of solar light. It does so because of inter-particle plasmonic coupling as well as heterogeneity in nanoparticle size. Black gold could also act as a catalyst and could convert carbon dioxide into methane at atmospheric pressure and temperature using solar energy.

“If we develop an artificial tree with leaves made out of back gold, it can perform artificial photosynthesis, capturing carbon dioxide and converting it into fuel and other useful chemicals,” added Prof Polshettiwar. The efficiency of conversion of carbon dioxide into fuel, at present, is low but researchers believe it could be improved in future.

In order to study solar energy harvesting ability of the new material, researchers dispersed it into water and exposed the solution to light for one hour and the temperature of the solution was measured. The temperature of the solution with pure silica spheres rose to 38 degrees while the ones with different concentrations of black gold rose to 67 to 88 degrees. The maximum increase in temperature was attributed creation of thermal hotspots due to the heterogeneity of the particle sizes as well as optimum inter- particle coupling.

Researchers said the material can be used as a nano-heater to covert seawater into potable water with good efficiency. “Our results indicate the potential application of black gold in purification of seawater to potable water via steam generation using solar energy under atmospheric reaction conditions,” according to the researchers.

Kabeer Jasuja (Indian Institute of Technology – Gandhinagar), who is not connected with the study, commented that "It is amazing to see these elegantly designed assemblies of gold nanoparticles could function as artificial leaves and capture the solar energy. This study is a significant step in current efforts towards reducing carbon footprint. It would be promising to see how the synthesis of these colloidosomes can be scaled up in the future."

The research team included Mahak Dhiman, Ayan Maity, Anirban Das, Rajesh Belgamwar, Bhagyashree Chalke and Vivek Polshettiwar (TIFT); Yeonhee Lee, Kyunjong Sim and Jwa-Min Nam (Seoul National University). The study was funded by the Department of Science and Technology (DST) and the Department of Atomic Energy (DAE).

Tuesday, 21 May 2019

Hydrogen Generation At Room Temperature Using Visible Light: Study

The study may provide an alternative approach to use hydrogen as a source of clean energy. 

By Ratneshwar Thakur

Organometallics & Sustainable Catalysis Lab @ IISER Tirupati  

In an effort to produce clean energy from hydrogen gas, researchers have designed a new catalytic system that operates under room temperature environment. Since hydrogen produces water as the sole by-product upon combustion, this study may provide an alternative approach to use hydrogen as a source of clean energy. 

Researchers from Indian Institute of Science Education and Research Tirupati (IISER-Tirupati) and CSIR-National Chemical Laboratory (CSIR-NCL, Pune) have reported a visible-light mediated dual catalytic system to produce hydrogen and value-added chemicals at room temperature environment from widespread amines in water. 

In the study, a dual catalytic system combining photo-redox and proton reduction catalysts has been used. Researchers explained that the staring material (amine) was taken in a vial along with the catalysts in degassed Milli-Q water under an argon atmosphere. The reaction mixture was irradiated under visible-light, using 36 W blue LED light bulb strips, at room temperature to get desired dehydrogenated product with the concomitant generation of molecular hydrogen. 

“The removal of dihydrogen atoms from adjacent atomic centres of organic molecules is a thermodynamically uphill process. However, this challenge was successfully addressed by designing a dual catalytic system by merging visible-light photoredox catalysis with proton reduction catalysis,” says Dr. Ekambaram Balaraman, Scientist and corresponding author of this study. 

“In this country, energy and sustainability are among the biggest challenge humanity faces. We believe that our strategy might have significant impact on energy storage, clean environment, and sustainable chemical synthesis,” he added. 

The research team included Manoj K. Sahoo and E. Balaraman, and the study was published in journal Green Chemistry. The research work was funded through Science and Engineering Research Board, and IISER-Tirupati.

Room temperature catalytic dehydrogenation of cyclic amines with the liberation of H2 using water as a solvent

Saturday, 4 May 2019

“Gut feelings” Of Worms Might Help In Understanding Sickness Behavior In Humans

Understanding of the message from the gut to the nervous system may provide broad insights into the modulation of behaviors such as appetite and anxiety that are also linked with the sickness behavior syndrome.

Jogender Singh (Left) and Alejandro Aballay 

Humans are not the only ones who hate germs, even the tiny worms try to run away once they recognize harmful microbes. While it could be the psychological issues for humans but running away from pathogenic bacteria is a matter of life and death for tiny worms like Caenorhabditis elegans. Therefore to improve the chances of survival, organisms need to recognize potential pathogens and defend themselves.

Now researchers Dr. Jogender Singh and Prof. Alejandro Aballay from Oregon Health and Science University, USA have shown that in worms bloating of the gut caused by pathogen infection helps both in recognition of pathogenic bacteria and activation of defense mechanisms. The results of this study were published in the journal Development Cell.

Scientists have known that worms like Caenorhabditis elegans use bacteria that are non-pathogenic or beneficial, as its food source, but also encounter pathogenic bacteria. After feeding on pathogenic bacteria for a few hours, the animals learn to avoid the pathogen. 

“We asked why the animals require a few hours to learn that what they are eating is harmful. Surprisingly, our initial results suggested that gut bloating caused by infection led to the pathogen avoidance behavior. However, it was difficult to understand how gut bloating was affecting behavior—a response that is normally controlled by brain or the nervous system,” says Dr. Jogender Singh, co-author in this study.

To understand this puzzle, researchers monitored changes in the nervous system as the gut of animals bloated. “It all made sense when we found that bloating of the gut was sending signals to the nervous system”, said Dr. Singh. 

According to the study bloating of the gut happens on pathogenic, but not on non-pathogenic bacteria, these defense mechanisms are induced only upon feeding on pathogenic bacteria. Therefore the state of the gut (happy vs unhappy) could modulate defense mechanisms and induce behavioral changes. 

It is known that pathogen infections in humans lead to behavioral changes called sickness behavior syndrome that includes symptoms such as lethargy, depression, anxiety, loss of appetite and sleepiness. However, it is not understood how pathogen infection evokes the sickness behavior syndrome. 

In an organism, message from different tissues are received and read by different receptors in the nervous system. Interestingly, similar forms of the receptor, that receives message from bloating of gut in worms, are also found in humans and other animals. These receptors are involved in the control of a diverse set of behavioral processes, including appetite, biological clock, and anxiety. 

Prof. Alejandro Aballay says, “Understanding of the message from the gut to the nervous system may provide broad insights into the modulation of behaviors such as appetite and anxiety that are also linked with the sickness behavior syndrome.” 

The study was supported by grants from the National Institutes of Health, USA.

Journal Reference:
Microbial Colonization Activates an Immune Fight-and-Flight Response via Neuroendocrine Signaling

Acknowledgement: Special thanks to Dr. Rajesh Gunage (Stem Cell Biologist and Post doctoral Fellow at Children’s Hospital-Harvard Medical School, Boston, USA) for stimulating suggestions to make this report digestible for non scientific people.

Scientists Present Novel Therapeutic Possibility For Inflammatory Disorders

Study provides a new framework to further improve the on-going clinical programs to modulate the human complement system with direct therapeutic implications in a wide range of inflammatory disorders including rheumatoid arthritis and sepsis.

Prof. Arun K. Shukla (right) and Shubhi Pandey at IIT kanpur

Our body has two types of immune system namely- the innate immune system and adaptive immune system. While adaptive immune system continues to evolve throughout our lives, contrary to this- the innate immunity is already encoded in the system at birth. 

A central component of the innate immunity is known as the complement system- a pool of several circulating inactive complement proteins in the blood whose receptors are presents in the cell membrane. When a pathogen attacks our system, the complement protein become active and engages with the membrane receptors for the further actions to clear the pathogens from our body. 

Of these, complement protein C5a works by activating two different membrane receptors, C5aR1 and C5aR2. The interaction of C5a with C5aR1 and their downstream signalling are critical in many inflammatory disorders such as sepsis, inflammatory bowel syndrome, rheumatoid arthritis and psoriasis. Therefore, a better understanding of C5a-C5aR1 interaction, and novel approaches to modulate this important signalling system has tremendous therapeutic potential.

Now in a collaborative study, research team led by Prof. Arun K. Shukla at the Indian Institute of Technology in Kanpur (India), and the laboratory of Prof. Trent Woodruff at the University of Queensland (Australia) have identified that a synthetic peptide C5apep derived from, and modified based on, C5a sequence- may provide an alternative therapeutic candidate compared to currently used ligands. The study is published in the Journal of Biological Chemistry.

“This is the first example where a designer protein is utilized to fine-tune the key cellular processes in the human complement system which is absolutely critical for body’s immune response. Our study provides a new framework to further improve the on-going clinical programs to modulate the human complement system with direct therapeutic implications in a wide range of inflammatory disorders including rheumatoid arthritis and sepsis,” said Prof. Arun K. Shukla.

The receptors C5aR1 and C5aR2 belong to a large family of cell surface proteins known as G protein-coupled receptors (GPCRs) and they are present on immune cells like macrophages and neutrophils. Most of the currently prescribed medicines act on GPCRs and work by turning them “on” or “off” i.e. by activating or blocking their downstream responses. 

According to the study, activation of C5aR1 receptor by C5a triggers robust mobilization of immune cells like neutrophils which may result into severe hyper-inflammation, and subsequently, inflammatory disorders. Thus molecules which can block the interaction of C5a with C5aR1 and downstream signal transduction are proposed to be promising therapeutic candidates to combat inflammatory diseases.

However, recent studies have shown that activation of C5aR1 by C5a may also result in inhibition of cytokine called interleukin-6 (IL-6) which is desirable to overcome inflammatory symptoms. Therefore, conventional C5aR1 antagonists may not be the optimal therapeutic candidates as they will also compromise C5a-induced inhibition of IL-6.

This problem was addressed by designing ligand C5apep which maintains the desirable properties of C5a i.e. inhibition of IL-6 but it has significantly lower capacity to trigger neutrophil migration compared to C5a. “C5apep can be a superior choice over conventional C5aR1 antagonists. Such ligands are known as “biased ligands” because they preferentially activate one functional outcome over the other, and this conceptual emerging framework has refined the landscape of novel drug discovery targeting GPCRs,” said Shubhi Pandey, the lead author in this study.

Prof. Shukla says, “Our study uncovers the first instance of a functionally biased ligand in the complement system that has the inherent potential to improve the therapeutic design in inflammatory diseases. We plan to carry out animal studies in future to measure the therapeutic potential of this novel ligand and also understand the molecular details of its interaction with the receptor at high resolution using structural studies.” 

The research team included Shubhi Pandey, Xaria X. Li, Ashish Srivastava, Mithu Baidya, Punita Kumari, Hemlata Dwivedi, Madhu Chaturvedi, Eshan Ghosh, Trent M. Woodruff and Arun K. Shukla. The study was supported by the LADY TATA Memorial Trust, SERB (DST) and the Wellcome Trust DBT India Alliance. (SCISOUP: A Science And Technology Blog)

Journal Reference:

Wednesday, 17 April 2019

New Technology May Help Engineer Natural Proteins In Human Body

The linchpin detaches within physiological conditions and provides unique reactivity for the installation of a probe of interest.

(Research team at Indian Institute of Science Education and Research- Bhopal)

Any machine is an assembly of multiple well-designed and organized components. Their smooth handling requires an understanding of the architecture and toolbox to tune the functions. Likewise, proteins are one of the most important components of the human body or bio-machines.  If we can learn how to engineer proteins with high precision, it could provide a tremendous boost to precision therapeutics.

Now Dr. Vishal Rai’s team at Indian Institute of Science Education and Research Bhopal- provides the first modular platform for precision engineering of native proteins. The study was published in the Journal of the American Chemical Society.

“Initially, our reagent delivers a reversible intermolecular reaction that places the “chemical linchpins” globally on all the accessible Lys amino acid residues. These linchpins can drive precise covalent labelling of proteins. The linchpin detaches within physiological conditions and provides unique reactivity for the installation of a probe of interest,” said Dr. Vishal Rai.

“The technology would provide researchers to install a reporter in a protein for a better understanding of the biological systems. Also, it will help in the development of next-generation protein-based drugs,” he added.

Researchers say this methodology could label even a single protein in a mixture of proteins without altering their structures. The team could successfully label myoglobin, cytochrome C, aldolase, and lysozyme C without changing their enzymatic activity. Interestingly, labelling of insulin did not alter cellular uptake and its downstream signalling process.

This study is promising and linchpin directed modification (LDM) may provide a route for the conjugation of a fluorophore and drug to the antibody for targeted treatments. The study will have a long-term implication on protein-based therapeutics as it enables the regulation of their design.

Besides Vishal Rai research team included Srinivasa Rao Adusumalli, Dattatraya Gautam Rawale, Usha Singh, Prabhanshu Tripathi, Rajesh Paul, Neetu Kalra, Ram Kumar Mishra, Sanjeev Shukla. This interdisciplinary study was supported by the Science and Engineering Research Board (SERB).

Journal Reference:

Monday, 8 April 2019

Scientists Present New Regulatory Clues To Mammalian Cell Division

Hook2 is behaving like linker protein—that binds to dynein and dynactin and regulates the function of dynein during cell division.

(Right To Left) Dr. Mahak Sharma and her lab member.
Indian researchers have revealed regulatory role of a protein in the process of cell cycle progression and separation of newly formed mammalian cells. This study may help understanding uncontrolled cell division related cues because many regulatory proteins of the cell cycle, such as the one that reported in this study, are mutated in cancer cells.

Scientists have known that dynein, a molecular machine- that generates force to move cellular cargo from one location to another, plays a crucial role during the cell division especially in dissolving or breaking nuclear envelope and separation of the chromosomes into two daughter cells. However, how dynein simultaneously performs multiple functions at multiple places largely remains an active area of study.

Dr. Sivaram and Amrita RCB Faridabad
Now in a collaborative study, published in the Journal of Cell Biology, research team of Dr. Mahak Sharma at Indian Institute of Science Education and Research (IISER, Mohali) and Dr. Sivaram V. S. Mylavarapu at Regional Centre for Biotechnology (RCB, Faridabad) - have uncovered the role of dynein binding partner and member of Hook family of protein, Hook2 in regulating specific dynein localization and thereby the tasks associated with these subcellular locations.

“We have been exploring the role of a recently characterized family of proteins known as the “Hook proteins” that bind to dynein and regulate its location and cellular function. Our gene silencing experiments revealed improper cell division upon loss of a Hook family member, and we started to pursue its role in dynein activation and mitosis,” said Dr. Mahak Sharma, Scientist at IISER, Mohali and study leader in this study.

During the separation process of newly formed cells, communication and the material transfer happen by transport of cellular cargo. “The transport itself is executed by the molecular machines or motors that generate force to move cargo on the cellular highways or as scientifically called “microtubule tracks,” explained Devashish Dwivedi, the first-author of the study.

In this study, microscopic imaging of cultured human cells were performed to determine the defects in cell division process when cells were depleted of the dynein or its newly identified regulator. “We observed that Hook2 is behaving like linker protein—that binds to dynein and dynactin and regulates the function of dynein during cell division,” said Dwivedi.

“Earlier studies have reported chromosomal translocations in the Hook protein in various cancer cells. Since unregulated cell division is a hallmark of all cancer cells, our findings might provide a partial explanation of why such changes in Hook2 gene locus might be a contributing factor in governing cancer progression,” added Dr. Sharma.
Besides Sharma M., Dwivedi D, Rathi S from IISER-Mohali, research team included Kumari A and Mylavarapu SVS -from RCB, Faridabad. The study was supported by Wellcome Trust/Department of Biotechnology India Alliance, and Science and Engineering Research Board (SERB), Govt. of India. (SCISOUP)

Monday, 4 February 2019

New Method Can Produce Designer Hydrogels

A new technique that promises to produce hydrogels that could be used for a variety of applications like cleaning of industrial wastewater.

BY Sunderarajan Padmanabhan & Ratneshwar Thakur Published in India Science Wire 

(Prof. Tapas Maji at his lab in JNCASR)

A team of scientists at the Bengaluru-based Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR) have developed a new technique that promises to produce hydrogels that could be used for a variety of applications like cleaning of industrial wastewater.

The method involves self-assembly of tiny cubes of metal-organic compounds into hydrogels with the help of molecular binders. The make-up of the resulting hydrogel depends on the size, shape and geometry of the molecular binder.

For instance, when researchers used cationic ammonia-based molecular binder, the resulting hydrogel had a nano-tubular shape with negative charge on its surface. It can be used as a gel-chromatography separator to separate cationic species from their anionic counterparts from any material.

This hydrogel can bind different types of metal ions including toxic heavy metal ions.The researchers have tried it out with waste water samples containing dyes. When they passed the samples through a column of the hydrogel, the dye with positive charged got attached to the surface and cleaner water flowed out.

“The hydrogel is responsive to changes with the acid and base content of the water. Addition of acid breaks the gel. It again reconstructs upon addition of alkaline solutions. This means the hydrogel can be reused multiple times by just changing the acid level. This could bring down the cost of wastewater treatment substantially. Further, the separation was found to be much faster than the conventional methods,” explained Prof. Tapas Maji, leader of the research team, while speaking to India Science Wire.

The second hydrogel was developed with a binder based on an organic chromophore, tetraphenylethene. It turned out to be highly photo-responsive. “The cyan colour emitting hydrogel can be used in writing. It will be visible only in ultraviolet light. It could have immense application for agencies dealing with highly sensitive documents,” Dr. Maji added.

Further, the group has developed a tri-component white light emitting hydrogel based on two different molecular binders. It can find potential application as white light-emitting substance.

Apart from Maji, his colleagues Papri Sutar, Venkata M. Suresh, Kolleboyina Jayaramulu and Arpan Hazra were involved in the work. The research results have been published in journal Nature Communication.The project was partly funded by Science and Engineering Research Board.

Journal Reference:
Binder driven self-assembly of metal-organic cubes towards functional hydrogels

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