20^th April 2022

– Rohith KMS

In collaboration with the Indian Space Research Organisation (ISRO), a team of researchers from the Indian Institute of Science (IISc) has developed a sustainable method for making bricks out of Martian soil, using bacteria and urea. These “space bricks” can be used to construct building-like structures on Mars that could facilitate human settlement on the red planet.

Photo: Nitin Gupta, PhD student, Department of Mechanical Engineering, IISc

The method for making these space bricks has been outlined in a study published in PLOS One. A slurry is first created by mixing Martian soil (simulant) with guar gum, a bacterium called Sporosarcina pasteurii, urea and nickel chloride (NiCl₂). This slurry can be poured into moulds of any desired shape, and over a few days the bacteria convert the urea into crystals of calcium carbonate. These crystals, along with biopolymers secreted by the microbes, act as cement holding the soil particles together.

An advantage of this method is the reduced porosity of the bricks, which has been a problem with other methods used to consolidate Martian soil into bricks. “The bacteria seep deep into the pore spaces, using their own proteins to bind the particles together, decreasing porosity and leading to stronger bricks,” says Aloke Kumar, Associate Professor in the Department of Mechanical Engineering at IISc, one of the senior authors of the paper.

The research group had previously worked on making bricks out of lunar soil (simulant), using a similar method. However, the previous method could only produce cylindrical bricks, while the current slurry-casting method can also produce bricks of complex shapes. The slurry-casting method was developed with the help of Koushik Viswanathan, Assistant Professor in the Department of Mechanical Engineering, IISc, whose lab works on advanced manufacturing processes. In addition, extending the method to Martian soil proved challenging. “Martian soil contains a lot of iron, which causes toxicity to organisms. In the beginning, our bacteria did not grow at all. Adding nickel chloride was the key step in making the soil hospitable to the bacteria,” explains Kumar.

The group plans to investigate the effect of Mars’ atmosphere and low gravity on the strength of the space bricks. The Martian atmosphere is 100 times thinner than Earth’s atmosphere, and contains over 95% carbon dioxide, which may significantly affect bacterial growth. The researchers have constructed a device called MARS (Martian AtmospheRe Simulator), which consists of a chamber that reproduces the atmospheric conditions found on Mars in the lab.

The team has also developed a lab-on-a-chip device that aims to measure bacterial activity in micro-gravity conditions. “The device is being developed keeping in mind our intention to perform experiments in micro-gravity conditions in the near future,” explains Rashmi Dikshit, a DBT-BioCARe Fellow at IISc and first author of the study, who had also previously worked on the lunar bricks. With ISRO’s help, the team plans to send such devices into space, so that they can study the effect of low gravity on the bacterial growth.

“I’m so excited that many researchers across the world are thinking about colonising other planets,” says Kumar. “It may not happen quickly, but people are actively working on it.”

REFERENCE:

Dikshit R, Gupta N, Dey A, Viswanathan K, Kumar A, Microbial induced calcite precipitation can consolidate martian and lunar regolith simulants, PLOS One, 17.4 (2022): e0266415. 

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0266415

CONTACT:

Aloke Kumar
Associate Professor
Department of Mechanical Engineering
Indian Institute of Science (IISc)
Email: alokekumar@iisc.ac.in
Phone (office): +91 80 22932958

NOTE TO JOURNALISTS: 

a) If any of the text in this release is reproduced verbatim, please credit the IISc press release.
b) For any queries about IISc press releases, please write to news@iisc.ac.in or pro@iisc.ac.in.

25^th April 2022

– Ranjini Raghunath

 A drug used to treat asthma and allergies can bind to and block a crucial protein produced by the virus SARS-CoV-2, and reduce viral replication in human immune cells, according to a new study by researchers at the Indian Institute of Science (IISc).   

 Approved by the US Food and Drug Administration (FDA), the drug, called montelukast, has been around for more than 20 years and is usually prescribed to reduce inflammation caused by conditions like asthma, hay fever and hives.  

 In the study published in eLife, the researchers show that the drug binds strongly to one end (‘C-terminal’) of a SARS-CoV-2 protein called Nsp1, which is one of the first viral proteins unleashed inside the human cells. This protein can bind to ribosomes – the protein-making machinery – inside our immune cells and shut down the synthesis of vital proteins required by the immune system, thereby weakening it. Targeting Nsp1 could therefore reduce the damage inflicted by the virus.   

 “The mutation rate in this protein, especially the C-terminal region, is very low compared to the rest of the viral proteins,” explains Tanweer Hussain, Assistant Professor in the Department of Molecular Reproduction, Development and Genetics (MRDG), IISc, and senior author of the study. Since Nsp1 is likely to remain largely unchanged in any variants of the virus that emerge, drugs targeting this region are expected to work against all such variants, he adds.   

 Hussain and his team first used computational modelling to screen more than 1,600 FDA-approved drugs in order to find the ones that bound strongly to Nsp1. From these, they were able to shortlist a dozen drugs including montelukast and saquinavir, an anti-HIV drug. “The molecular dynamic simulations generate a lot of data, in the range of terabytes, and help to figure out the stability of the drug-bound protein molecule. To analyse these and identify which drugs may work inside the cell was a challenge,” says Mohammad Afsar, former Project Scientist at MRDG, currently a postdoc at the University of Texas at Austin, and first author of the study.  

 Working with the group of Sandeep Eswarappa, Associate Professor in the Department of Biochemistry, Hussain’s team then cultured human cells in the lab that specifically produced Nsp1, treated them with montelukast and saquinavir separately, and found that only montelukast was able to rescue the inhibition of protein synthesis by Nsp1. 

Targeting Nsp1 with montelukast helps prevent shutdown of host protein synthesis (Credit: Mohammad Afsar) 

“There are two aspects [to consider]: one is affinity and the other is stability,” explains Afsar. This means that the drug needs to not only bind to the viral protein strongly, but also stay bound for a sufficiently long time to prevent the protein from affecting the host cell, he adds. “The anti-HIV drug (saquinavir) showed good affinity, but not good stability.” Montelukast, on the other hand, was found to bind strongly and stably to Nsp1, allowing the host cells to resume normal protein synthesis.   

Hussain’s lab then tested the effect of the drug on live viruses, in the Bio-Safety Level 3 (BSL-3) facility at the Centre for Infectious Disease Research (CIDR), IISc, in collaboration with Shashank Tripathi, Assistant Professor at CIDR, and his team. They found that the drug was able to reduce viral numbers in infected cells in the culture.  

 “Clinicians have tried using the drug … and there are reports that said that montelukast reduced hospitalisation in COVID-19 patients,” says Hussain, adding that the exact mechanisms by which it works still need to be fully understood. His team plans to work with chemists to see if they can modify the structure of the drug to make it more potent against SARS-CoV-2. They also plan to continue hunting for similar drugs with strong antiviral activity.   

REFERENCE: 

Afsar M, Narayan R, Akhtar MN, Das D, Rahil H, Nagaraj SK, Eswarappa SM, Tripathi S, Hussain T, Drug targeting Nsp1-ribosomal complex shows antiviral activity against SARS-CoV-2, eLife (2022). 

https://elifesciences.org/articles/74877 

CONTACT: 

Tanweer Hussain
Assistant Professor,
Department of Molecular Reproduction, Development and Genetics (MRDG),
Indian Institute of Science (IISc)
hussain@iisc.ac.in
080-2293 3262 

Mohammad Afsar
Former Project Scientist,
Department of Molecular Reproduction, Development and Genetics (MRDG),
Indian Institute of Science (IISc)
afsar3232@gmail.com 

NOTE TO JOURNALISTS: 

a) If any of the text in this release is reproduced verbatim, please credit the IISc press release.

b) For any queries about IISc press releases, please write to news@iisc.ac.in or pro@iisc.ac.in.

4^th May 2022

– Mohammed Asheruddin

Soft wearable glove for stroke rehabilitation (Photo: Mesoscopic Lab, Department of Physics, IISc)

Stroke is India’s third leading cause of death and the sixth leading cause of disability. Physiotherapy is one of the few treatments available for rehabilitating stroke victims and patients with physical injuries. However, physiotherapy can take days to months depending on the severity of the disability, making it challenging for patients as well as their attendants.

To help such patients, researchers in the Department of Physics at the Indian Institute of Science (IISc) have developed a soft, wearable device that exploits the fundamental properties of light to sense a patient’s limb or finger movements. The customisable, 3D printed gloves can be remotely controlled, opening up the possibility of teleconsultation by physiotherapists.   

“We wanted to develop something affordable, and available to a person at all times at their convenience. The product should be easy to use and must provide feedback,” says Aveek Bid, Associate Professor at the Department of Physics, whose team has developed the device.

Bid explains that quantifiable feedback – for example, the units of pressure applied while squeezing a ball or the degree of bending of a leg with a knee injury – is crucial for doctors to monitor the patient, even remotely. Such feedback can also motivate patients to perform better in every consecutive session.   

Another challenge is that physiotherapy often requires daily hospital visits. Home visits by professionals or sophisticated devices to monitor patients remotely, although ideal, are not readily available and are expensive.   

To address these challenges, the team has developed a mechanism by which customisable wearables like hand gloves can be designed, 3D printed, and controlled remotely. “The idea behind the device is that you wear something like a glove, the physiotherapist controls the device from a remote location through the internet, and makes your hands and fingers move,” describes Bid.  The device can sense various hand and finger movements, and precisely detect parameters like pressure, bending angle and shape.

The technology that drives the device is based on the fundamental properties of light: refraction and reflection. A light source is placed at one end of a transparent rubbery material, and the other end has a light detector. Any movement in the finger or arm of the patient causes the flexible material to deform. The deformation alters the path of light, and thereby its properties. The device translates this change in light properties to a quantifiable unit. Since light travels across the entire length of the device, movement along any part of the patient’s finger or arm can be accurately measured.

Visual schematic of a soft wearable glove for remotely monitoring stroke rehatbilitation (Image: Mesoscopic Lab, Department of Physics, IISc)

The device is highly sensitive – enough to respond to the touch of a butterfly, says team member Abhijit Chandra Roy, DST-Inspire Faculty at the Department of Physics and the brains behind the project. In addition, while existing devices can only detect the bending of a finger, the new device can even measure the degree of bending at every joint of the finger, he explains.   

For their device, the researchers used a silicon-based polymer material that is transparent (facilitating manipulation of light), soft (for comfort and repeated use), and most importantly, 3D printed; it can therefore be customised to fit each patient’s arm and fingers. The device can also capture and store data, and transmit it over the internet, facilitating remote monitoring by clinicians or physiotherapists.

The researchers say that the device has been tested for stability for over 10 months, and no loss of sensitivity or accuracy was found. Bid adds that the device has been entirely designed and manufactured in India, and is expected to cost less than Rs 1,000. A patent has been filed for the device and the researchers hope to launch it in the market soon. The approach can also be extended to applications like augmented reality and real-time monitoring of health parameters.

CONTACT:  

Aveek Bid 
Associate Professor 
Department of Physics 
Indian Institute of Science (IISc)
Email: aveek@iisc.ac.in 
Phone: +91-80-2293 3340 
http://www.physics.iisc.ac.in/~aveek_bid/

Abhijit Roy 
DST-Inspire Faculty  
Department of Physics 
Indian Institute of Science (IISc)
Email: abhijitroy@iisc.ac.in 
https://abhiphn09.wixsite.com/softbioelectrolab 

NOTE TO JOURNALISTS: 

a) If any of the text in this release is reproduced verbatim, please credit the IISc press release. 

b) For any queries about IISc press releases, please write to news@iisc.ac.in or pro@iisc.ac.in. 

16^th May 2022

– Ranjini Raghunath

Nano-sized robots manipulated using a magnetic field can help kill bacteria deep inside dentinal tubules, and boost the success of root canal treatments, a new study by researchers at the Indian Institute of Science (IISc) and IISc-incubated startup, Theranautilus, shows.

Root canal treatments are routinely carried out to treat tooth infections in millions of patients. The procedure involves removing the infected soft tissue inside the tooth, called the pulp, and flushing the tooth with antibiotics or chemicals to kill the bacteria that cause the infection. But many times, the treatment fails to completely remove all the bacteria – especially antibiotic-resistant bacteria such as Enterococcus faecalis – which remain hidden inside microscopic canals in the tooth called dentinal tubules.

“The dentinal tubules are very small, and bacteria reside deep in the tissue. Current techniques are not efficient enough to go all the way inside and kill the bacteria,” explains Shanmukh Srinivas, Research Associate at the Centre for Nano Science and Engineering (CeNSE), IISc, and co-founder of Theranautilus.

In the study published in Advanced Healthcare Materials, the researchers designed helical nanobots made of silicon dioxide coated with iron, which can be controlled using a device that generates a low intensity magnetic field. These nanobots were then injected into extracted tooth samples and their movement was tracked using a microscope.

By tweaking the frequency of the magnetic field, the researchers were able to make the nanobots move at will, and penetrate deep inside the dentinal tubules. “We have also established that we can retrieve them … we can pull them back out of the patient’s teeth,” says Srinivas.

Crucially, the team was able to manipulate the magnetic field to make the surface of the nanobots generate heat, which can kill the bacteria nearby. “No other technology in the market can do this right now,” says Debayan Dasgupta, Research Associate at CeNSE, and another co-founder of Theranautilus.

Left: Nanobots entering a dentinal tubule. Centre top and bottom: Schematic representation and electron microscope image of nanobot moving through dentinal tubule to reach bacterial colony. Right: How locally induced heat from nanobot can kill bacteria. Live bacteria are green and dead bacteria are red. Bottom right shows band where targeted treatment has been done in human teeth (Image: Theranautilus) 

Previously, scientists have used ultrasound or laser pulses to create shockwaves in the fluid used to flush out bacteria and tissue debris, in order to improve the efficiency of root canal treatment. But these pulses can only penetrate up to a distance of 800 micrometers, and their energy dissipates fast. The nanobots were able to penetrate much further – up to 2,000 micrometers. Using heat to kill the bacteria also provides a safer alternative to harsh chemicals or antibiotics, the researchers say.

Theranautilus was spun out of several years of work on magnetically-controlled nanoparticles carried out in the lab of Ambarish Ghosh, Professor at CeNSE. His group, along with collaborators, has previously shown that such nanoparticles can trap and move objects using light, swim through blood and inside living cells, and stick strongly to cancer cells. “These studies have shown that they are safe to use in biological tissues,” says Dasgupta.

The team has tested the dental nanobots in mice models and found them to be safe and effective. They are also working on developing a new kind of medical device that can easily fit inside the mouth, and allow the dentist to inject and manipulate the nanobots inside the teeth during root canal treatment.

“We are very close to deploying this technology in a clinical setting, which was considered futuristic even three years ago,” says Ghosh. “It is a joy to see how a simple scientific curiosity is shaping into a medical intervention that can impact millions of people in India alone.”

REFERENCE:

Dasgupta D, Peddi S, Saini DK, Ghosh A, Mobile Nanobots for Prevention of Root Canal Treatment Failure, Advanced Healthcare Materials (2022).

https://doi.org/10.1002/adhm.202200232

CONTACT:

Ambarish Ghosh
Professor, Centre for Nano Science and Engineering (CeNSE)
Co-founder, Theranautilus
Indian Institute of Science (IISc)
Email: ambarish@iisc.ac.in

Shamukh Srinivas
Co-founder and CEO, Theranautilus
Research Associate, Centre for Nano Science and Engineering (CeNSE)
Indian Institute of Science (IISc)
Email: shanmukhs@iisc.ac.in

Debayan Dasgupta
Co-founder, Theranautilus
Research Associate, Centre for Nano Science and Engineering (CeNSE)
Indian Institute of Science (IISc)
Email: debayan@iisc.ac.in

NOTE TO JOURNALISTS: 

a) If any of the text in this release is reproduced verbatim, please credit the IISc press release.
b) For any queries about IISc press releases, please write to news@iisc.ac.in or pro@iisc.ac.in.

27^th May 2022

– Rohith KMS

In October 2017, tech giant Yahoo! disclosed a data breach that had leaked sensitive information of over 3 billion user accounts, exposing them to identity theft. The company had to force all affected users to change passwords and re-encrypt their credentials. In recent years, there have been several instances of such security breaches that have left users vulnerable.

“Almost everything we do on the internet is encrypted for security. The strength of this encryption depends on the quality of random number generation,” says Nithin Abraham, a PhD student at the Department of Electrical Communication Engineering (ECE), Indian Institute of Science (IISc). Abraham is a part of a team led by Kausik Majumdar, Associate Professor at ECE, which has developed a record-breaking true random number generator (TRNG), which can improve data encryption and provide improved security for sensitive digital data such as credit card details, passwords and other personal information. The study describing this device has been published in the journal ACS Nano.

Encrypted information can be decoded only by authorised users who have access to a cryptographic “key”. But the key needs to be unpredictable and, therefore, randomly generated to resist hacking. Cryptographic keys are typically generated in computers using pseudorandom number generators (PRNGs), which rely on mathematical formulae or pre-programmed tables to produce numbers that appear random but are not. In contrast, a TRNG extracts random numbers from inherently random physical processes, making it more secure.

In IISc’s breakthrough TRNG device, random numbers are generated using the random motion of electrons. It consists of an artificial electron trap constructed by stacking atomically-thin layers of materials like black phosphorus and graphene. The current measured from the device increases when an electron is trapped, and decreases when it is released. Since electrons move in and out of the trap in a random manner, the measured current also changes randomly. The timing of this change determines the generated random number. “You cannot predict exactly at what time the electron is going to enter the trap. So, there is an inherent randomness that is embedded in this process,” explains Majumdar.

The image of the fabricated electronic chip that generates the random number. The chip is loaded into the measurement setup, where the randomness of the electron trapping/de-trapping is converted into binary outputs (Credit: Nithin Abraham)

The performance of the device on the standard tests for cryptographic applications designed by the US National Institute of Standards and Technology (NIST) has exceeded Majumdar’s own expectations. “When the idea first struck me, I knew it would be a good random number generator, but I didn’t expect it to have a record-high min-entropy,” he says.

Min-entropy is a parameter used to measure the performance of TRNGs. Its value ranges from 0 (completely predictable) to 1 (completely random). The device from Majumdar’s lab showed a record-high min-entropy of 0.98, a significant improvement over previously reported values, which were around 0.89. “Ours is by far the highest reported min-entropy among TRNGs,” says Abraham.

The team’s electronic TRNG is also more compact than its clunkier counterparts that are based on optical phenomena, says Abraham. “Since our device is purely electronic, millions of such devices can be created on a single chip,” adds Majumdar. He and his group plan to improve the device by making it faster and developing a new fabrication process that would enable the mass production of these chips.

REFERENCE: 

Abraham N, Watanabe K, Taniguchi T, Majumdar K, A High-Quality Entropy Source Using van der Waals Heterojunction for True Random Number Generation, ACS Nano (2022)
https://pubs.acs.org/doi/abs/10.1021/acsnano.1c11084 

CONTACT: 

Kausik Majumdar
Associate Professor
Department of Electrical Communication Engineering (ECE), Indian Institute of Science (IISc)
Phone: +91-80-2293-2742
Email: kausikm@iisc.ac.in

NOTE TO JOURNALISTS:

a) If any of the text in this release is reproduced verbatim, please credit the IISc press release. 
b) For any queries about IISc press releases, please write to news@iisc.ac.in or pro@iisc.ac.in. 

2^nd June 2022

– Ranjini Raghunath

In a breakthrough, researchers at the Indian Institute of Science (IISc) and their collaborators have discovered how next-generation solid-state batteries fail and devised a novel strategy to make these batteries last longer and charge faster.

Solid-state batteries are poised to replace the lithium-ion batteries found in almost every portable electronic device. But on repeated or excessive use, they develop thin filaments called ‘dendrites’ which can short-circuit the batteries and render them useless.

In a new study published in Nature Materials, the researchers have identified the root cause of this dendrite formation – the appearance of microscopic voids in one of the electrodes early on. They also show that adding a thin layer of certain metals to the electrolyte surface significantly delays dendrite formation, extending the battery’s life and enabling it to be charged faster.

Schematic (a) representing a Li-metal solid-state battery with a discontinuous interface. These voids and discontinuities are the main driving factor for dendrite growth through solid electrolytes. These voids can be minimised by using an appropriate interlayer (b) (Credit: Vikalp Raj)

Conventional lithium-ion batteries – the kind that you might find in your smartphone or laptop – contain a liquid electrolyte sandwiched between a positively charged electrode (cathode) made of a transition metal (such as iron and cobalt) oxide and a negatively charged electrode (anode) made of graphite. When the battery is charging and discharging (using up power), lithium ions shuttle between the anode and cathode in opposite directions. These batteries have a major safety issue – the liquid electrolyte can catch fire at high temperatures. Graphite also stores much less charge than metallic lithium.

A promising alternative, therefore, is solid-state batteries that switch out the liquid for a solid ceramic electrolyte and swap graphite with metallic lithium. Ceramic electrolytes perform even better at higher temperatures, which is especially useful in tropical countries like India. Lithium is also lighter and stores more charge than graphite, which can significantly cut down the battery cost.

“Unfortunately, when you add lithium, it forms these filaments that grow into the solid electrolyte, and short out the anode and cathode,” explains Naga Phani Aetukuri, Assistant Professor in the Solid State and Structural Chemistry Unit (SSCU) and corresponding author of the study.

To investigate this phenomenon, Aetukuri’s PhD student, Vikalp Raj, artificially induced dendrite formation by repeatedly charging hundreds of battery cells, slicing out thin sections of the lithium-electrolyte interface, and peering at them under a scanning electron microscope. When they looked closely at these sections, the team realised that something was happening long before the dendrites formed – microscopic voids were developing in the lithium anode during discharge. The team also computed that the currents concentrated at the edges of these microscopic voids were about 10,000 times larger than the average currents across the battery cell, which was likely creating stress on the solid electrolyte and accelerating the dendrite formation.

“This means that now our task to make very good batteries is very simple,” says Aetukuri. “All that we need is to ensure that the voids don’t form.”

To ensure this, the researchers introduced an ultrathin layer of a refractory metal – a metal that is resistant to heat and wear – between the lithium anode and solid electrolyte. “The refractory metal layer shields the solid electrolyte from the stress and redistributes the current to an extent,” says Aetukuri. He and his team collaborated with researchers at Carnegie Mellon University in the US, who carried out computational analysis which clearly showed that the refractory metal layer indeed delayed the growth of microscopic lithium voids.

Advanced battery testing facility at IISc (Credit: Naga Phani Aetukuri)

Applying extreme pressure that can push lithium against the solid electrolyte can prevent voids and delay dendrite formation, but that may not be practical for everyday applications. Other researchers have also proposed the idea of using metals like aluminium that alloy or mix well with lithium at the interface. But over time, this metal layer blends with lithium, becoming indistinguishable, and does not prevent dendrite formation. “What we are saying is different,” explains Raj. “If you use a metal like tungsten or molybdenum that doesn’t alloy with lithium, the performance which you get from the cell is even better.”

The researchers say that the findings are a critical step forward in realising practical and commercial solid-state batteries. Their strategy can also be extended to other types of batteries that contain metals like sodium, zinc and magnesium.

REFERENCE: 

Vikalp Raj, Victor Venturi, Varun R Kankanallu, Bibhatsu Kuiri, Venkatasubramanian Viswanathan and Naga Phani B Aetukuri, Direct Correlation Between Void Formation and Lithium Dendrite Growth in Solid State Electrolytes with Interlayers, Nature Materials (2022).

DOI: 10.1038/s41563-022-01264-8

https://www.nature.com/articles/s41563-022-01264-8

CONTACT:
Naga Phani Aetukuri
Assistant Professor
Solid State and Structural Chemistry Unit (SSCU)
Indian Institute of Science (IISc)
phani@iisc.ac.in
+91-80-2293 3534
https://sites.google.com/view/qlab-iisc/home

NOTE TO JOURNALISTS:

1. a) If any of the text in this release is reproduced verbatim, please credit the IISc press release.
2. b) For any queries about IISc press releases, please write to news@iisc.ac.inor pro@ac.in.

4^th June 2022

– Narmada Khare

 The rapid emergence of new strains of the SARS-CoV-2 virus has diminished the protection offered by COVID-19 vaccines. A new approach developed by researchers at the Indian Institute of Science (IISc) now provides an alternative mechanism to render viruses like SARS-CoV-2 inactive. 

 In a study published in Nature Chemical Biology, the researchers report the design of a new class of artificial peptides or miniproteins that can not only block virus entry into our cells but also clump virions (virus particles) together, reducing their ability to infect.  

 A protein-protein interaction is often like that of a lock and a key. This interaction can be hampered by a lab-made miniprotein that mimics, competes with, and prevents the ‘key’ from binding to the ‘lock’, or vice versa.  

 In the new study, the team has exploited this approach to design miniproteins that can bind to, and block the spike protein on the surface of the SARS-CoV-2 virus. This binding was further characterised extensively by cryo-electron microscopy (cryo-EM) and other biophysical methods.

 These miniproteins are helical, hairpin-shaped peptides, each capable of pairing up with another of its kind, forming what is known as a dimer. Each dimeric ‘bundle’ presents two ‘faces’ to interact with two target molecules. The researchers hypothesised that the two faces would bind to two separate target proteins locking all four in a complex and blocking the targets’ action. “But we needed proof of principle,” says Jayanta Chatterjee, Associate Professor in the Molecular Biophysics Unit (MBU), IISc, and the lead author of the study. The team decided to test their hypothesis by using one of the miniproteins called SIH-5 to target the interaction between the Spike (S) protein of SARS-CoV-2 and ACE2 protein in human cells.  

The S protein is a trimer – a complex of three identical polypeptides. Each polypeptide contains a Receptor Binding Domain (RBD) that binds to the ACE2 receptor on the host cell surface. This interaction facilitates viral entry into the cell.  

The SIH-5 miniprotein was designed to block the binding of the RBD to human ACE2. When a SIH-5 dimer encountered an S protein, one of its faces bound tightly to one of the three RBDs on the S protein trimer, and the other face bound to an RBD from a different S protein. This ‘cross-linking’ allowed the miniprotein to block both S proteins at the same time. “Several monomers can block their targets,” says Chatterjee. “[But] cross-linking of S proteins blocks their action many times more effectively. This is called the avidity effect.”  

Dimerisation of spike protein by ‘two-faced peptide’ (Credit: Bhavesh Khatri) 

Under cryo-EM, the S proteins targeted by SIH-5 appeared to be attached head-to-head. “We expected to see a complex of one spike trimer with SIH-5 peptides. But I saw a structure that was much more elongated,” says Somnath Dutta, Assistant Professor at MBU and one of the corresponding authors. Dutta and the others realised that the spike proteins were being forced to form dimers and clumped into complexes with the miniprotein. This type of clumping can simultaneously inactivate multiple spike proteins of the same virus and even multiple virus particles. “I have worked with antibodies raised against the spike protein before and observed them under a cryo-EM. But they never created dimers of the spikes,” says Dutta.  

The miniprotein was also found to be thermostable – it can be stored for months at room temperature without deteriorating.   

The next step was to ask if SIH-5 would be useful for preventing COVID-19 infection.  

To answer this, the team first tested the miniprotein for toxicity in mammalian cells in the lab and found it to be safe. Next, in experiments carried out in the lab of Raghavan Varadarajan, Professor at MBU, hamsters were dosed with the miniprotein, followed by exposure to SARS-CoV-2. These animals showed no weight loss and had greatly decreased viral load as well as much less cell damage in the lungs, compared to hamsters exposed only to the virus.

 The researchers believe that with minor modifications and peptide engineering, this lab-made miniprotein could inhibit other protein-protein interactions as well. 

REFERENCE:  

Khatri B, Pramanick I, Malladi SK, Rajmani RS, Kumar S, Ghosh P, Sengupta N, Rahisuddin R, Kumar N, Kumaran S, Ringe RP, Varadarajan R, Dutta S, Chatterjee J, A dimeric proteomimetic prevents SARS-CoV-2 infection by dimerizing the spike protein, Nature Chemical Biology (2022). 

https://www.nature.com/articles/s41589-022-01060-0

CONTACT:  

Jayanta Chatterjee
Associate Professor
Molecular Biophysics Unit (MBU)
Indian Institute of Science (IISc)
jayanta@iisc.ac.in
080-2293 2053

Somnath Dutta
Assistant Professor
Molecular Biophysics Unit (MBU)
Indian Institute of Science (IISc)
somnath@iisc.ac.in
080-2293 3453

NOTE TO JOURNALISTS:

a) If any of the text in this release is reproduced verbatim, please credit the IISc press release. 
b) For any queries about IISc press releases, please write to news@iisc.ac.in or pro@iisc.ac.in.  

13^th June 2022

– Mohammed Asheruddin

Researchers in the Department of Mechanical Engineering, Indian Institute of Science (IISc), in collaboration with the Karnataka Institute of Endocrinology and Research (KIER), have developed a set of unique self-regulating footwear for persons with diabetes.  

Foot injuries or wounds in persons with diabetes heal at a slower rate than in healthy individuals, which increases the chance of infection, and may lead to complications that require amputation in extreme cases.  

The footwear – a pair of specially-designed sandals – developed by the IISc-led team is 3D printed and can be customised to an individual’s foot dimensions and walking style. Unlike conventional therapeutic footwear, a snapping mechanism in these sandals keeps the feet well-balanced, enabling faster healing of the injured region and preventing injuries from arising in other areas of the feet.  

Footwear with self-offloading insole underneath the top sole (b) one of the volunteers wearing the self-offloading footwear (Credit: Priyabrata Maharana, Jyoti Sonawane)

The footwear can be especially beneficial for people who have diabetic peripheral neuropathy – those who suffer from nerve damage caused by diabetes, leading to a loss of sensation in the foot. “Diabetic peripheral neuropathy is one of the long-term complications of diabetes, and its diagnosis is mostly neglected,” says Pavan Belehalli, Head of the Department of Podiatry at KIER, and one of the authors of the study published in Wearable Technologies. This loss of sensation leads to irregular walking patterns in persons with diabetes, he says.   

For example, a healthy person usually places their heel first on the ground, followed by the foot and toes, and then the heel again – this ‘gait cycle’ distributes the pressure evenly across the foot. But due to the loss of sensation, persons with diabetes may not always follow this sequence, which means that the pressure is unevenly distributed. Regions of the foot where the pressure exerted is high are at greater risk of developing ulcers, corns, calluses and other complications.   

 Most of the therapeutic footwear available in the market is ineffective at off-loading the uneven pressure exerted by the ‘abnormal’ gait cycle of persons with diabetes, the researchers say. To address this challenge, they designed arches in their sandals that ‘snap’ to an inverted shape when a pressure beyond a certain threshold is applied. “When we remove the pressure, [the arch] will automatically come back to its initial position – this is what is called self-offloading,” explains first author Priyabrata Maharana, PhD student in the Department of Mechanical Engineering, IISc. “We consider the individual’s weight, foot size, walking speed and pressure distribution to arrive at the maximum force that has to be off-loaded.” Multiple arches have been designed along the length of the footwear to off-load the pressure effectively. 

3D-printed prototype of self-offloading insole showing the arrangement of array of arches ((a) top view and (b) side view) to offload the high-pressure areas (Credit: Priyabrata Maharana, Jyoti Sonawane)

“This is a mechanical solution to a problem,” explains GK Ananthasuresh, Professor in the Department of Mechanical Engineering, IISc, and senior author of the study. “Most of the time, people use electromechanical solutions.” Such solutions involve using sensors and actuators that can rack up the price of the footwear and make them very expensive, he adds.   

 The team is collaborating with start-ups Foot Secure and Yostra Labs to commercialise their product. “There are a lot of commercial shoe manufacturers selling costly footwear in the name of giving comfort using what they call memory foam, but we have tested them, and they don’t have the required characteristics,” says Ananthasuresh. “This footwear can be used not only by people suffering from diabetic neuropathy, but by others as well.”  

REFERENCE:  

Maharana P, Sonawane J, Belehalli P, Ananthasuresh GK, Self-offloading therapeutic footwear using compliant snap-through arches, Wearable Technologies (2022). 

https://www.cambridge.org/core/journals/wearable-technologies/article/selfoffloading-therapeutic-footwear-using-compliant-snapthrough-arches/4217BA71EBBD52A973160415F5F614C3

CONTACT:

G K Ananthasuresh
Professor
Department of Mechanical Engineering
Indian Institute of Science (IISc)
Email: suresh@iisc.ac.in
Telephone: +91 (80) 2293 2334

Pavan Belehalli
Head of Department
Department of Podiatry
Karnataka Institute of Endocrinology and Research (KIER)
Email: docbelehalli@gmail.com

Priyabrata Maharana
PhD student
Department of Mechanical Engineering
Indian Institute of Science
Email:<priyabratam@iisc.ac.in

NOTE TO JOURNALISTS: 

a) If any of the text in this release is reproduced verbatim, please credit the IISc press release.
b) For any queries about IISc press releases, please write to news@iisc.ac.in or pro@iisc.ac.in.

17^th June 2022

– Pratibha Gopalakrishna

When a person sneezes or coughs, they can potentially transmit droplets carrying viruses like SARS-CoV-2 to others in their vicinity. Does talking to an infected person also carry an increased risk of infection? How do speech droplets or “aerosols” move in the air space between the people interacting?

To answer these questions, a research team has carried out computer simulations to analyse the movement of the speech aerosols. The team includes researchers from the Department of Aerospace Engineering, Indian Institute of Science (IISc), along with collaborators from the Nordic Institute for Theoretical Physics (NORDITA) in Stockholm and the International Centre for Theoretical Sciences (ICTS) in Bengaluru. Their study was published in the journal Flow.

The team visualised scenarios in which two maskless people are standing two, four or six feet apart and talking to each other for about a minute, and then estimated the rate and extent of spread of the speech aerosols from one to another. Their simulations showed that the risk of getting infected was higher when one person acted as a passive listener and didn’t engage in a two-way conversation. Factors like the height difference between the people talking and the quantity of aerosols released from their mouths also appear to play an important role in viral transmission.

“Speaking is a complex activity … and when people speak, they’re not really conscious of whether this can constitute a means of virus transmission,” says Sourabh Diwan, Assistant Professor in the Department of Aerospace Engineering, and one of the corresponding authors.

In the early days of the COVID-19 pandemic, experts believed that the virus mostly spread symptomatically through coughing or sneezing. Soon, it became clear that asymptomatic transmission also leads to the spread of COVID-19. However, very few studies have looked at aerosol transport by speech as a possible mode of asymptomatic transmission, according to Diwan.

To analyse speech flows, he and his team modified a computer code they had originally developed to study the movement and behaviour of cumulus clouds – the puffy cotton-like clouds that are usually seen on a sunny day. The code (called Megha-5) was written by S Ravichandran from NORDITA, the other corresponding author on the paper, and was used recently for studying particle-flow interaction in Rama Govindarajan’s group at ICTS. The analysis carried out by the team on speech flows incorporated the possibility of viral entry through the eyes and mouth in determining the risk of infection – most previous studies had only considered the nose as the point of entry.

Interactions of speech jets during short conversations between two people separated by a distance of four feet, visualised by an iso-surface of the aerosol concentration. Three different height differences are shown. The blue and red colours represent the simulated speech jets emanating from the mouths of the two people. The simulations were performed on SahasraT at IISc (Image: Rohit Singhal)

“The computational part was intensive, and it took a lot of time to perform these simulations,” explains Rohit Singhal, first author and PhD student at the Department of Aerospace Engineering. Diwan adds that it is hard to numerically simulate the flow of speech aerosols because of the highly-fluctuating (“turbulent”) nature of the flow; factors like the flow rate at the mouth and the duration of speech also play a role in shaping its evolution.

In the simulations, when the speakers were either of the same height, or of drastically different heights (one tall and another short), the risk of infection was found to be much lower than when the height difference was moderate – the variation looked like a bell curve. Based on their results, the team suggests that just turning their heads away by about nine degrees from each other while still maintaining eye contact can reduce the risk for the speakers considerably.

Moving forward, the team plans to focus on simulating differences in the loudness of the speakers’ voices and the presence of ventilation sources in their vicinity to see what effect they can have on viral transmission. They also plan to engage in discussions with public health policymakers and epidemiologists to develop suitable guidelines. “Whatever precautions we can take while we come back to normalcy in our daily interactions with other people, would go a long way in minimising the spread of infection,” Diwan says.

REFERENCE:

Singhal R, Ravichandran S, Govindarajan R, and Diwan S, Virus transmission by aerosol transport during short conversations, Flow, 2 (2022): E13. doi:10.1017/flo.2022.7.

https://www.cambridge.org/core/journals/flow/article/virus-transmission-by-aerosol-transport-during-short-conversations/2F7E421D937DBE4ACD08E2C09E4D1F2A

CONTACT:

Sourabh S Diwan
Assistant Professor
Department of Aerospace Engineering
Indian Institute of Science (IISc)
Email: sdiwan@iisc.ac.in
Phone: +91-80-22932423

NOTE TO JOURNALISTS:
a) If any of the text in this release is reproduced verbatim, please credit the IISc press release.
b) For any queries about IISc press releases, please write to news@iisc.ac.in or pro@iisc.ac.in.

27^th June 2022

– Praveen Jayakumar

A new GPU-based machine learning algorithm developed by researchers at the Indian Institute of Science (IISc) can help scientists better understand and predict connectivity between different regions of the brain.

The algorithm, called Regularized, Accelerated, Linear Fascicle Evaluation, or ReAl-LiFE, can rapidly analyse the enormous amounts of data generated from diffusion Magnetic Resonance Imaging (dMRI) scans of the human brain. Using ReAL-LiFE, the team was able to evaluate dMRI data over 150 times faster than existing state-of-the-art algorithms.

“Tasks that previously took hours to days can be completed within seconds to minutes,” says Devarajan Sridharan, Associate Professor at the Centre for Neuroscience (CNS), IISc, and corresponding author of the study published in the journal Nature Computational Science.

The image shows the superior longitudinal fasciculus (SLF), a white matter tract that connects the prefrontal and parietal cortex, two attention-related brain regions. The tract was estimated with diffusion MRI and tractography in the living human brain (Credits: Varsha Sreenivasan and Devarajan Sridharan)

Millions of neurons fire in the brain every second, generating electrical pulses that travel across neuronal networks from one point in the brain to another through connecting cables or “axons”. These connections are essential for computations that the brain performs. “Understanding brain connectivity is critical for uncovering brain-behaviour relationships at scale,” says Varsha Sreenivasan, PhD student at CNS and first author of the study. However, conventional approaches to study brain connectivity typically use animal models, and are invasive. dMRI scans, on the other hand, provide a non-invasive method to study brain connectivity in humans.

The cables (axons) that connect different areas of the brain are its information highways. Because bundles of axons are shaped like tubes, water molecules move through them, along their length, in a directed manner. dMRI allows scientists to track this movement, in order to create a comprehensive map of the network of fibres across the brain, called a connectome.

Unfortunately, it is not straightforward to pinpoint these connectomes. The data obtained from the scans only provide the net flow of water molecules at each point in the brain. “Imagine that the water molecules are cars. The obtained information is the direction and speed of the vehicles at each point in space and time with no information about the roads. Our task is similar to inferring the networks of roads by observing these traffic patterns,” explains Sridharan.

The image shows connections between the midbrain and various regions of the neocortex. Connections to each region are shown in a different colour, and were all estimated with diffusion MRI and tractography in the living human brain (Credits: Varsha Sreenivasan and Devarajan Sridharan)

To identify these networks accurately, conventional algorithms closely match the predicted dMRI signal from the inferred connectome with the observed dMRI signal. Scientists had previously developed an algorithm called LiFE (Linear Fascicle Evaluation) to carry out this optimisation, but one of its challenges was that it worked on traditional Central Processing Units (CPUs), which made the computation time-consuming.

In the new study, Sridharan’s team tweaked their algorithm to cut down the computational effort involved in several ways, including removing redundant connections, thereby improving upon LiFE’s performance significantly. To speed up the algorithm further, the team also redesigned it to work on specialised electronic chips – the kind found in high-end gaming computers – called Graphics Processing Units (GPUs), which helped them analyse data at speeds 100-150 times faster than previous approaches.

This improved algorithm, ReAl-LiFE, was also able to predict how a human test subject would behave or carry out a specific task. In other words, using the connection strengths estimated by the algorithm for each individual, the team was able to explain variations in behavioural and cognitive test scores across a group of 200 participants.

Such analysis can have medical applications too. “Data processing on large scales is becoming increasingly necessary for big-data neuroscience applications, especially for understanding healthy brain function and brain pathology,” says Sreenivasan.

For example, using the obtained connectomes, the team hopes to be able to identify early signs of aging or deterioration of brain function before they manifest behaviourally in Alzheimer’s patients. “In another study, we found that a previous version of ReAL-LiFE could do better than other competing algorithms for distinguishing patients with Alzheimer’s disease from healthy controls,” says Sridharan.  He adds that their GPU-based implementation is very general, and can be used to tackle optimisation problems in many other fields as well.

REFERENCE: 

Sreenivasan V, Kumar S, Pestilli F, Talukdar P, Sridharan D, GPU-accelerated connectome discovery at scale. Nature Computational Science 2, 298–306 (2022).

https://doi.org/10.1038/s43588-022-00250-z

The research was supported by the DBT Wellcome Trust India Alliance, among other funding agencies.

CONTACT:

Devarajan Sridharan
Associate Professor, Centre for Neuroscience (CNS)
Indian Institute of Science (IISc)
Email: sridhar@iisc.ac.in
Phone: +91-80-22933434

Varsha Sreenivasan
PhD student, Centre for Neuroscience (CNS)
Indian Institute of Science (IISc)
Email: varshas@iisc.ac.in

NOTE TO JOURNALISTS:

1. If any of the text in this release is reproduced verbatim, please credit the IISc press release.
2. For any queries about IISc press releases, please write to news@iisc.ac.inor pro@iisc.ac.in.