“The amount and location of hemoglobin in the body provide critical information about blood perfusion or accumulation in specific locations. Our device shows great potential in close monitoring of high-risk groups, enabling timely interventions at urgent moments,” said Sheng Xu, a professor of nanoengineering at UC San Diego and corresponding author of the study.

The paper, “A photoacoustic patch for three-dimensional imaging of hemoglobin and core temperature,” is published in the December 15, 2022 issue of Nature Communications.

Low blood perfusion inside the body may cause severe organ dysfunctions and is associated with a range of ailments, including heart attacks and vascular diseases of the extremities. At the same time, abnormal blood accumulation in areas such as in the brain, abdomen or cysts can indicate cerebral or visceral hemorrhage or malignant tumors. Continuous monitoring can aid diagnosis of these conditions and help facilitate timely and potentially life-saving interventions.

The new sensor overcomes some significant limitations in existing methods of monitoring biomolecules. Magnetic resonance imaging (MRI) and X-ray-computed tomography rely on bulky equipment that can be hard to procure and usually only provide information on the immediate status of the molecule, which makes them unsuitable for long-term biomolecule monitoring.

“Continuous monitoring is critical for timely interventions to prevent life-threatening conditions from worsening quickly,” said Xiangjun Chen, a nanoengineering PhD student in the Xu group and study co-author. “Wearable devices based on electrochemistry for biomolecules detection, not limited to hemoglobin, are good candidates for long-term wearable monitoring applications. However, the existing technologies only achieve the ability of skin-surface detection.”

The new, flexible, low form-factor wearable patch comfortably attaches to the skin, allowing for noninvasive long-term monitoring. It can perform three-dimensional mapping of hemoglobin with a submillimeter spatial resolution in deep tissues, down to centimeters below the skin, versus other wearable electrochemical devices that only sense the biomolecules on the skin surface. It can achieve high contrast to other tissues. Due to its optical selectivity, it can expand the range of detectable molecules, integrating different laser diodes with different wavelengths, along with its potential clinical applications.

The patch is equipped with arrays of laser diodes and piezoelectric transducers in its soft silicone polymer matrix. Laser diodes emit pulsed lasers into the tissues. Biomolecules in the tissue absorb the optical energy, and radiate acoustic waves into surrounding media.

“Piezoelectric transducers receive the acoustic waves, which are processed in an electrical system to reconstruct the spatial mapping of the wave-emitting biomolecules,” said Xiaoxiang Gao, a postdoctoral researcher in Xu’s lab and co-author of the study.

“With its low-power laser pulses, it is also much safer than X-ray techniques that have ionizing radiation,” said Hongjie Hu, a postdoctoral researcher in the Xu group and study coauthor.

Based on its success so far, the team plans to further develop the device, including shrinking the backend controlling system to a portable-sized device for laser diode driving and data acquisition, greatly expanding its flexibility and potential clinical utility.

They also plan to explore the wearable’s potential for core temperature monitoring. “Because the photoacoustic signal amplitude is proportional to the temperature, we have demonstrated core temperature monitoring on ex-vivo experiments,” Xu said. “However, validating the core temperature monitoring on the human body requires interventional calibration.”

They are continuing to work with physicians to pursue more potential clinical applications.

The work was supported in part by Air Force Research Laboratory under agreement number FA8650-18-2-5402, and the National Institutes of Health grants 1R21EB025521-01 (S.X.), 1R21EB027303-01A1 (S.X.), and 3R21EB027303-02S1 (S.X.).

Their work has numerous potential impacts, especially in the context of understanding and responding to autoimmune disorders and inflammation.

While our immune system serves a very important function protecting us from infection and injury, when immune responses become too aggressive this can lead to damaging inflammation, which occurs in conditions such as rheumatoid arthritis and psoriasis. Inflammation is triggered when our bodies produce “alarm proteins” (interleukins), which ramp up our defenses against infection and injury by switching on different components of our immune system.

Understanding how and when such alarm proteins are produced and how they activate our immune system has led to major breakthroughs in the treatment of many immune conditions.

Now, scientists from the Smurfit Institute of Genetics at Trinity College Dublin, led by Seamus Martin, Smurfit Professor of Genetics, have found that Interleukin-37 has an unexpected function as an immune-activating molecule, as previous studies suggested that this interleukin instead served as an “off switch” for the immune system.

Professor Martin said:

“Interleukins play key roles in regulating our immune systems in response to bacterial and fungal infections. However, Interleukin-37 has long remained an enigma, as it isn’t found in mammals such as mice. This has presented a major obstacle to figuring out what it does as much of what we know about the human immune system has first been discovered in model organisms whose biological make-ups are similar to ours.”

Prior to the new study, Interleukin-37 was thought to have immune-suppressive functions but how exactly it switched off inflammation was hotly debated. However, the Trinity scientists now report that, when activated in the correct way, Interleukin-37 displays potent pro-inflammatory activity.

Professor Martin added:

“This pro-inflammatory impact was highly unexpected. Our work shows that the protein binds to an interleukin receptor in the skin that is known to play a key role in driving psoriasis. And, to add further intrigue to the story, this brings the total number of immune alarm molecules that signal via this particular interleukin receptor to four.

“Why there are so many interleukins that bind to the same receptor is a mystery, but if we were to speculate it may be because this receptor serves a very important sentinel function in our skin, and that one alarm protein may simply not be enough to respond to the many different infectious agents that our skin encounters. Our skin is the major barrier between our bodies and the outside world that microbes must breach if they are to gain entry to our bodies and, in many respects, represents the first line of defense in our immune systems.”

As such, Interleukin-37 and other immune alarm proteins may have evolved to become distinct variations on the same theme that enable our bodies to detect different types of infection by becoming activated by enzymes that are distinct to each infectious agent.

The research has just been published in the journal, Science Immunology, and was a collaboration between several Trinity research groups led by Professor Martin’s team, which included post-doctoral scientists Dr Graeme Sullivan and Dr Pavel Davidovich, along with research groups led by Professor Ed Lavelle (School of Biochemistry and Immunology) and Professor Pat Walsh (School of Clinical Medicine).

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Materials provided by Trinity College Dublin. Note: Content may be edited for style and length.

The discovery makes it possible to ‘derive’ any Sanskrit word — to construct millions of grammatically correct words including ‘mantra’ and ‘guru’ — using Pāṇini’s revered ‘language machine’ which is widely considered to be one of the great intellectual achievements in history.

Leading Sanskrit experts have described Rajpopat’s discovery as ‘revolutionary’ and it could now mean that Pāṇini’s grammar can be taught to computers for the first time.

While researching his PhD, published today, Dr Rajpopat decoded a 2,500 year old algorithm which makes it possible, for the first time, to accurately use Pāṇini’s ‘language machine’.

Pāṇini’s system — 4,000 rules detailed in his greatest work, the Aṣṭādhyāyī, which is thought to have been written around 500BC — is meant to work like a machine. Feed in the base and suffix of a word and it should turn them into grammatically correct words and sentences through a step-by-step process.

Until now, however, there has been a big problem. Often, two or more of Pāṇini’s rules are simultaneously applicable at the same step leaving scholars to agonise over which one to choose.

Solving so-called ‘rule conflicts’, which affect millions of Sanskrit words including certain forms of ‘mantra’ and ‘guru’, requires an algorithm. Pāṇini taught a metarule* to help us decide which rule should be applied in the event of ‘rule conflict’ but for the last 2,500 years, scholars have misinterpreted this metarule meaning that they often ended up with a grammatically incorrect result.

In an attempt to fix this issue, many scholars laboriously developed hundreds of other metarules but Dr Rajpopat shows that these are not just incapable of solving the problem at hand — they all produced too many exceptions — but also completely unnecessary. Rajpopat shows that Pāṇini’s ‘language machine’ is ‘self-sufficient’.

Rajpopat said: “Pāṇini had an extraordinary mind and he built a machine unrivalled in human history. He didn’t expect us to add new ideas to his rules. The more we fiddle with Pāṇini’s grammar, the more it eludes us.”

Traditionally, scholars have interpreted Pāṇini’s metarule as meaning: in the event of a conflict between two rules of equal strength, the rule that comes later in the grammar’s serial order wins.

Rajpopat rejects this, arguing instead that Pāṇini meant that between rules applicable to the left and right sides of a word respectively, Pāṇini wanted us to choose the rule applicable to the right side. Employing this interpretation, Rajpopat found Pāṇini’s language machine produced grammatically correct words with almost no exceptions.

Take ‘mantra’ and ‘guru’ as examples. In the sentence ‘devāḥ prasannāḥ mantraiḥ’ (‘The Gods [devāḥ] are pleased [prasannāḥ] by the mantras [mantraiḥ]’) we encounter ‘rule conflict’ when deriving mantraiḥ ‘by the mantras’. The derivation starts with ‘mantra + bhis’. One rule is applicable to left part ‘mantra’ and the other to right part ‘bhis’. We must pick the rule applicable to the right part ‘bhis’, which gives us the correct form ‘mantraiḥ’.

And in the the sentence ‘jñānaṁ dīyate guruṇā’ (‘Knowledge [jñānaṁ] is given [dīyate] by the guru [guruṇā]’) we encounter rule conflict when deriving guruṇā ‘by the guru’. The derivation starts with ‘guru + ā’. One rule is applicable to left part ‘guru’ and the other to right part ‘ā’. We must pick the rule applicable to the right part ‘ā’, which gives us the correct form ‘guruṇā’.

Eureka moment

Six months before Rajpopat made his discovery, his supervisor at Cambridge, Vincenzo Vergiani, Professor of Sanskrit, gave him some prescient advice: “If the solution is complicated, you are probably wrong.”

Rajpopat said: “I had a eureka moment in Cambridge. After 9 months trying to crack this problem, I was almost ready to quit, I was getting nowhere. So I closed the books for a month and just enjoyed the summer, swimming, cycling, cooking, praying and meditating. Then, begrudgingly I went back to work, and, within minutes, as I turned the pages, these patterns starting emerging, and it all started to make sense. There was a lot more work to do but I’d found the biggest part of the puzzle.”

“Over the next few weeks I was so excited, I couldn’t sleep and would spend hours in the library including in the middle of the night to check what I’d found and solve related problems. That work took another two and half years.”

Significance

Professor Vincenzo Vergiani said: “My student Rishi has cracked it — he has found an extraordinarily elegant solution to a problem which has perplexed scholars for centuries. This discovery will revolutionise the study of Sanskrit at a time when interest in the language is on the rise.”

Sanskrit is an ancient and classical Indo-European language from South Asia. It is the sacred language of Hinduism, but also the medium through which much of India’s greatest science, philosophy, poetry and other secular literature have been communicated for centuries. While only spoken in India by an estimated 25,000 people today, Sanskrit has growing political significance in India, and has influenced many other languages and cultures around the world.

Rajpopat said: “Some of the most ancient wisdom of India has been produced in Sanskrit and we still don’t fully understand what our ancestors achieved. We’ve often been led to believe that we’re not important, that we haven’t brought enough to the table. I hope this discovery will infuse students in India with confidence, pride, and hope that they too can achieve great things.”

A major implication of Dr Rajpopat’s discovery is that now we have the algorithm that runs Pāṇini’s grammar, we could potentially teach this grammar to computers.

Rajpopat said: “Computer scientists working on Natural language Processing gave up on rule-based approaches over 50 years ago.

“So teaching computers how to combine the speaker’s intention with Pāṇini’s rule-based grammar to produce human speech would be a major milestone in the history of human interaction with machines, as well as in India’s intellectual history.”

Reference

R.A. Rajpopat, ‘In Pāṇini We Trust: Discovering the Algorithm for Rule Conflict Resolution in the Aṣṭādhyāyī’,PhD thesis (University of Cambridge, 2022).DOI: 10.17863/CAM.80099

Notes:

* Dr Rishi Rajpopat names Pāṇini’s metarule ‘1.4.2 vipratiṣedhe paraṁ kāryam’

Pāṇini is thought to have lived in a region in what is now north-west Pakistan and south-east Afghanistan.

The research, led by UCLA planetary scientists and published in two papers in Geophysical Research Letters, could also indicate that alternating layers of volcanic and sedimentary rocks lie beneath the surface.

The 4.7 magnitude earthquake, or marsquake, happened in May 2022 and lasted more than four hours, releasing five times more energy than any previously recorded quake. Though moderate by Earth standards, the temblor was nonetheless powerful enough to send seismic surface waves completely around the planet’s circumference, the first time this phenomenon has been observed on Mars.

The readings were taken from InSight, which landed on Mars in 2018. InSight is the first outer space seismometer to study in-depth the “inner space” of Mars: its crust, mantle and core.

“The seismometer aboard the InSight lander has recorded thousands of marsquakes but never one this large, and it took over three years after landing to record it,” said corresponding author Caroline Beghein, a professor of Earth, planetary and space sciences. “This quake generated different kinds of waves, including two types of waves trapped near the surface. Only one of those two has been observed on Mars before, after two impact events, never during a marsquake.”

Mapping the seismic activity, the location and frequency of impacts on Mars and the interior structure is important for future missions to the red planet as it will inform scientists and engineers where and how to build structures to ensure the safety of future human explorers.

As on Earth, studying how seismic waves travel through rocks can give scientists clues about the temperature and composition of the planet below the surface that help inform the search for underground water or magma. It also helps scientists understand the past forces that shaped the planet.

Beghein’s group combined measurements from two types of surface waves, called Love and Rayleigh waves, to infer the speed of underground shear-waves, which travel horizontally and move rocks perpendicular to the direction of wave propagation. This is the first time Love waves have been observed in conjunction with Rayleigh waves on Mars.

The measurements showed that the shear-waves move faster in the crust when rocks between 10 and 25 kilometers underground oscillate in a direction almost parallel to the planet surface than if the rocks vibrate in the vertical direction.

“This wave speed information is related to deformations inside the crust,” Beghein said. “Alternating volcanic rocks and sedimentary layers, which were deposited long ago, or a very large impact, such as a meteoroid, most likely account for the seismic wave measurements we observed.”

These data also enabled Jiaqi Li, a UCLA postdoctoral researcher in Beghein’s group, to learn that shear-waves move faster in the Martian southern highland areas than in the northern lowlands. The northern hemisphere of Mars has a lower elevation and is covered with more craters than the southern hemisphere. A large impact in the lowlands has been the prevalent theory to explain the origin of this difference.

The new data point toward the presence of thick accumulations of sedimentary rocks and relatively higher porosity in the lowlands. Larger amounts of gas, such as trapped air in these sedimentary rocks, slow the waves down.

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Materials provided by University of California – Los Angeles. Original written by Holly Ober. Note: Content may be edited for style and length.