Day: 12/23/2022

Glioblastoma-Specific Epigenetic Mechanism Identified that Scuppers Tumor Suppressor

Posted by

0


Researchers at Cold Spring Harbor Laboratory (CSHL) say they have discovered that a protein known as BRD8 may represent a previously unknown vulnerability in the deadly brain cancer glioblastoma (GBM). The results of laboratory studies by Alea Mills, PhD, and colleagues demonstrated how BRD8 underpins a glioblastoma-specific epigenetic mechanism that acts to prevent the key tumor suppressor protein p53 from functioning normally. The researchers’ in vitro experiments and study in a glioblastoma mouse model suggested that targeting BRD8 could effectively unlock p53 activity, representing a therapeutic strategy that could lead to the development of new treatment options and better patient outcomes.

They reported on their findings in Nature, in a paper titled, “BRD8 maintains glioblastoma by epigenetic reprogramming of the p53 network,” in which they concluded, “This work identifies BRD8 as a selective epigenetic vulnerability for a malignancy for which treatment has not improved for decades.”

Patients with GBM have a median survival of 12–14 months and a 5-year survival of less than 5% because of the lack of effective treatments, the authors noted. “The aggressiveness of glioblastoma is notorious,” said Mills. “The norm is to do surgery, treat with harsh drugs, and just hope for the best.”

The CSHL team has now solved a decades-old mystery surrounding glioblastoma’s aggressiveness by linking the BRD8 protein to the tumor suppressor protein p53, which is encoded by the gene TP53. A staple in the body’s natural cancer defenses, p53 prevents cells from overgrowing and turning into tumors. Almost all cancers depend on p53 becoming mutated (TP53Mut) and thus disabled. However, in the majority of glioblastoma cases, the gene remains unmutated (TP53WT) and so the p53 protein is also normal. “ … p53 remains unmutated in the majority of cases of GBM—the most common and deadly adult brain malignancy,” the investigators wrote. As CSHL postdoctoral fellow Xueqin Sun, PhD, questioned, “So why does this cancer act like p53 is broken?” The authors acknowledged, “Thus, how p53-mediated tumor suppression is countered in TP53WT GBM is unknown.” It was this critical query that led Mills’ team to discover that BRD8 had effectively gone rogue in glioblastoma, crippling p53 in a way that hadn’t been previously known.

BRD8 works by shutting down access to genes in chromosomes. If a gene is wound up tightly, it cannot be used—it’s as if it were “asleep.” The study by Mills and her team, including experiments in patient-derived cell lines and in mouse models of glioblastoma, revealed that BRD8 was inappropriately active in glioblastoma, preventing many of p53’s critical anticancer defenses from getting to work. “Our findings demonstrated that BRD8 bypasses p53 tumor suppressive activity by enforcing a compact chromatin conformation to restrain the accessibility of p53 to its targets.” When the researchers inactivated BRD8 via genome editing, p53’s “arsenal” suddenly woke up and began blocking tumor growth.

“It’s like BRD8 is saying ‘NO ENTRY’ to p53’s tumor-preventing power, but when we hit BRD8 in the right way—go in there almost like a scalpel, but molecularly—the tumor is annihilated,” Mills explained. She and her team implanted tumor cells from glioblastoma patients into mice and watched the tumors grow in the brain. When BRD8 was inactivated, p53 was unlocked—the tumors stopped growing and the mice lived longer. “Here we identified BRD8 as an epigenetic vulnerability for TP53WT GBM, which to our knowledge has not been previously associated with this brain malignancy,” the authors stated. “… we demonstrated that BRD8 was essential for the growth of human TP53WT GBM in vivo and that BRD8 depletion significantly prolonged the survival of mice bearing TP53WT but not TP53Mut GBM.”

The finding suggests that drugs targeting BRD8 could work against glioblastoma. Mills hopes her team’s discovery will help to turn this deadly brain cancer into a treatable disease and for the first time in a generation extend the life expectancy of patients who are diagnosed with it. “Taken together, this study revealed that TP53WT GBM is sensitive to BRD8 depletion, which provides an encouraging way to awaken the sleeping guardian p53 in the majority of GBM cases,” Mills and colleagues concluded.

Novel Insights into Immune Function Illuminated by Spatial Lung Atlas

Posted by

0


The Wellcome Sanger Institute and collaborators report they have developed a lung cell atlas that reveals 11 new lung cell types and provides new insights into an immune process involved in fighting lung infections.

Their findings, “A spatially resolved atlas of the human lung characterizes a gland-associated immune niche,” are published in Nature Genetics and highlight multiple immune cells, barrier cells, and their environments in the lung that are implicated in respiratory diseases and infections.

“Single-cell transcriptomics has allowed unprecedented resolution of cell types/states in the human lung, but their spatial context is less well defined,” wrote the researchers. “To (re)define tissue architecture of lung and airways, we profiled five proximal-to-distal locations of healthy human lungs in depth using multi-omic single cell/nuclei and spatial transcriptomics (queryable at lungcellatlas.org). Using computational data integration and analysis, we extend beyond the suspension cell paradigm and discover macro- and micro-anatomical tissue compartments including previously unannotated cell types in the epithelial, vascular, stromal, and nerve bundle micro-environments.”

The new lung cell atlas, which is part of the wider international Human Cell Atlas Initiative, combined single-cell sequencing with spatial transcriptomics to provide a fuller picture of how cells interact and communicate with each other.

Researchers from the Wellcome Sanger Institute and collaborators, genetically profiled nearly 200,000 cells from the lung tissue of 13 donors, discovering 11 new cell types, and showing the exact location of 80 cell types in total.

Of the new cell types, peribronchial fibroblasts were found to be implicated in COPD and idiopathic pulmonary fibrosis.

Further research is required to observe how these cells are involved, yet discovery demonstrates the potential of using the lung atlas to uncover new links between cell pathways and disease.

“By being able to analyze multiple locations of the same lung, we were able to get key information about a range of cells in a single study, many of which were not previously mapped,” explained Elo Madissoon, PhD, joint first author and postdoctoral fellow at the Wellcome Sanger Institute and EMBL’s European Bioinformatics Institute (EMBL-EBI).

“In addition, the link we found between peribronchial fibroblasts and chronic lung conditions shows how this atlas goes beyond reference data and can offer new insights into disease.”

The researchers were also able to define a lung microenvironment which they call the gland-associated immune niche (GAIN).

“Our study provides unique information about how cells communicate in the human lung and airways,” said Amanda Oliver, PhD, joint first author and postdoctoral research fellow at the Wellcome Sanger Institute. “By integrating single cell and spatial data, we were able to study how epithelial, endothelial, and immune cells interact to form an immune niche— the GAIN—which is likely to be important for protection against respiratory infections. Our single-cell data allows us to drill into the signaling circuits that enable this immune niche to function and could be crucial in developing new ways to treat disease in the future.”

The atlas provides a detailed understanding of cells and may explain many aspects of human health and disease. Their findings could help identify which pathways or cells in the lung could be targeted to help improve immunity in individuals with impaired lung function.

How Turmeric Can Save the Aging Brain From Dementia and Premature Death

Posted by

0


How Turmeric Can Save the Aging Brain From Dementia and Premature Death

Presently, there are no pharmaceutical interventions that effectively slow, and certainly not reverse, age-related cerebrovascular pathologies linked to conditions such as Alzheimer’s disease and stroke. A new study on turmeric extract, however, indicates that a natural curative agent already exists and is close to the everyday consumer as their spice rack. 

A promising study published in Cellular Physiology and Biochemistry titled, “Dietary Curcumin Ameliorates Aging-Related Cerebrovascular Dysfunction through the AMPK/Uncoupling Protein 2 Pathway,”[i] reveals the primary polyphenol in turmeric known as curcumin (which gives it its golden hue) may provide what the study authors describe as an “effective therapeutic strategy to reverse age-related cerebrovascular dysfunction.”

Age-related cerebrovascular dysfunction is occurring on an epidemic scale in Western countries and include, “stroke, cerebral amyloid angiopathy, cognitive decline and neurodegenerative diseases.”  Presently, very few if any conventional medical interventions are capable of providing effective solutions, and none have been found to reverse underlying pathologies in conditions whose trajectories are generally characterized as ‘incurable.’ All the more reason why the new study holds so much promise in providing an evidence-based natural solution that is safe, effective, affordable and easily accessible as a familiar food ingredient.

The study was conducted using a rat model. 24-month old male rodents were given dietary curcumin (.2%), with young control rodents 6-months of age.  After one month of curcumin treatment, the researchers observed a ‘remarkable restoration’ of the impaired cerebrovascular endothelium-dependent vasorelaxation (i.e. the ability of the blood vessels to naturally relax) in the aging rats. They observed three distinct ‘molecular’ ameliorative effects:

  • Curcumin promoted eNOS and AMPK phosphylation: Increasing nitric oxide (NO) bioavailability enables the inner lining of the blood vessels (endothelium) to fully dilate, reducing cardiovascular risk factors such as hypertension and associated damage to the arteries. Increased 5′-AMP activated protein kinase (AMPK) activity is also associated with improved age-related endothelial function.
  • Curcumin upregulated mitochondrial uncoupling protein 2 (UCP2): UCP2 plays an important role in mitochondrial homeostasis and its optimal functionaing has been associated with increased lifespan.
  • Curcumin reduced Reactive Oxygen Species (ROS) production: ROS reduction is associated with decreased oxidative stress and related cellular damage.

The authors summarized their findings as follows:

“In summary, our findings provide the first evidence that chronic pharmacological AMPK/UCP2 pathway activation by curcumin treatment may be an effective therapeutic strategy to reverse age-related cerebrovascular dysfunction. Curcumin administration may represent a promising lifestyle intervention for preventing age-related cerebrovascular disturbances.”

A Massive Body of Research On Curcumin’s Brain Protective Properties

GreenMedInfo.com houses a database of over 3,000 abstracts from the National Library of Medicine on the health value of turmeric and/or curcumin in over 900 health conditions. View them all here: turmeric health benefits.  Of the 280 distinct beneficial physiological actions documented within this literature, 276 of them concern the spice’s neuroprotective properties. View them here: neuroprotective properties of turmeric.

While this latest study, and most of the research on our turmeric database is preclinical, there are reports of turmeric causing significant improvements in cerebrovascular dysfunction diseases such as Alzheimer’s. In a previous article titled, “Turmeric Produces ‘Remarkable’ Rocvery iin Alzheimer’s Patients,” we reported on the ability of turmeric to produce dramatic improvement in patients suffering from behavioral and psychological symptoms of dementia.

As we discussed in the article, other documented Anti-Alzheimer’s disease mechanisms of turmeric include:

  • Anti-inflammatory: Curcumin has been found to play a protective role against β-amyloid protein associated inflammation.[11]
  • Anti-oxidative: Curcumin may reduce damage via antioxidant properties.[12]
  • Anti-cytotoxic: Curcumin appears to protect against the cell-damaging effects of β-amyloid proteins.[13] [14]
  • Anti-amyloidogenic: Turmeric contains a variety of compounds (curcumin, tetrahydrocurcumin, demethoxycurcumin and bisdemethoxycurcumin) which may strike to the root pathological cause of Alzheimer’s disease by preventing β-amyloid protein formation.[15] [16] [17] [18]
  • Neurorestorative: Curcuminoids appear to rescue long-term potentiation (an indication of functional memory) impaired by amyloid peptide, and may reverse physiological damage by restoring distorted neurites and disrupting existing plaques.[19] [20]
  • Metal-chelating properties: Curcumin has a higher binding affinity for iron and copper rather than zinc, which may contribute to its protective effect in Alzheimer’s disease, as iron-mediated damage may play a pathological role.[21] [22]

Turmeric, of course, is not the only natural substance that has been proven to have value in neurodegenerative conditions.  For those looking for additional research on food and spice-based natural alternatives that are evidence based, here are additional substances that may be of value:

  • Coconut Oil: This remarkable substance contains approximately 66% medium chain triglycerides by weight, and is capable of improving symptoms of cognitive decline in those suffering from dementia by increasing brain-boosing ketone bodies, and perhaps more remarkably,within only one dose, and within only two hours.[23]
  • Cocoa: A 2009 study found that cocoa procyanidins may protect against lipid peroxidation associated with neuronal cell death in a manner relevant to Alzheimer’s disease.[24]
  • Sage: A 2003 study found that sage extract has therapeutic value in patients with mild to moderate Alzheimer’s disease.[25]
  • Folic acid: While most of the positive research on this B vitamin has been performed on the semi-synthetic version, which may have unintended, adverse health effects,  the ideal source for this B vitamin is foliage, i.e. green leafy vegetables, as only foods provide folate. Also, the entire B group of vitamins, especially including the homocysteine-modulating B6 and B12,[26] may have the most value in Alzheimer’s disease prevention and treatment. 
  • Resveratrol: this compound is mainly found in the Western diet in grapes, wine, peanuts and chocolate. There are 16 articles on our website indicating it has anti-Alzheimer’s properties.[27]
  • Gingko biloba: is one of the few herbs proven to be at least as effective as the pharmaceutical drug Aricept in treating and improving symptoms of Alzheimer’s disease.[28] [29]
  • Melissa offinalis: this herb, also known as Lemon Balm, has been found to have therapeutic effect in patients with mild to moderate Alzheimer’s disease.[30]
  • Saffron: this herb compares favorably to the drug donepezil in the treatment of mild-to-moderate Alzheimer’s disease.[31]

Finally, it is of utmost importance to understand that turmeric contains a wide range of therapeutic biomolecules and not to get fixated on simply curcumin. There are also water and alcohol soluble components of the plant that you won’t find in extracts standardized simply to curcuminoid content. For example, a fat soluble component known as aromatic turmerone has been found to be especially important for brain regeneration, capable as it is of stimulating the regeneration of neural stem cells and their subsequent differentation into functional and fully differentiated neurons. To learn more about the remarkable healing properties of aromatic tumerone and whole turmeric read my previous article on the topic: How WHOLE Turmeric Heals The Damaged Brain.

References

[i] Yunfei Pu, Hexuan Zhang, Peijian Wang, Yu Zhao, Qiang Li, Xing Wei, Yuanting Cui, Jing Sun, Qianhui Shang, Daoyan Liu, Zhiming Zhu. Dietary curcumin ameliorates aging-related cerebrovascular dysfunction through the AMPK/uncoupling protein 2 pathway. Cell Physiol Biochem. 2013 ;32(5):1167-77. Epub 2013 Nov 11. PMID: 24335167

What Can ChatGPT Do For Your Practice?

Posted by

0


Impressive AI text generator still has notable limitations

A photo of a man accessing ChatGPT on a laptop

At the end of November, a new artificial intelligence chatbot was released for public use. Just 2 weeks later, Clifford Stermer, MD, found an intriguing new use for the technology in his rheumatology practice, which he shared on TikTok.

In the videoopens in a new tab or window, Stermer typed a prompt into ChatGPT, developed by OpenAI, requesting that the chatbot write a letter to a medical insurance company to explain why a patient with systemic sclerosis should be approved for an echocardiogram. Seconds later, on camera, the program started writing a full letter, complete with appropriate heading and formatting.

Stermer, who owns One Rheumatology in Palm Beach Gardens, Florida, narrated the writing of the letter during the TikTok video. He highlighted the most impressive elements, such as the explanation of the treatment and use of references. He concluded the video by saying, “Amazing stuff. Use this in your daily practice, okay. It will save time. It will save effort.”

That video went viral almost immediately, he said, and now has more than 130,000 views. It was widely shared on other social media sites as well, including Twitter, where it sparked a wide-ranging conversationopens in a new tab or window about other uses of this tool in healthcare.

Beyond the ChatGPT Hype

Since ChatGPT was released on November 30, it has become one of the internet’s most referenced and tested programs in recent weeks.

“I was talking to some other doctors about it online, and there was a question about how can we use this to our advantage,” Stermer told MedPage Today. He said that insurance denial letters were one of the first things that came to his mind when he learned about the program. “This seems like one of the tasks that we need to do regularly that it may be able to help with.”

According to the OpenAI websiteopens in a new tab or window, ChatGPT was created using a language model trained to produce text, known as GPT-3.5. And it was designed to create texts, like insurance denial letters, using a method that models previously demonstrated texts created by humans “to guide the model toward desired behavior.”

After the video took off, Stermer realized that the program had more limitations than he first thought. For one, he said, the references in the letter were not realopens in a new tab or window. ChatGPT made them up.

In fact, Stermer has found that much of the information produced by the program has been inaccurate or only partially correct.

“The sources were kind of half right,” he said. “The authors were right, and then some of the articles were right, but it didn’t piece it together exactly. So it’s not something you could just send off to an insurance company, or really use at this point.”

“It wrote a beautiful text, and it kind of got the points across,” he said. “But it was still not where it needs to be.”

OpenAI acknowledges that ChatGPT is not connected to the internet, so it can produce incorrect answers. In fact, ChatGPT has limited knowledge of “events after 2021 and may also occasionally produce harmful instructions or biased content,” according to the organization’s website.

A Future of Possibilities

However, ChatGPT still holds some unique potential in easing a physician’s daily tasks, according to urologic oncologist Anobel Odisho, MD, MPH, of University of California San Francisco.

In particular, Odisho noted that repetitive writing is a big part of his job as a clinician, a practice manager, and a researcher.

“In each of those roles, we do some repetitive, low-value writing and administrative work which I think we can automate, either with ChatGPT or other tools,” Odisho told MedPage Today.

Odisho said he has used the program to generate first drafts of letters that he then reviewed and edited. He also used it to generate more patient-friendly descriptions of procedures or post-procedure instructions. He even used it to create a draft of an on-call schedule.

“I think the possible use cases are only limited by your creativity and ability to write a good chat ‘prompt,'” Odisho said.

But he also acknowledged that this technology has serious limitations as well. He emphasized that healthcare professionals should be careful about what information they share with this program, especially when it comes to patients.

“Do not trust it, it is not ready for primetime,” Odisho warned.

Ultimately, Odisho said ChatGPT is just the beginning of this kind of technology in medicine. His primary takeaway is that this is the future, and he believes all healthcare professionals should start getting comfortable with it.

“I think in the future you really will have two classes, one group that can seamlessly and fluidly utilize these tools effectively in their personal and work lives, and another that cannot, and will struggle to keep pace,” Odisho said.

Stermer agreed that ChatGPT is a preview of things to come, but right now he acknowledged it is not as useful for his practice as he first hoped.

“It’s more a look into the future of the possibilities, or how things are going to be done,” he said “But it does not replace medical expertise.”

After 50 years, fusion power hits a major milestone. The future of energy begins today

Posted by

0


Its implications go well beyond the Earth itself, affecting even the future of space travel.

Key Takeaways

  • Researchers at the National Ignition Facility in Livermore, California achieved net energy gain in a thermonuclear fusion experiment. But how great of a breakthrough is this, really?
  • As soon as physicists realized how the Sun made its energy, they dreamed of getting the same process to work on Earth. They have worked on it since the 1950s and finally achieved success.
  • There is still a long way to go. But we can now say with confidence that in the not-too-distant future, fusion power stations will generate all the world’s energy needs, cleanly and at incredibly low cost.

On Tuesday, the U.S. Department of Energy announced that researchers at the National Ignition Facility in Livermore, California, had achieved net energy gain in a thermonuclear fusion experiment. The result was hailed as one of the most important scientific breakthroughs of the 21st century and the first step toward the holy grail of a cheap, plentiful source of clean energy. The news ping-ponged around the media. I had the chance, very briefly, to explain what it meant on both NBC and MSNBC. 

But what does it all mean? Are the results really as remarkable as the Department of Energy touts? And how long before we all have a Mr. Fusion in our kitchens?

Core fusion concepts 

Along with being a professor at the University of Rochester Physics and Astronomy Department, I am also a scientist at the Laboratory for Laser Energetics, located just south of campus. The Laboratory is a premier laser fusion research facility, with $30 million per year in funding from the Department of Energy. It’s the smaller cousin of National Ignition Facility — a place where many ideas are first explored before taking them to Livermore. (The LLE can fire its lasers once every hour, while the NIF can only fire about once a day.) 

From that vantage point, I have spent more than 20 years watching the push for fusion. And I can tell you that yes, without a doubt, Tuesday’s announcement is a very big deal indeed.

The Sun is powered by thermonuclear fusion reactions in its core. Four hydrogen nuclei — each with a single proton — are squeezed together to form a helium nucleus, with its two protons and two neutrons. In the process they release some energy, as described by E = mc2. The Sun pulls off this trick by using the gravitational crush of its ponderous mass — 330,000 times the mass of the Earth. All that gravitational squeeze forces temperatures at the Sun’s core past 10 million degrees Kelvin. This creates pressures that slam the hydrogen nuclei together hard enough for the needed nuclear transmutation to occur. 

As soon as physicists realized this was how the Sun made its energy, they started to dream of getting the same process to work on Earth. But scientists don’t have 330,000 Earths-worth of mass to get things going, and there is a long-standing joke in fusion science circles that no matter when you ask, fusion will always be 20 years away. First, scientists tried using magnetic fields to generate the needed pressures. Later, they saw they could use converging laser beams to generate the squeeze. Regardless of the method, what matters is that since the 1950s there has been someone, somewhere, working to achieve fusion in a lab. The process has been painful and the progress slow. 

It took decades, but we finally gained energy

While magnetic fusion and laser fusion(also called inertial confinement) have battled for supremacy, neither method had reached a point where any energy extracted by fusion reactions was greater than the energy put in to initiate those reactions. Simply put, there was no net energy gain. 

When the Department of Energy decided to build the National Ignition Facility at the beginning of this century, the NIF immediately became the granddaddy of all laser fusion machines. It was so big that everyone expected net energy gain was just a few years away. But the Facility failed to deliver on those promises initially. Laser energy that was supposed to reach the target — a tiny capsule of deuterium and tritium — was being shunted away by the plasma generated in the capsule’s implosion. These initial failures left some wondering whether achieving fusion in the laboratory was simply impossible. Maybe the process was just too complicated, with too many instabilities that could thwart fusion ignition.

But the scientists at the National Ignition Facility finally prevailed. With patience and ingenuity, they worked and reworked the design of their experiments — the laser pulse, the fuel capsule, and anything else they could think of — and slowly they inched closer to their goal. Finally, they triggered a runaway thermonuclear ignition. Like a struck match, once the deuterium-tritium fuel started to burn, it gave off more energy than had been used to start the thermonuclear reactions. This result finally put the first part of the old “20-year” quip to rest. Fusion scientists have waited 50 years for this milestone, and now it is in the history books.

So, when will fusion power stations start to generate all the world’s energy needs, cleanly and at incredibly low cost? Well… in about 20 years. But the goal is attainable now. Before, we did not even know if fusion in the lab was possible. Now we know it is. Moving forward from here is about solving a lot of technical and engineering challenges. That will definitely take more than 10 years, but 20 or 30 years is now a realistic timetable for the development of a working commercial reactor. Now that we know it’s possible, there really is nothing to stop us. 

Smarter faster: the Big Think newsletter

Subscribe for counterintuitive, surprising, and impactful stories delivered to your inbox every Thursday

Fields marked with an * are required

The consequences of such a breakthrough are hard to fathom. Imagine what the world could do with a near-limitless supply of cheap, clean energy. What could we achieve? How might we progress? The implications soar beyond Earth. Nuclear fusion rockets would make continuous acceleration/deceleration to Mars and the rest of the solar system a reality. Rather than taking six to nine months to reach Mars, you could keep your motor on, accelerating and decelerating at 1G to arrive in just weeks. So indeed, there are many ways achieving fusion ignition is a game changer.

PhD student solves a mysterious ancient Sanskrit text algorithm after 2,500 years

Posted by

0


A Cambridge Ph.D. student has solved a grammatical problem that has befuddled Sanskrit scholars since the 5th century BC.

sanskrit

Key Takeaways

  • Pāṇini’s Aṣṭādhyāyī is an important work for understanding classical Sanskrit.
  • But for centuries, a grammatical problem surrounding a meta-rule has risked readers misinterpreting the text. 
  • Rishi Rajpopat, a Cambridge Ph.D. student, has solved the grammatical problem by rediscovering Pāṇini’s original intention.

Around 350 BC, the scholar Pāṇini composed a grammatical treatise of astounding breadth and comprehension. Known as the Aṣṭādhyāyī, it contained 4,000 sūtras, or rules, for writing classical Sanskrit. The extensive work also distinguishes between how the language should be expressed colloquially or when reciting sacred texts.

To put that in perspective for a modern, English-speaking audience, the Aṣṭādhyāyī is what you would get if William Strunk Jr. and E.B. White’s The Elements of Style was an eight-volume tome designed to not only dole out advice but offered meticulous instruction for crafting any word or sentence in the language. (Fortunately for English 101 students the world over, Strunk and White’s efforts were less extensive.)

Although Pāṇini had his predecessors, his workis the oldest surviving example of a complete linguistic text. Its influence on modern linguists, such as Ferdinand de Saussure, has led some to honor Pāṇini as the “father of linguistics.”

Not long after Pāṇini produced his masterwork, scholars did what they do best: They argued over how to best interpret it. The intervening centuries of scholarly debate generated a convoluted lineage of explanations for understanding the Aṣṭādhyāyī — and in doing so, how we should read classical Sanskrit.

More than 2,500 years later, a University of Cambridge Ph.D. student, Rishi Rajpopat, may have solved the mystery of how to use Pāṇini’s language machine accurately.

A palm-leaf page from the Aṣṭādhyāyī
The page of the Aṣṭādhyāyī was written on palm-leaf paper.

An ancient language machine

Before discussing Rajpopat’s solution, it’s worth considering what exactly is meant by “language machine.” Pāṇini’s treatise isn’t meant to just describe classical Sanskrit or prescribe usage like a fussy language arts teacher. It’s designed to help its readers generate “flawless” Sanskrit.

Although the Indian subcontinent has produced many writing systems — historian Steven Roger Fischer calls it “the world’s richest treasury of scripts” — it also maintains a strong oral tradition. The Brahmins, India’s priestly class, long considered speech superior to writing. Even centuries after the Indians adopted writing, the Brahmins continued to pass down the hymns of the Vedas, Hinduism’s oldest four sacred texts, orally.

This tradition meant the desire to use language correctly wasn’t simply a matter of avoiding an embarrassing correction in the comments section. It was of the utmost religious consequence.

With the Aṣṭādhyāyī, Pāṇini didn’t only want to teach the language. He aimed to protect Hinduism’s sacred texts from corruption. He built a system of operations that allowed a reader to combine base words and affixes to generate proper word forms. The user could then combine those words to construct impeccable sentences. All readers had to do was follow the instructions.

Effectively, he created an analog algorithm that would produce the same Sanskrit word, sentence, and hymn each time — preserving the language and settling disputes over correct usage for time immemorial.

An enigma in the machine 

If only. 

Unfortunately for later scholars, Pāṇini’s style is succinct, economical, and intricately self-referential. Preceding rules affect later rules in the operation but without explicitly stating so. As Rajpopat writes in his Ph.D. thesis: “There is no universal convention as to which terms are supposed to or can become [continued] into a certain rule.” 

These stylistic choices make the Aṣṭādhyāyī shorter and easier to memorize than it would be otherwise — some historians believe it was initially composed orally — but also incredibly dense. That density leads to rule conflicts, in which two rules may apply simultaneously to the same word yet produce different outcomes.

Pāṇini did provide a meta-rule to solve such conflicts. According to traditional scholarship, this meta-rule states that “in the event of a conflict between two rules of equal strength, the rule that comes later in the serial order of the Aṣṭādhyāyī wins.”

Seems simple enough. But when applied, this meta-rule yields many exceptions. To correct those exceptions, scholars have for centuries created their own meta-rules. However, those meta-rules yielded even more exceptions, which required the creation of additional meta-rules (meta-meta-rules?). Those meta-rules in turn created even more exceptions — and you see where this is going.

Dr. Rishi Rajpopat
Dr. Rishi Rajpopat solved the grammatical problem of Pāṇini’s metarule and published the results in his Ph.D. thesis. (Credit: Cambridge University Library)

One meta-rule to rule them all

While working on his thesis, Rajpopat decided that this meta morass could not have been what Pāṇini intended with the Aṣṭādhyāyī. “Pāṇini had an extraordinary mind and he built a machine unrivaled 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,” Rajpopat said in a press release.

Smarter faster: the Big Think newsletter

Subscribe for counterintuitive, surprising, and impactful stories delivered to your inbox every Thursday

Fields marked with an * are required

Rajpopat returned to Pāṇini’s original meta-rule and considered it with a fresh lens. When he found a rule conflict, rather than give preference to the later rule in serial order, he deferred to the word that came later in the sentence. Because Sanskrit is written left to right, that meant applying the rule appropriate to the word on the right.

An example shared by Rajpopat is the sentence “devāḥ prasannāḥ mantraiḥ” (“The Gods are pleased by the mantras”). Rajpopat notes that a rule conflict arises when trying to derive the word mantraih (“by the mantras”). One rule applies to the left word, mantra, and another to the right word, bhis. By applying his interpretation of the meta-rule, he followed the rule for bhis and arrived at the correct form of mantraih.

Rajpopat’s research looked at many other rule conflicts, and thorough textual evidence shows that the meta-rule results in the correct form time and again. This potentially makes it possible to construct millions of grammatically correct classical Sanskrit texts.

“[Rajpopat] has found an extraordinarily elegant solution to a problem which has perplexed scholars for centuries. This discovery will revolutionize the study of Sanskrit at a time when interest in the language is on the rise,” Vincenzo Vergiani, a professor of Asian and Middle Eastern studies at Cambridge, said in the same release.

A sage idol of the grammarian Pāṇini
A sage idol of Pāṇini found at Panini Tapobhumi, Arghakhanchi. (Credit: Panini Khabar/Wikimedia Commons)

From language machine to learning machines

Sanskrit isn’t only the sacred language of Hinduism. Throughout India’s history, works of poetry, philosophy, mathematics, and literature have been written in the script. By solving this grammatical problem, Rajpopat has given modern scholars a fresh means to interpret and understand this wealth of human achievement.

And now unlocked, Panini’s ancient algorithm could also potentially be taught to computers. This may not only improve the accuracy of modern translations but dramatically increase the speed at which such scholarship can be undertaken.

“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,” Rajpopat said.

The top 10 science stories of 2022

Posted by

0


As the year draws to a close, it’s time to look back at the groundbreaking advances that made news in 2022 and will shape the world for years to come. Here are Big Think’s selections for the top science stories of 2022:

10. For the first time, a human wears augmented reality contacts

In July, the startup Mojo Vision announced that their CEO wore the company’s prototype augmented reality (AR) contact lenses for the first time. Each device is equipped with a display that is 30 times sharper than an iPhone’s and is outfitted with all the technology needed to track a user’s eye movements. Though extremely preliminary, the technology makes real the sci-fi dream of implanted vision that allows the wearer to seamlessly interact with digital images overlaid on perceptual reality.

9. An experiment suggests that consciousness relies on quantum entanglement

By orders of magnitude, the human brain is pound for pound the most powerful computer in the known Universe. Researchers have spent a great deal of energy trying to uncover its operational secrets, which enable creativity, imagination, and consciousness, among other wonders. Recently, a team at Trinity College Dublin conducted a mind-bending experiment that led them to an unconventional conclusion: the brain could be quantum. The researchers correlated subjects’ heartbeat potentials with seemingly unconnected interactions among proton spins in their brains, hinting that quantum entanglement might be at play. Brain activity, and maybe even consciousness, might operate on a quantum level.

8. The rings of Saturn may finally be explained

Let’s be honest, Earth is beautiful, but Saturn, with its transcendent rings, is the real “looker” in our Solar System. Amazingly, the sixth planet from the Sun’s signature feature has defied explanation for centuries, until 2022, that is. Astronomers from MIT and UC-Berkeley put forth an explanation that not only accounts for the planet’s rings, but also its numerous unique moons. They suggest that Saturn once had an icy moon, which they dubbed Chrysalis, that was torn apart approximately 160 million years ago by tidal gravitational interactions from Saturn and its moon Titan. Saturn’s rings are the shimmering remains.

saturn rings
Credit: NASA / JPL-Caltech / Space Science Institute

7. NASA’s DART spacecraft successfully deflects an asteroid

Earth’s myriad inhabitants can slumber a little more peacefully after 2022, as NASA successfully carried out a mission to redirect an asteroid. The agency’s 610-kg DART spacecraft smacked into the asteroid Dimorphos at a blistering speed of four miles per second, slightly altering the space rock’s trajectory. Dimorphos was never a danger to Earth, but if astronomers ever do spot a large object hurtling toward our planet — potentially risking our extinction — we now know that it’s possible to deflect it.

6. Researchers synthesize the “wonder material” graphyne in bulk

You’ve no doubt heard of graphene. The Nobel Prize-winning nanomaterial is 100 times stronger than the strongest steel at the same thickness, while being electrically conductive and surprisingly transparent. But have you heard of its cousin? Graphyne has many of the same properties, but greatly outperforms graphene for semiconductor applications. In August, University of Colorado-Boulder and Qingdao University of Science and Technology reported that they had synthesized graphyne in meaningful amounts for the first time.

5. The story of human evolution is shaken by two discoveries

The timeline of human evolution is constantly in flux as new fossils of ancient humans are unearthed. This year, two discoveries altered that timeline yet again, albeit in a slightly different manner. In each, scientists re-analyzed previously discovered fossils with novel dating methods. Purdue scientists found that an Australopithecus, one of the earliest relatives of the genus Homo, found in South Africa was between 3.4 and 3.7 million years old, more than a million years older than the previous estimate. Another group from the University of Cambridge discovered that a modern human fossil found in Ethiopia was actually 230,000 years old, not 190,000. For comparison, humans were thought to have arisen as early as 300,000 years ago.

4. Artemis I launches at last

The Space Launch System (SLS) mega-rocket is meant to be America’s vehicle for a long-time-coming crewed return to the Moon. Finally, after more than a decade of development and numerous frustrating delays, it flew at last on November 16, 2022, sending the Orion spacecraft on a flawless journey to the Moon and back. Next up is a crewed lunar flyby slated for 2024, and then a highly anticipated human return to the Moon itself. And after that? The SLS could very well take humans farther out into the Solar System, going where no one has gone before.

NASA’s Space Launch System rocket carrying the Orion spacecraft launches on the Artemis I flight test, Wednesday, Nov. 16, 2022, from Launch Complex 39B at NASA’s Kennedy Space Center in Florida. (Credit: NASA / Joel Kowsky)

3. A man received a transplant of a genetically engineered pig heart

In January, a terminally ill 57-year-old man in need of a heart transplant but ineligible for the procedure became the first human to successfully receive a transplant of a pig heart. Xenotransplantations like this are usually swiftly rejected by the human body, but this heart came from a pig with ten gene edits intended to lower the risk that the human immune system would attack it. The heart functioned well, but the man, David Bennett, eventually died two months after the groundbreaking procedure. The advance will undoubtedly open the door to using more animal organ transplants to prolong human lives.

2. Google’s AI AlphaFold predicts the structure of 200 million proteins, nearly every one known to science

In 2021, Science Magazine hailed the AI AlphaFold as their “breakthrough of the year.” The tool can determine the 3D structure of a protein in seconds, an undertaking that previously took months or even years. The shape of a protein defines what it can do and how it can be used, so having the structure of every protein in a readily accessible database is an absolutely incredible tool for researchers trying to create new pharmaceutical drugs, but it also has broader implications. “With this new addition of structures illuminating nearly the entire protein universe, we can expect more biological mysteries to be solved each day,” Eric Topol, Founder and Director of the Scripps Research Translational Institute, said.

1. The James Webb Space Telescope starts exploring the Universe

After the James Webb Space Telescope’s successful launch and setup in late 2021 and early 2022, the successor to the legendary Hubble Space Telescope began full operations this summer, with awe-inspiring results. Our Solar System, far-off galaxies, and even the Universe’s earliest stars were showcased in entirely new light. With luck, we’ll be wowed by the newest flagship space telescope for decades to come!

Climate Change Is Harming Physical and Mental Health

Posted by

0


Laken Brooks, a 27-year-old PhD student at the University of Florida, has dealt with the skin condition psoriasis since she was a preteen. It’s always been a painful and difficult condition to manage, but over the past several years, Brooks has struggled even more. She suspects her psoriasis is worse thanks to climate change.

 “Each year, the summer seems to last a bit longer,” Brooks says. “When I first moved to Florida (5 years ago), I noticed that sunburn and sweat made my skin feel even itchier than normal. I tried to alleviate some of the symptoms by wearing hats and head scarves, and I expected that I would acclimate to the new climate. But it’s difficult to acclimate when each year, the temperatures continue going up and my skin can never really get accustomed to the Florida climate.”

Brooks is onto something — climate change is having increasingly bigger impacts on health. The seventh annual The Lancet Countdown on Health and Climate Change, released this fall, confirms that. The report, authored by nearly 100 experts from over 50 academic institutions and agencies, tracks the impact of climate change on global health. The 2022 version revealed that every year, in every region of the globe, climate change is undermining health.  Slideshow

Global Warning: 10 Ways Climate Change Increases Rates of Lung Cancer

Share Share on Facebook Share on Twitter Share on Pinterest

Reviewed by Carmelita Swiner on 10/5/2022

The Lancet report this year identified four major harms from climate change: air quality, heat-related illness, infectious disease, and mental health.

Renee Salas, MD, of the Center for Climate, Health, and the Global Environment at Harvard’s T.H. Chan School of Public Health, is one of the report’s authors. She’s regularly sees how climate change is harming her patients’ health — especially those who cannot afford to mitigate its impacts. 

“We had a patient present to the emergency room last summer with a core temperature of 106,” she explains. “He met the criteria for heat stroke. He and his wife lived in an upper story apartment with no access to A/C.”

Salas sees it as part of her responsibility to her patients to make the connections between climate change and health effects. Heat, in particular, is a palpable way for people to understand that connection, she says. 

The impacts go beyond heat, however. “I have concerns about all of them,” says Salas. “And how climate change impacts a person will be impacted by how they live and the resources they have.” 

Climate’s Impact on Mental Health 

While heat might be the most obvious of harms people recognize from climate change, the mental health piece of the equation is likely the least. Susan Clayton, PhD, is a professor of psychology and environmental studies at the College of Wooster in Ohio. She’s been studying the link between the two for several years and has written three papers on the subject, the first in 2014. 

“We’re reaching a point where people express that they’re anxious about climate change, but they don’t recognize that as a mental health threat,” she says. 

In her work on the subject, Clayton has identified four categories where climate change impacts mental health: 

  • Increasingly severe weather events: As more people experience devastating weather events, more people are also experiencing PTSD, clinical anxiety, depression, and substance abuse.
  • Slower changes: It doesn’t take a category 5 hurricane to dole out mental health harm. As temperatures rise higher than normal for longer periods of time, so too do the rates of suicide and psychiatric hospitalizations.
  • Involuntary displacement: Many people love and are rooted to where they live. As coastal flooding, wildfires, and other weather events displace them, they suffer deteriorating mental health. 
  • Awareness of climate change: As everyone bears witness to climate change and become increasingly aware of its impacts, collective anxiety levels rise. For most people this is manageable, but it’s still harmful.

While talking about climate change and how it harms mental health can sometimes increase feelings of anxiety and other conditions, it’s an essential conversation to have, says Clayton. “When you’re overwhelmed and disempowered, it can be too much to cope with,” she explains. “But it can also encourage you to attend to the issue.” 

Mitigation in the Meantime 

As the data continues to pour out and demonstrate the link between climate change and health, it remains difficult for people to understand. For Salas, this can often be frustrating. 

“I often have to walk upstream to understand what’s causing patients’ issues in the first place,” she says. “That’s why I do the work I do — I cannot just treat patients in the ER and call it good. That’s like putting a band aid on a bullet wound.” 

Recognizing and pointing out that those in the line of fire are often those with fewer resources to change how climate is impacting their health is a starting point. 

“We recognize that policy and higher-level decisions have drive these situations,” Salas says. “So I try to find the risks, educate patients, and then give them recommendations to protect themselves.”

This might look like suggesting a patient add an air filtration system in their home, or ensuring they have a back-up plan for using a nebulizer if the electricity is knocked out. The biggest message to get across, says Salas, is that health is harmed by what is happening “upstream.” “We need political and social will to change,” she says. “We’re beginning to see this — the health community is rising up and recognizing it as fundamental to the mission of medicine.” 

For people like Brooks, who are not able to relocate now, the temporary fix is trying to minimize how climate change exacerbates existing conditions. “I have been able to mitigate some flare-ups by taking cool showers,” she says. “I don’t plan to live in Florida forever, but right now I don’t have the resources to transplant my life and move somewhere else.”

Moderna, Merck Announce Progress on Joint Skin Cancer Vaccine

Posted by

0


t woman feeling skin

Moderna and Merck jointly announced Tuesday progress on a drug combination to fight the recurrence of melanoma, a deadly skin cancer.

The potential vaccine is formed by combining messenger RNA (mRNA) technology – common in coronavirus vaccines — and Merck’s cancer immunotherapy drug Keytruda, the companies said. 

Patients in a trial who received the combination had a 44% lower risk of recurrence or death compared to those who received only Keytruda.

“Today’s results are highly encouraging for the field of cancer treatment. mRNA has been transformative for COVID-19, and now, for the first time ever, we have demonstrated the potential for mRNA to have an impact on outcomes in a randomized clinical trial in melanoma,” Stéphane Bancel, Moderna’s chief executive officer, said in a press release.

Moderna developed one of the most used COVID-19 vaccines.

“The study is the first randomized trial to show that combining mRNA vaccine technology with a drug that revs up the immune response would offer a better result for melanoma patients and potentially for other cancers,” Reuters reported,

The Wall Street Journal said the companies will run a larger study to next year, further strengthening the safety and efficacy of the combination. “Positive results of that study could clear the way for potential regulatory approval of Moderna’s experimental cancer vaccine,” the Journal wrote.

Moderna and Merck also plan to test the combination in other types of cancers. 

“We will begin additional studies in melanoma and other forms of cancer with the goal of bringing truly individualized cancer treatments to patients,” Bancel said. “We look forward to publishing the full data set and sharing the results at an upcoming oncology medical conference, as well as with health authorities.”

The new study followed 157 patients with stage III/IV melanoma. Their tumors were surgically removed before treatment with the combination or just Keytruda.

Beyond Inattention: How ADHD May Be Affecting Your Life

Posted by

0


Compulsive Eating

Compulsive Eating

1/13

Having ADHD often means you struggle with the ability to set limits on your behavior (like eating). What’s more, ADHD often lowers your level of dopamine, the hormone involved in your brain’s pleasure center. Gorging on food is a way to temporarily raise your dopamine levels and get that good feeling again.

Anxiety

Anxiety

2/13

Worry that won’t go away and keeps you from living your life like you want to is a sign of anxiety. About half of adults with ADHD also have an anxiety disorder. Sometimes your ADHD symptoms cause that on-edge feeling. When that’s the case, treating your ADHD also helps your anxiety.

Substance Misuse

Substance Misuse

3/13

The same “thrill-seeking” behavior that leads to out-of-control eating can play a role in the overuse and misuse of drugs and alcohol. Doctors think there may be a link between ADHD and drug or alcohol use disorders.

Chronic Stress

Chronic Stress

4/13

Your ADHD symptoms can be stressful. It’s likely that your stress level stays up for longer than most when you have the disorder. Over time, stress can lead to other issues like:

  • Muscle tension and pain
  • Breathing problems
  • Heart issues
  • Trouble controlling your blood sugar
  • Digestion issues
Sleep Problems

Sleep Problems

5/13

ADHD can affect your ZZZs. It raises your chances of snoring, sleep apnea, and restless legs syndrome (an urge to move your legs when you’re at rest). It can also throw off your body’s internal clock, called the circadian rhythm. That means your sleeping gets out of sync with the natural rising and setting of the sun. That can make you struggle to fall asleep and wake up at regular times.

Employment Problems

Employment Problems

6/13

Though all workplaces are different, most expect you to be organized, on time, attentive, focused, and do the work you’re asked to do. ADHD can make all of these harder. As a result, you may not be able to live up to your employer’s expectations. So it may be a struggle to keep a job.

Trouble With Deadlines

Trouble With Deadlines

7/13

ADHD can make you forgetful and distracted. You’re also likely to have trouble with time management because of your problems with focus. All of these symptoms can lead to missed due dates for work, school, and personal projects.

Impulsive Spending

Impulsive Spending

8/13

Buying things just because you want to gives you a brief boost in those “feel-good” hormones. But that can come at a price. You may find yourself with a drained bank account or bad credit from all of your unplanned spending.

Financial Issues

Financial Issues

9/13

Dropping deadlines and having risky spending practices are just two of the things that raise the chance you’ll leave bills unpaid. You also have to keep up with paper statements and your checkbook — two tasks that are much harder when your ADHD symptoms aren’t under control.

Screen Addiction

Screen Addiction

10/13

It’s true that ADHD makes it hard to keep focus. But when it comes to smartphones, video games, and televisions, your attention can get hooked by the constant change of images, comments, graphics, and games. Your brain craves the reward it gets when you’re on a screen, which can make it hard to tear yourself away.

Sexual Problems

Sexual Problems

11/13

If your ADHD symptoms show up during sex, they can really dampen the mood. Your mind can wander off your partner and the overall experience. Lack of patience can keep you from going the distance. You also need good communication for a healthy sex life, and that may be a struggle for you.

Relationship Problems

Relationship Problems

12/13

It’s common for couples to struggle with communication when ADHD is part of the relationship, especially if you aren’t treating your symptoms. It may feel like you’re constantly nagged by your partner as they try to deal with certain traits of yours, like forgetfulness or lack of focus.

Emotional Outbursts

Emotional Outbursts

13/13

One way ADHD affects your brain is that it makes it harder for you to control how you respond to things. You could explode in anger or lash out in annoyance or impatience. It can also be why you worry so much over minor things.