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Biology

A Bold Theory May Propel Alzheimer’s Disease Research in a Novel Direction

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Alzheimer’s disease is a significant health concern for humanity currently. In recent years, there has been significant progress in the creation of highly promising medicinal treatments, along with the testing of revolutionary medicines and diagnostic methods. Debates persist over the true etiology of the disease. A novel proposal proposes that a complex interaction between two proteins may reveal a “mechanical basis” for Alzheimer’s disease.

The paper has recently been published as a preprint and has not yet been subjected to external peer review. The authors from around the world explained the experiments that were used to come up with a six-part theory about how the protein talin interacts with the Alzheimer’s protein amyloid precursor protein (APP) and how it might play a part in the development of the disease. They also discussed the possibility of targeting this system with drugs.

We spoke to Dr. Ben Goult, a senior author and Professor of Mechanistic Cell Biology at the University of Liverpool, regarding the new research.

Goult has a longstanding relationship with the talin protein. In 2021, he proposed a new theory dubbed the MeshCODE theory to explain how memories could be preserved in the brain. The hypothesis proposes that memories could be physically encoded using a talin molecule’s capacity to transition between two stable configurations, similar to how a mechanical computer utilizes binary switches, with each talin shape representing either “0” or “1.”.

Goult and the team have conducted a number of experiments suggesting that talin may not only be responsible for encoding memories in the brain but also be involved in their deterioration in Alzheimer’s disease.

“The significant milestones included demonstrating experimentally the binding of talin to APP and creating a scaled model of APP,” Goult explained to IFLScience. “This video we created accurately depicts full-length proteins to scale, allowing viewers to easily understand the processes.”

Goult promptly reached out to Dr. Julien Chapuis at the Institut Pasteur de Lille, France, with the obtained results. Chapuis’ team had been methodically evaluating various proteins’ impacts on APP. Talin was omitted from their published findings since it did not meet their established criteria.

“Talin has a significant impact on APP processing compared to other proteins when analyzing the data.” Goult informed IFLScience.

Upon integrating our research on talin as a memory molecule with MeshCODE, I recognized a coherent connection, prompting me to commence writing this new study. As everything began to align, it was quite remarkable. Observing the genetic and molecular data coming together was exhilarating over the final months of writing this.

The scientists propose that APP proteins may form a mesh structure that physically links the two sides of a synapse, the space between two neurons where nerve signals travel. Accurate processing of amyloid precursor protein (APP) is crucial for preserving the synchronization of the synapse. However, errors in this process might result in the development of Alzheimer’s disease by disrupting the binary code, known as the MeshCODE, composed of talin “1s” and “0s,” as discussed above. Alzheimer’s disease progresses through the brain when this failure extends throughout brain networks.

This study offers a novel perspective on the potential role of APP in normal neuronal activity. Goult explained to IFLScience that errors in mechanical homeostasis can lead to issues.

The explanation fits with what we are learning about the pathology of Alzheimer’s, especially the presence of misfolded amyloid-β protein plaques in the brains of people with the disease, which are caused by improper processing of APP.

“It also suggests several potential new approaches to treating Alzheimer’s or detecting it sooner,” Goult remarked.

This is all still theoretical. Goult and colleagues propose that the next phase should involve thorough experimental confirmation and improvement of these theories, which they are now doing in the laboratory and plan to progress to animal research soon.

This aligns with the pivotal sixth aspect of the theory, suggesting the potential repurposing of current medications to mitigate the progression of Alzheimer’s disease.

Focal adhesions (FAs) are substantial protein structures that link cellular components to their external surroundings. Previous genetic studies indicate a connection between the stability of fatty acids (FAs) and the stability of amyloid precursor protein (APP) at the synapse. We already possess medicines that are recognized for their ability to stabilize FAs, commonly employed in cancer therapy. Could these possibly exert a similar impact on amyloid precursor protein (APP) in the brain by restoring the APP’s mechanical structure and inhibiting the degradation that results in Alzheimer’s disease?

Goult and colleagues are eager to further examine this intriguing idea.

Goult’s experience with talin has been full of shocks, and this bold new idea is the latest addition to that list.

Goult expressed enthusiasm for studying individual proteins and their functions, appearance, and interactions, which can generate innovative concepts that span from molecular complexes to synapses, neurons, and the entire brain.

Hopefully, these new data and the resulting theories can expedite the development of novel treatments for this condition.

The preprint is accessible on bioRxiv but has not been reviewed by external peers yet.

As Editor here at GeekReply, I'm a big fan of all things Geeky. Most of my contributions to the site are technology related, but I'm also a big fan of video games. My genres of choice include RPGs, MMOs, Grand Strategy, and Simulation. If I'm not chasing after the latest gear on my MMO of choice, I'm here at GeekReply reporting on the latest in Geek culture.

Biology

Living bacteria may still be in a 44,000-year-old wolf that is frozen in permafrost

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An ancient wolf that has been frozen like a popsicle for more than 44,000 years has been analyzed by scientists in Russia. The results will give us a lot of information about how it lived as a top predator during the Ice Age.

Over 40 meters (131 feet) of permanent ice covered the Tirekhtyakh River in the Abyysky District in the Far East of Russia in 2021. This is where the wolf was found.

The body was taken to the Academy of Sciences of the Republic of Sakha (Yakutia). Since then, scientists from the Mammoth Museum of the North-Eastern Federal University and the European University at Saint Petersburg have been busy examining it.

Under clean conditions, the team cut open the body and took samples of the organs inside as well as the food that went through the digestive system. The germs in a wolf’s gut might help us figure out what it eats and how healthy it is.

“His stomach has been kept in a pure form, with no other substances present, so the job is not easy.” After the preparation, we hope to get a picture of the plants and animals that lived in the Pleistocene era. We have the chance to find out what it ate because it was a big, busy predator. Albert Protopopov, head of the department for the study of mammoth fauna at the Academy of Sciences of Yakutia, said in a statement, “The things that his victims ate also ended up in his stomach.”

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“Also, we chose one premolar tooth to figure out how old the find was biologically.” We can tell that this is an adult male because the teeth are worn down and the sagittal ridge has grown, said Maxim Cheprasov, who is in charge of the lab at the North-Eastern Federal University Mammoth Museum.

Researchers are hopeful that some of the germs that live inside the animal might still be alive after being frozen in a state similar to hibernation for tens of thousands of years at temperatures below zero. We might even be able to use them to help with science today if they have survived.

“Working with the NEFU Mammoth Museum on science projects has helped us learn more about the bacteria that lived in the mammoth steppe during the Pleistocene period.” Expert in the study of diseases and infections at North-Western State Medical University, Artemy Goncharov, said, “We see that living bacteria can survive in fossil animal finds for thousands of years, which are a kind of witnesses of those ancient times.”

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“We are hoping for good results that will help us learn a little more about what ancient microbial communities were, what they did, and how many dangerous pathogenic bacteria were in their structure. “Maybe microorganisms will be found that can be used in medicine and biotechnology as promising sources of substances that have biological activity,” Goncharov said.

The North-Eastern Federal University also has another interesting specimen. They just bought a frozen wolf from the Nizhnekolymsk area of Yakutia, Siberia, and they plan to start studying it as soon as they finish studying this one.

This part of the world has a lot of permafrost, which is a layer of forever frozen soil below the Earth’s surface. It is perfect for storing and preserving living things from the Ice Age. In recent years, a wide range of ancient animals, including a 49,000-year-old bird and a beautifully kept puppy named “Dogor,” have been found in this very cold part of Siberia.

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Artificial Intelligence

Eric Lefkofsky, the billionaire founder of Groupon, has launched another initial public offering (IPO),tempus is an artificial intelligence (AI) health technology company

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Eric Lefkofsky is no stranger to the world of public listings, and he’s gearing up to embark on his fourth venture. With a net worth of nearly $4 billion, this serial entrepreneur has successfully taken three of his own businesses public.

Today, he is the founder of Tempus, a genomic testing and data analysis company that is preparing to go public. However, he gained significant recognition as one of the co-founders of Groupon, a daily deal pioneer. Groupon made headlines in 2011 when it went public with a valuation of nearly $13 billion, marking one of the most notable debuts of that year.

Groupon’s initial public offering (IPO) and the subsequent years were notoriously challenging. However, the public listings of Lefkofsky’s other two companies, InnerWorkings in 2006 and Echo Global Logistics in 2009, didn’t cause major concerns for investors and performed successfully. InnerWorkings, a supply chain startup that was founded in 2001, was recently sold to private equity for a significantly lower amount than its initial public offering market capitalization.

Throughout its 11-year tenure as a publicly traded company, the stock of Echo Global Logistics experienced a consistent increase in value. Eventually, a private equity firm bought it for a significant 50% premium over its closing trading price in 2021.

There were some controversies surrounding Groupon, including a situation where Lefkofsky allegedly took a significant amount of money from the company’s pre-IPO round. This left the company with limited working capital and resulted in a significant decrease in reported revenue after regulators examined the financials. This unconventional decision has also revealed another transaction based on his previous experiences. He successfully sold his dot-com-era business, Starbelly.com, in 2000, but regrettably, the company that bought it filed for bankruptcy a year later, according to some sources.

Lefkofsky has gained a reputation for having a knack for success, although it may not always translate to long-term gains for investors in his companies.

Tempus is Lefkofsky’s latest endeavor in building a company that will stand the test of time and provide significant value. His wife’s successful breast cancer treatment reportedly inspired him to establish Tempus in 2015.

He expressed his surprise at the lack of data involved in her care during an interview with Forbes last year. “I became obsessed with the notion that there existed a wealth of technology designed for various industries that could be utilized in cancer care to empower physicians to make informed decisions based on data.”

He resigned as Groupon’s CEO in 2015, at a time when the company’s value had dropped to $2.6 billion. Groupon currently has a market capitalization of approximately $600 million. During that period, Lefkofsky directed his attention towards Lightbank, an early-stage venture firm.

It is worth noting that, according to the Tempus S-1 filing, he has not received any salary in the past two years. Unfortunately, the S-1 did not disclose more than two years’ worth of executive compensation for any named officer. Additionally, the filing states that he is entitled to receive a payment of $800,000 and a $800,000 bonus commencing in 2025. Furthermore, despite not receiving a salary, he received a substantial $5.3 million dividend from company stock this year, as indicated in the prospectus. In addition, the filing revealed that Tempus has taken care of the expenses related to $7.5 million worth of preferred shares and has also covered his private plane costs, amounting to $200,000.

Tempus saw a significant increase in revenues, with a growth of 66% from $321 million in 2022 to $531 million in 2023. However, the company continues to experience significant financial losses, with net losses of $290 million in 2023 and $214 million in 2022. Despite the challenging financials, there is a positive development in the operating loss margin, which has decreased from 83% in 2022 to 37% in 2023, as stated in the S-1 filing.

Additionally, Lefkofsky-founded Pathos AI and Tempus have a partnership. Pathos AI is a drug discovery platform that was established in 2020. Pathos compensates Tempus for the privilege of licensing its data. Meanwhile, Ryan Fukushima, the COO of Tempus, also takes on the role of CEO at Pathos and divides his time between the two companies.

There are additional signs that suggest Lefkofsky has a greater level of influence at Tempus than is typically seen.

Tempus has not yet disclosed its principal stockholder’s chart, but it is evident that Lefkofsky, a billionaire, is among them and owns a minimum of 5% of the company. It is clear that he is determined to maintain complete control of the company once it becomes publicly traded. Tempus has given his shares an impressive 30 votes per share. It is not uncommon to have super voting shares, but typically 10 votes per share is more common, while 20 votes is considered to be on the higher side. It is noteworthy that the CEO of a healthcare company has a significantly high level of shareholder influence. It remains to be seen if this influence will be diminished in future S-1s, which would indicate potential investor concerns.

However, Tempus’ S-1 filing makes it abundantly clear that Lefkofsky plays a crucial role in the company’s future. According to a healthcare VC interviewed, Tempus owes much of its growth and success in raising capital to Lefkofsky’s impressive marketing and fundraising abilities.

Tempus secured an impressive $1.42 billion in funding from a range of investors, including Lightbank, NEA, Revolution Growth, T. Rowe Price, Novo Holdings, Franklin Templeton, and Baillie Gifford. The company’s most recent valuation was $8.1 billion in October 2022. Tempus’ S-1 filing disclosed a recent $200 million investment from SoftBank.

No matter the amount of capital raised in its IPO, Tempus’ prospectus clearly states that the company is still a long way from reaching breakeven and will require additional capital in the future. Typically, unprofitable companies make sure to include this information in their prospectuses. However, it is important to note that investors may anticipate Tempus to have a follow-on public offering in the future, which could potentially impact their share price negatively.

Despite generating only $5.5 million in revenue from AI, which represents approximately 1% of its total revenue in 2023, Tempus is actively positioning itself as an AI company.

“Tempus is taking a risk by betting on their growth and the opportune moment for AI in the life sciences industry. However, the company’s current offering has yet to demonstrate its effectiveness,” commented the healthcare investor.

The company stated in its S-1 filing that its AI product line is still in its early stages, but it intends to incorporate AI, including generative AI, into all of its diagnostic tools. Tempus has chosen not to provide any additional comments beyond the information stated in the S-1.

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Biology

Weight Loss Launchpad: Space Technology Enhances the Effectiveness of Obesity mRNA Treatment

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Researchers at Penn Engineering have devised an innovative approach for the synthesis of a vital component of lipid nanoparticles (LNPs), drawing inspiration from space shuttle technology. LNPs play a crucial role in the administration of mRNA therapeutics, as exemplified by the Pfizer-BioNTech and Moderna COVID-19 vaccines. They enhance the ease of LNP manufacturing and enhance their efficacy in facilitating the transportation of mRNA into cells for medical interventions.

In an article published in Nature Communications, Michael J. Mitchell, an Associate Professor in the Department of Bioengineering, presents a novel approach for the synthesis of ionizable lipidoids. These lipidoids are crucial chemical constituents of lipid nanoparticles (LNPs) that play a crucial role in safeguarding and delivering therapeutic payloads. In this study, Mitchell et al. conducted an investigation of the efficacy of mRNA drug delivery for the treatment of obesity as well as the potential of gene-editing techniques for the management of hereditary disorders.

Optimizing the Production Process
Prior research has demonstrated that lipidoids possessing branching tails exhibit superior efficacy in delivering mRNA to cells. However, the processes involved in synthesizing these molecules are both time-consuming and expensive. According to Xuexiang Han, a postdoctoral student in the Mitchell Lab and co-first author of the research, we present an innovative approach for the effective and economical production of these lipidoids.

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The procedure entails the amalgamation of three chemical compounds, namely an amine “head,” two alkyl epoxide “tails,” and two acyl chloride “branched tails.” The observed similarity between the fully developed lipidoid and a space shuttle affixed to two booster rockets is not a mere coincidence. Han, a college student, recounts that a documentary on the space shuttle left a lasting impression on him due to the remarkable design of the solid rocket boosters that facilitated the shuttle’s entry into orbit. According to Han, it was determined that the addition of two branch tails as “boosters” to the lipidoid might enhance the transportation of mRNA.

The addition of branching tails greatly improved the ability of LNPs containing the new lipidoid to deliver mRNA to specific cells, similar to how boosters help a rocket get into the atmosphere. “We saw a big increase in the production of a hormone that controls metabolism in certain cells after these lipidoids were used to deliver mRNA.” This development is highly promising, particularly in the context of obesity treatment,” states Mitchell.

The article titled “In situ combinatorial synthesis of degradable branched lipidoids for systemic delivery of mRNA therapeutics and gene editors,” authored by Xuexiang Han, Junchao Xu, Ying Xu, Mohamad-Gabriel Alameh, Lulu Xue, Ningqiang Gong, Rakan El-Mayta, Rohan Palanki, Claude C. Warzecha, Gan Zhao, Andrew E. Vaughan, James M. Wilson, Drew Weissman, and Michael J. Mitchell, was published in Nature Communications on February 26, 2024.
The provided DOI, 10.1038/s41467-024-45537-z,

The research was carried out at the University of Pennsylvania School of Engineering and Applied Science and received funding from the National Institutes of Health (Award DP2 TR002776), the Burroughs Wellcome Fund Career Award at the Scientific Interface, the National Science Foundation CAREER Award (CBET-2145491), and the American Cancer Society (Grant RSG-22-122-01-ET).

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