Zebrafish use surprising strategy to regrow spinal cord

Zebrafish are members of a rarefied group of vertebrates capable of fully healing a severed spinal cord. A clear understanding of how this regeneration takes place could provide clues toward strategies for healing spinal cord injuries in people. Such injuries can be devastating, causing permanent loss of sensation and movement.

A new study from Washington University School of Medicine in St. Louis maps out a detailed atlas of all the cells involved -- and how they work together -- in regenerating the zebrafish spinal cord. In an unexpected finding, the researchers showed that survival and adaptability of the severed neurons themselves is required for full spinal cord regeneration. Surprisingly, the study showed that stem cells capable of forming new neurons -- and typically thought of as central to regeneration -- play a complementary role but don't lead the process.

The study is published Thursday, Aug. 15, in the journal Nature Communications.

Unlike humans' and other mammals' spinal cord injuries, in which damaged neurons always die, the damaged neurons of zebrafish dramatically alter their cellular functions in response to injury, first to survive and then to take on new and central roles in orchestrating the precise events that govern healing, the researchers found. Scientists knew that zebrafish neurons survive spinal cord injury, and this new study reveals how they do it.

"We found that most, if not all, aspects of neural repair that we're trying to achieve in people occur naturally in zebrafish," said senior author Mayssa Mokalled, PhD, an associate professor of developmental biology. "The surprising observation we made is that there are strong neuronal protection and repair mechanisms happening right after injury. We think these protective mechanisms allow neurons to survive the injury and then adopt a kind of spontaneous plasticity -- or flexibility in their functions -- that gives the fish time to regenerate new neurons to achieve full recovery. Our study has identified genetic targets that will help us promote this type of plasticity in the cells of people and other mammals."

By mapping out the evolving roles of various cell types involved in regeneration, Mokalled and her colleagues found that the flexibility of the surviving injured neurons and their capacity to immediately reprogram after injury lead the chain of events that are required for spinal cord regeneration. If these injury-surviving neurons are disabled, zebrafish do not regain their normal swim capacity, even though regenerative stem cells remain present.

When the long wiring of the spinal cord is crushed or severed in people and other mammals, it sets off a chain of toxicity events that kills the neurons and makes the spinal cord environment hostile against repair mechanisms. This neuronal toxicity could provide some explanation for the failure of attempts to harness stem cells to treat spinal cord injuries in people. Rather than focus on regeneration with stem cells, the new study suggests that any successful method to heal spinal cord injuries in people must start with saving the injured neurons from death.

"Neurons by themselves, without connections to other cells, do not survive," Mokalled said. "In zebrafish, we think severed neurons can overcome the stress of injury because their flexibility helps them establish new local connections immediately after injury. Our research suggests this is a temporary mechanism that buys time, protecting neurons from death and allowing the system to preserve neuronal circuitry while building and regenerating the main spinal cord."

There is some evidence that this capacity is present but dormant in mammalian neurons, so this may be a route to new therapies, according to the researchers.

"We are hopeful that identifying the genes that orchestrate this protective process in zebrafish -- versions of which also are present in the human genome -- will help us find ways to protect neurons in people from the waves of cell death that we see following spinal cord injuries," she said.

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Losing a loved one may speed up aging

Losing someone close, like a family member, can make you age faster, says a new study from Columbia University Mailman School of Public Health and the Butler Columbia Aging Center. The study found that people who lost a parent, partner, sibling, or child, showed signs of older biological age compared to those who hadn't experienced such losses. The research was published in JAMA Network Open.

Biological aging is the gradual decline in how well your cells, tissues, and organs function, leading to a higher risk of chronic diseases. Scientists measure this type of aging using DNA markers known as epigenetic clocks.

"Few studies have looked at how losing a loved one at different stages of life affects these DNA markers, especially in study samples that represent the U.S .population," said Allison Aiello, PhD, the James S. Jackson professor of health longevity in Epidemiology and the study's lead author. "Our study shows strong links between losing loved ones across the life course from childhood to adulthood and faster biological aging in the U.S."

The study, a collaboration with the Carolina Population Center at UNC Chapel Hill, suggests that the impact of loss on aging can be seen long before middle age and may contribute to health differences among racial and ethnic groups.

The researchers used data from the National Longitudinal Study of Adolescent to Adult Health, which started in 1994-95. It followed participants from their teenage years into adulthood.

To measure familial loss during childhood or adolescence from the longitudinal study, Aiello and colleagues followed participants through various waves, and aging timeframes. Wave I surveyed 20,745 adolescents in grades 7-12, most of whom were aged 12-19. Participants have been followed ever since. Wave V took place between 2016 and 2018 and completed interviews with 12,300 of the original participants. In the latest wave, between 2016 and 2018, participants were invited for an additional home exam where a blood sample of the nearly 4,500 visited was provided for DNA testing.

The study looked at losses experienced during childhood or adolescence (up to 18 years old) and adulthood (19 to 43 years old). They also examined the number of losses experienced across this time period. Biological aging data were assessed from blood DNA methylation using epigenetic clocks including DunedinPACE which was developed by by Aiello's Aging Center colleague and study co-author Dan Belsky and his collaborators at Duke University.

Nearly 40 percent of participants experienced at least one loss in adulthood between the ages of 33 and 43. Parental loss was more common in adulthood versus in childhood and adolescence (27 percent versus 6 percent). A larger proportion of Black (57 percent) and Hispanic (41 percent) participants experienced at least one loss compared to White participants (34 percent).

People who experienced two or more losses had older biological ages according to several epigenetic clocks. Experiencing two or more losses in adulthood was more strongly linked to biological aging than one loss and significantly more so than no losses.

"The connection between losing loved ones and health problems throughout life is well-established," Aiello noted. "But some stages of life might be more vulnerable to the health risks associated with loss and the accumulation of loss appears to be a significant factor."

For example, losing a parent or sibling early in life can be very traumatic, often leading to mental health issues, cognitive problems, higher risks of heart disease, and a greater chance of dying earlier. Losing a close family member at any age poses health risks, and repeated losses can increase the risks of heart disease, mortality, and dementia; and impacts may persist or become apparent long after the event.

Aiello and her co-authors emphasize that while loss at any age can have long-lasting health impacts, the effects might be more severe during key developmental periods like childhood or early adulthood. "We still don't fully understand how loss leads to poor health and higher mortality, but biological aging may be one mechanism as suggested in our study. Future research should focus on finding ways to reduce disproportionate losses among vulnerable groups. For those who experience loss, providing resources for coping and addressing the trauma is essential. ," Aiello concluded.

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Researchers create artificial cells that act like living cells

In a new study published in Nature Chemistry, UNC-Chapel Hill researcher Ronit Freeman and her colleagues describe the steps they took to manipulate DNA and proteins -- essential building blocks of life -- to create cells that look and act like cells from the body. This accomplishment, a first in the field, has implications for efforts in regenerative medicine, drug delivery systems, and diagnostic tools.

"With this discovery, we can think of engineering fabrics or tissues that can be sensitive to changes in their environment and behave in dynamic ways," says Freeman, whose lab is in the Applied Physical Sciences Department of the UNC College of Arts and Sciences.

Cells and tissues are made of proteins that come together to perform tasks and make structures. Proteins are essential for forming the framework of a cell, called the cytoskeleton. Without it, cells wouldn't be able to function. The cytoskeleton allows cells to be flexible, both in shape and in response to their environment.

Without using natural proteins, the Freeman Lab built cells with functional cytoskeletons that can change shape and react to their surroundings. To do this, they used a new programmable peptide-DNA technology that directs peptides, the building blocks of proteins, and repurposed genetic material to work together to form a cytoskeleton.

"DNA does not normally appear in a cytoskeleton," Freeman says. "We reprogrammed sequences of DNA so that it acts as an architectural material, binding the peptides together. Once this programmed material was placed in a droplet of water, the structures took shape."

The ability to program DNA in this way means scientists can create cells to serve specific functions and even fine-tune a cell's response to external stressors. While living cells are more complex than the synthetic ones created by the Freeman Lab, they are also more unpredictable and more susceptible to hostile environments, like severe temperatures.

"The synthetic cells were stable even at 122 degrees Fahrenheit, opening up the possibility of manufacturing cells with extraordinary capabilities in environments normally unsuitable to human life," Freeman says.

Instead of creating materials that are made to last, Freeman says their materials are made to task -- perform a specific function and then modify themselves to serve a new function. Their application can be customized by adding different peptide or DNA designs to program cells in materials like fabrics or tissues. These new materials can integrate with other synthetic cell technologies, all with potential applications that could revolutionize fields like biotechnology and medicine.

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Breakthrough rice bran nanoparticles show promise as affordable and targeted anticancer agent

Plant-derived nanoparticles have demonstrated significant anticancer effects. Researchers recently developed rice bran-derived nanoparticles (rbNPs) that efficiently suppressed cell proliferation and induced programmed cell death of only cancer cells. Furthermore, rbNPs successfully suppressed the growth of tumors in mice having aggressive adenocarcinoma in their peritoneal cavity, without any adverse effects. Given their low production costs and high efficacy, rbNPs hold great promise for developing affordable and safe anticancer agents.

Several types of conventional cancer therapies, such as radiotherapy or chemotherapy, destroy healthy cells along with cancer cells. In advanced stages of cancer, tissue loss from treatments can be substantial and even fatal. Cutting-edge cancer therapies that employ nanoparticles can specifically target cancer cells, sparing healthy tissue. Recent studies have demonstrated that plant-derived nanoparticles (pdNPs) that have therapeutic effects can be an effective alternative to traditional cancer treatments. However, no pdNPs have been approved as anticancer therapeutic agents till date.

Rice bran is a byproduct generated during rice refining process that has limited utility and low commercial value. However, it contains several compounds with anticancer properties, such as γ-oryzanol and γ-tocotrienol. To explore these therapeutic properties of rice bran, a team of researchers led by Professor Makiya Nishikawa from Tokyo University of Science (TUS) in Japan developed nanoparticles from rice bran and tested their effectiveness in mice models. Their study, published in Volume 22 of Journal of Nanobiotechnology on 16 March 2024, was co-authored by Dr. Daisuke Sasaki, Ms. Hinako Suzuki, Associate Professor Kosuke Kusamori, and Assistant Professor Shoko Itakura from TUS.

"In recent years, an increasing number of new drug modalities are being developed. At the same time, development costs associated with novel therapies have increased dramatically, contributing to the burden of medical expenses. To address this issue, we used rice bran, an industrial waste with anticancer properties, to develop nanoparticles," explains Prof. Nishikawa.

The study evaluated the anticancer effects of rice bran-derived nanoparticles (rbNPs), which were obtained by processing and purifying a suspension of Koshihikari rice bran in water. When a cancer cell line named colon26 was treated with rbNPs, cell division was arrested and programmed cell death was induced, indicating strong anticancer effects of the nanoparticles. The observed anticancer activity of rbNPs can be attributed to γ-tocotrienol and γ-oryzanol, that are easily taken up by cancer cells resulting in cell cycle arrest and programmed cell death. Additionally, rbNPs reduced the expression of proteins, such as β-catenin (a protein associated with Wnt signaling pathway involved in cell proliferation) and cyclin D1, which are known to promote cancer recurrence and metastases. Moreover, the rbNPs reduced the expression of β-catenin only in colon26 cells without affecting the non-cancerous cells.

"A key concern in the context of pdNPs is their low pharmacological activity compared to pharmaceutical drugs. However, rbNPs exhibited higher anticancer activity than DOXIL®, a liposomal pharmaceutical formulation of doxorubicin. Additionally, doxorubicin is cytotoxic to both cancer cells and non-cancerous cells, whereas rbNPs are specifically cytotoxic to cancer cells, suggesting that rbNPs are safer than doxorubicin," highlights Prof.Nishikawa.

To confirm the anticancer properties of rbNPs in the living body, the researchers injected rbNPs into mice having aggressive adenocarcinoma in their peritoneal cavity (enclosed by the diaphragm, abdominal muscles, and pelvis and houses organs like intestines, liver, and kidneys). They observed significant suppression of tumor growth with no adverse effects on the mice. Additionally, the rbNPs significantly inhibited metastatic growth of murine melanoma B16-BL6 cells in a lung metastasis mouse model.

Rice bran has several attributes that make it an excellent source of therapeutic pdNPs. Firstly, it is economic as compared to many other sources of pdNPs. Nearly 40% of the rice bran is discarded in Japan, providing a readily available source of raw material. Secondly, the preparation efficiency of rbNPs is higher than that of previously reported pdNPs. Besides being practical and safe as an anticancer therapeutic, the physicochemical properties of rbNPs are very stable. However, a few parameters, such as establishment of separation technologies at the pharmaceutical level, assessing production process control parameters, and evaluation of efficacy and safety in human cancer cell lines and xenograft animal models, must be investigated prior to clinical trials in humans.

In conclusion, rice bran, an agricultural waste product, is a source of therapeutic pdNPs that are affordable, effective, and safe, and has the potential to revolutionize cancer treatment in the future.

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Nerve cells not entirely 'young at heart'

Most human nerve cells last a lifetime without renewal. A trait echoed within the cells' components, some enduring as long as the organism itself. New research by Martin Hetzer, molecular biologist and president of the Institute of Science and Technology Austria (ISTA), and colleagues discovered RNA, a typical transient molecule, in the nerve cells of mice that remain stable for their entire lives. Published in Science, these findings contribute to unraveling the complexities of brain aging and associated diseases.

After two decades in the United States, Martin Hetzer returned home to Austria in 2023 to become the 2nd President of the Institute of Science and Technology Austria (ISTA). A year into his new role, the molecular biologist remains engaged in the realm of aging research.

Hetzer is fascinated by the biological puzzles surrounding the aging processes in organs like the brain, heart, and pancreas. Most cells comprising these organs are not renewed throughout a human's entire life span. Nerve cells (neurons) in the human brain, for instance, can be as old as the organism, even up to more than a century, and must function for a lifetime. This remarkable age of neurons might be a major risk factor for neurodegenerative disorders such as Alzheimer's disease. Crucial to comprehending these kinds of ailments is a deeper understanding of how nerve cells function over time and maintain control. This potentially opens doors to therapeutically counteract the aging processes of these specific cells.

The latest collaborative publication by Hetzer, Tomohisa Toda from the Friedrich-Alexander University Erlangen-Nürnberg (FAU), who is also associated with the Max Planck Center for Physics and Medicine, Erlangen, and colleagues, gives new insights into this underexplored field of intricate mechanisms. For the first time in mammals, the study shows that RNA -- an essential group of molecules important for various biological processes inside the cell -- can persist throughout life. The scientists identified specific RNAs with genome-protecting functions in the nuclei of nerve cells of mice that remain stable for two years, covering their entire lives. The findings, published in the journal Science, underpin the importance of long-lived key molecules for maintaining a cell's function.

Longevity of key molecules

The inside of cells is a very dynamic place. Some components are constantly renewed and updated; others stay the same their whole lives. It is like a city in which the old buildings blend in with the new ones. DNA found in the nucleus -- the city's heart -- for instance, is as old as the organism. "DNA in our nerve cells is identical to DNA within the developing nerve cells in our mother's womb," explains Hetzer.

Unlike stable DNA, which is constantly being repaired, RNA, especially messenger RNA (mRNA), which forms proteins upon DNA's information, is characterized by its transient nature. The cellular scope, however, extends beyond mRNA to a group of so-called non-coding RNAs. They do not turn into proteins; instead, they have specific duties to contribute to the overall organization and function of the cell. Intriguingly, their lifespan remained a mystery. Until now.

RNAs that last the whole life

Hetzer and Co. set out to decipher that secret. Therefore, RNAs were labeled, i.e. "marked," in the brains of newborn mice. "For this labeling, we used RNA analogs -- structurally similar molecules -- with little chemical hooks that click fluorescent molecules on the actual RNAs," explains Hetzer. This assured efficient tracking of the molecules and powerful microscopic snapshots at any given time point in the mice's lives.

"Surprisingly, our initial images revealed the presence of long-lived RNAs, in various cell types within the brain. We had to further dissect the data to identify the ones in the nerve cells," Hetzer explains. "Fruitful collaboration with Toda's lab enabled us to make sense of that chaos during brain mapping." Collaboratively, the researchers were able to focus solely on long-lived RNAs in neurons. They quantified the molecules' concentration throughout a mouse's life, examined their composition and analyzed their positions.

While humans have an average life expectancy of around 70 years, the typical lifespan of a mouse is 2.5 years. After one year, the concentration of long-lived RNAs was slightly reduced compared to newborns. However, even after two years, they remained detectable indicating a lifelong persistence of these molecules.

RNAs help protect the genome

Additionally, the scientists proved long-lived RNAs' prominent role in cellular longevity. They found out that long-lived RNAs in neurons consist of mRNAs and non-coding RNAs and accumulate near the heterochromatin -- the densely packed region of the genome, typically homing inactive genes. Next they further investigated the function of these long-lived RNAs.

In molecular biology, the most effective approach to achieve this is by reducing the molecule of interest and observing its subsequent effects. "As their name and our previous experiments suggest, these long-lived RNAs are extremely stable," says Hetzer. The scientists, therefore, employed an in vitro (outside a living organism) approach, using neuronal progenitor cells -- stem cells with the capacity to give rise to neural cells, including neurons. The model system allowed them to effectively intervene with these long-lived RNAs. A lower amount of long-lived RNAs caused problems in the heterochromatin architecture and stability of genetic material, eventually affecting the cells' viability. Thus, the important role of long-lived RNAs' in cellular longevity was clarified.

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Artificial cartilage with the help of 3D printing

Is it possible to grow tissue in the laboratory, for example to replace injured cartilage? At TU Wien (Vienna), an important step has now been taken towards creating replacement tissue in the lab -- using a technique that differs significantly from other methods used around the world.

A special high-resolution 3D printing process is used to create tiny, porous spheres made of biocompatible and degradable plastic, which are then colonized with cells.

These spheroids can then be arranged in any geometry, and the cells of the different units combine seamlessly to form a uniform, living tissue.

Cartilage tissue, with which the concept has now been demonstrated at TU Wien, was previously considered particularly challenging in this respect.

Tiny spherical cages as a scaffold for the cells

"Cultivating cartilage cells from stem cells is not the biggest challenge. The main problem is that you usually have little control over the shape of the resulting tissue," says Oliver Kopinski-Grünwald from the Institute of Materials Science and Technology at TU Wien, one of the authors of the current study.

"This is also due to the fact that such stem cell clumps change their shape over time and often shrink."

To prevent this, the research team at TU Wien is working with a new approach: specially developed laser-based high-resolution 3D printing systems are used to create tiny cage-like structures that look like mini footballs and have a diameter of just a third of a millimeter.

They serve as a support structure and form compact building blocks that can then be assembled into any shape.

Stem cells are first introduced into these football-shaped mini-cages, which quickly fill the tiny volume completely.

"In this way, we can reliably produce tissue elements in which the cells are evenly distributed and the cell density is very high. This would not have been possible with previous approaches," explains Prof.

Aleksandr Ovsianikov, head of the 3D Printing and Biofabrication research group at TU Wien.

Growing together perfectly

The team used differentiated stem cells -- i.e. stem cells that can no longer develop into any type of tissue, but are already predetermined to form a specific type of tissue, in this case cartilage tissue.

Such cells are particularly interesting for medical applications, but the construction of larger tissue is challenging when it comes to cartilage cells.

In cartilage tissue, the cells form a very pronounced extracellular matrix, a mesh-like structure between the cells that often prevents different cell spheroids from growing together in the desired way.

If the 3D-printed porous spheres are colonized with cells in the desired way, the spheres can be arranged in any desired shape.

The crucial question is now: do the cells of different spheroids also combine to form a uniform, homogeneous tissue?

"This is exactly what we have now been able to show for the first time," says Kopinski-Grünwald.

"Under the microscope, you can see very clearly: neighboring spheroids grow together, the cells migrate from one spheroid to the other and vice versa, they connect seamlessly and result in a closed structure without any cavities -- in contrast to other methods that have been used so far, in which visible interfaces remain between neighboring cell clumps."

The tiny 3D-printed scaffolds give the overall structure mechanical stability while the tissue continues to mature.

Over a period of a few months, the plastic structures degrade, they simply disappear, leaving behind the finished tissue in the desired shape.

First step towards medical application

In principle, the new approach is not limited to cartilage tissue, it could also be used to tailor different kinds of larger tissues such as bone tissue.

However, there are still a few tasks to be solved along the way -- after all, unlike in cartilage tissue, blood vessels would also have to be incorporated for these tissues above a certain size.

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Surprisingly vibrant color of 12-million-year-old snail shells

Snail shells are often colourful and strikingly patterned. This is due to pigments that are produced in special cells of the snail and stored in the shell in varying concentrations. Fossil shells, on the other hand, are usually pale and inconspicuous because the pigments are very sensitive and have already decomposed. Residues of ancient colour patterns are therefore very rare. This makes this new discovery by researchers from the University of Göttingen and the Natural History Museum Vienna (NHMW) all the more astonishing: they found pigments in twelve-million-year-old fossilised snail shells. These are the world's first pigments from the chemical group of polyenes that have been preserved almost unchanged and found in fossils. The study was published in the journal Palaeontology.

Palaeontologists from the NHMW found snail shells of the superfamily Cerithioidea in Burgenland, Austria.

The snails lived there twelve million years ago on the shores of a tropical sea.

Professor Mathias Harzhauser at NHMW, who was involved in the discovery, explains: "It was unclear whether the patterns of reddish colour were from the original shell or were formed by later processes in the sediment." Researchers at Göttingen University's Geoscience Center solved the mystery.

They analysed the pigments using Raman spectroscopy. This involves irradiating samples with laser light.

The scattered light reflected from the sample can be used to clearly identify chemical compounds.

They detected pigments in the fossilised shells that belong to the polyene group of chemicals.

These are organic compounds that include the well-known "carotenoids," which are responsible for producing the vibrant red, orange and yellow colours seen in birds' feathers, carrots and egg yolks, for instance.

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The fountain of youth is ... a T cell?

The fountain of youth has eluded explorers for ages. It turns out the magic anti-aging elixir might have been inside us all along.

Cold Spring Harbor Laboratory (CSHL) Assistant Professor Corina Amor Vegas and colleagues have discovered that T cells can be reprogrammed to fight aging, so to speak.

Given the right set of genetic modifications, these white blood cells can attack another group of cells known as senescent cells.

These cells are thought to be responsible for many of the diseases we grapple with later in life.

Senescent cells are those that stop replicating. As we age, they build up in our bodies, resulting in harmful inflammation.

While several drugs currently exist that can eliminate these cells, many must be taken repeatedly over time.

As an alternative, Amor Vegas and colleagues turned to a "living" drug called CAR (chimeric antigen receptor) T cells.

They discovered CAR T cells could be manipulated to eliminate senescent cells in mice.

As a result, the mice ended up living healthier lives. They had lower body weight, improved metabolism and glucose tolerance, and increased physical activity.

All benefits came without any tissue damage or toxicity.

"If we give it to aged mice, they rejuvenate. If we give it to young mice, they age slower. No other therapy right now can do this, " says Amor Vegas.

Perhaps the greatest power of CAR T cells is their longevity.

The team found that just one dose at a young age can have lifelong effects.

That single treatment can protect against conditions that commonly occur later in life, like obesity and diabetes.

"T cells have the ability to develop memory and persist in your body for really long periods, which is very different from a chemical drug, " explains Amor Vegas.

"With CAR T cells, you have the potential of getting this one treatment, and then that's it. For chronic pathologies, that's a huge advantage. Think about patients who need treatment multiple times per day versus you get an infusion, and then you're good to go for multiple years."

CAR T cells have been used to treat a variety of blood cancers, receiving FDA approval for this purpose in 2017.

But Amor Vegas is one of the first scientists to show that CAR T cells' medical potential goes even further than cancer.

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Surprisingly simple model explains how brain cells organize and connect

A new study by physicists and neuroscientists from the University of Chicago, Harvard and Yale describes how connectivity among neurons comes about through general principles of networking and self-organization, rather than the biological features of an individual organism.

The research, published on January 17, 2024 in Nature Physics, accurately describes neuronal connectivity in a variety of model organisms and could apply to non-biological networks like social interactions as well.

"When you're building simple models to explain biological data, you expect to get a good rough cut that fits some but not all scenarios," said Stephanie Palmer, PhD, Associate Professor of Physics and Organismal Biology and Anatomy at UChicago and senior author of the paper.

"You don't expect it to work as well when you dig into the minutiae, but when we did that here, it ended up explaining things in a way that was really satisfying."

Understanding how neurons connect

Neurons form an intricate web of connections between synapses to communicate and interact with each other.

While the vast number of connections may seem random, networks of brain cells tend to be dominated by a small number of connections that are much stronger than most.

This "heavy-tailed" distribution of connections (so-called because of the way it looks when plotted on a graph) forms the backbone of circuitry that allows organisms to think, learn, communicate and move.

Despite the importance of these strong connections, scientists were unsure if this heavy-tailed pattern arises because of biological processes specific to different organisms, or due to basic principles of network organization.

To answer these questions, Palmer and Christopher Lynn, PhD, Assistant Professor of Physics at Yale University, and Caroline Holmes, PhD, a postdoctoral researcher at Harvard University, analyzed connectomes, or maps of brain cell connections.

The connectome data came from several different classic lab animals, including fruit flies, roundworms, marine worms and the mouse retina.

To understand how neurons form connections to one another, they developed a model based on Hebbian dynamics, a term coined by Canadian psychologist Donald Hebb in 1949 that essentially says, "neurons that fire together, wire together." This means the more two neurons activate together, the stronger their connection becomes.

Across the board, the researchers found these Hebbian dynamics produce "heavy-tailed" connection strengths just like they saw in the different organisms.

The results indicate that this kind of organization arises from general principles of networking, rather than something specific to the biology of fruit flies, mice, or worms.

The model also provided an unexpected explanation for another networking phenomenon called clustering, which describes the tendency of cells to link with other cells via connections they share.

A good example of clustering occurs in social situations. If one person introduces a friend to a third person, those two people are more likely to become friends with them than if they met separately.

"These are mechanisms that everybody agrees are fundamentally going to happen in neuroscience," Holmes said.

"But we see here that if you treat the data carefully and quantitatively, it can give rise to all of these different effects in clustering and distributions, and then you see those things across all of these different organisms."

Accounting for randomness

As Palmer pointed out, though, biology doesn't always fit a neat and tidy explanation, and there is still plenty of randomness and noise involved in brain circuits.

Neurons sometimes disconnect and rewire with each other -- weak connections are pruned, and stronger connections can be formed elsewhere.

This randomness provides a check on the kind of Hebbian organization the researchers found in this data, without which strong connections would grow to dominate the network.

The researchers tweaked their model to account for randomness, which improved its accuracy.

"Without that noise aspect, the model would fail," Lynn said.

"It wouldn't produce anything that worked, which was surprising to us. It turns out you actually need to balance the Hebbian snowball effect with the randomness to get everything to look like real brains."

Since these rules arise from general networking principles, the team hopes they can extend this work beyond the brain.

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Stranger than friction: A force initiating life

As the potter works the spinning wheel, the friction between their hands and the soft clay helps them shape it into all kinds of forms and creations. In a fascinating parallel, sea squirt oocytes (immature egg cells) harness friction within various compartments in their interior to undergo developmental changes after conception. A study from the Heisenberg group at the Institute of Science and Technology Austria (ISTA), published in Nature Physics, now describes how this works.

The sea is full of fascinating life forms. From algae and colorful fish to marine snails and sea squirts, a completely different world reveals itself underwater.

Sea squirts or ascidians in particular are very unusual: after a free-moving larvae stage, the larva settles down, attaches to solid surfaces like rocks or corals, and develops tubes (siphons), their defining feature.

Although they look like rubbery blobs as adults, they are the most closely related invertebrate relatives to humans.

Especially at the larval stages, sea squirts are surprisingly similar to us.

Therefore, ascidians are often used as model organisms to study the early embryonic development of vertebrates to which humans belong.

"While ascidians exhibit the basic developmental and morphological features of vertebrates, they also have the cellular and genomic simplicity typical of invertebrates," explains Carl-Philipp Heisenberg, Professor at the Institute of Science and Technology Austria (ISTA). "Especially the ascidian larva is an ideal model for understanding early vertebrate development."

His research group's latest work, published in Nature Physics, now gives new insights into their development.

The findings suggest that upon fertilization of ascidian oocytes, friction forces play a crucial role in reshaping and reorganizing their insides, heralding the next steps in their developmental cascade.

Decoding oocyte transformation

Oocytes are female germ cells involved in reproduction. After successful fertilization with male sperm, animal oocytes typically undergo cytoplasmic reorganization, altering their cellular contents and components.

This process establishes the blueprint for the embryo's subsequent development.

In ascidians, for instance, this reshuffling leads to the formation of a bell-like protrusion -- a little bump or nose shape -- known as the contraction pole (CP), where essential materials gather that facilitate the embryo's maturation.

The underlying mechanism driving this process, however, has been unknown.

A group of scientists from ISTA, Université de Paris Cité, CNRS, King's College London, and Sorbonne Université set out to decipher that mystery.

For this endeavor, the Heisenberg group imported adult ascidians from the Roscoff Marine Station in France.

Almost all sea squirts are hermaphrodites, as they produce both male and female germ cells.

"In the lab, we keep them in saltwater tanks in a species-appropriate manner to obtain eggs and sperm for studying their early embryonic development," says Silvia Caballero-Mancebo, the first author of this study and previous PhD student in the Heisenberg lab.

The scientists microscopically analyzed fertilized ascidian oocytes and realized that they were following very reproducible changes in cell shape leading up to the formation of the contraction pole.

The researchers' first investigation focused on the actomyosin (cell) cortex -- a dynamic structure found beneath the cell membrane in animal cells.

Composed of actin filaments and motor proteins, it generally acts as a driver for shape changes in cells.

"We uncovered that when cells are fertilized, increased tension in the actomyosin cortex causes it to contract, leading to its movement (flow), resulting in the initial changes of the cell's shape," Caballero-Mancebo continues.

The actomyosin flows, however, stopped during the expansion of the contraction pole, suggesting that there are additional players responsible for the bump.

Friction forces impact cell reshaping

The scientists took a closer look at other cellular components that might play a role in the expansion of the contraction pole.

In doing so, they came across the myoplasm, a layer composed of intracellular organelles and molecules (related forms of which are found in many vertebrate and invertebrate eggs), positioned in the lower region of the ascidian egg cell.

"This specific layer behaves like a stretchy solid -- it changes its shape along with the oocyte during fertilization," Caballero-Mancebo explains.

During the actomyosin cortex flow, the myoplasm folds and forms many buckles due to the friction forces established between the two components.

As actomyosin movement stops, the friction forces also disappear.

"This cessation eventually leads to the expansion of the contraction pole as the multiple myoplasm buckles resolve into the well-defined bell-like-shaped bump," Caballero-Mancebo adds.

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Scientists unveil complete cell map of a whole mammalian brain

For the first time ever, an international team of researchers has created a complete cell atlas of a whole mammalian brain. This atlas serves as a map for the mouse brain, describing the type, location, and molecular information of more than 32 million cells and providing information on connectivity between these cells. The mouse is the most commonly used vertebrate experimental model in neuroscience research, and this cellular map paves the way for a greater understanding of the human brain -- arguably the most powerful computer in the world. The cell atlas also lays the foundation for the development of a new generation of precision therapeutics for people with mental and neurological disorders of the brain.

The findings were funded by the National Institutes of Health's Brain Research Through Advancing Innovative Neurotechnologies® Initiative, or The BRAIN Initiative®, and appear in a collection of 10 papers published in Nature.

"The mouse atlas has brought the intricate network of mammalian brain cells into unprecedented focus, giving researchers the details needed to understand human brain function and diseases," said Joshua A. Gordon, M.D., Ph.D., Director of the National Institute of Mental Health, part of the National Institutes of Health.

The cell atlas describes the types of cells in each region of the mouse brain and their organization within those regions.

In addition to this structural information, the cell atlas provides an incredibly detailed catalog of the cell's transcriptome -- the complete set of gene readouts in a cell, which contains instructions for making proteins and other cellular products.

The transcriptomic information included in the atlas is hierarchically organized, detailing cell classes, subclasses, and thousands of individual cell clusters within the brain.

The atlas also characterizes the cell epigenome -- chemical modifications to a cell's DNA and chromosomes that alter the way the cell's genetic information is expressed -- detailing thousands of epigenomic cell types and millions of candidate genetic regulation elements for different brain cell types.

Together, the structural, transcriptomic, and epigenetic information included in this atlas provide an unprecedented map of cellular organization and diversity across the mouse brain.

The atlas also provides an accounting of the neurotransmitters and neuropeptides used by different cells and the relationship among cell types within the brain.

This information can be used as a detailed blueprint for how chemical signals are initiated and transmitted in different parts of the brain.

Those electrical signals are the basis for how brain circuits operate and how the brain functions overall.

"This product is a testament to the power of this unprecedented, cross-cutting collaboration and paves our path for more precision brain treatments," said John Ngai, Ph.D., Director of the NIH BRAIN Initiative."

Of the 10 studies included in this collection, seven are funded through the NIH BRAIN Initiative Cell Census Network (BICCN), and two are funded through the larger NIH BRAIN Initiative.

The core aim of the BICCN, a groundbreaking, cross-collaborative effort to understand the brain's cellular makeup, is to develop a comprehensive inventory of the cells in the brain -- where they are, how they develop, how they work together, and how they regulate their activity -- to better understand how brain disorders develop, progress, and are best treated.

"By leveraging the unique nature of its multi-disciplinary and international collaboration, the BICCN was able to accomplish what no other team of scientists has been able to before," said Dr. Ngai.

"Now we are ready to take the next big step -- completing the cell maps of the human brain and the nonhuman primate brain."

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New drug-like molecule extends lifespan, ameliorates pathology in worms and boosts function in mammalian muscle cells

Having healthy mitochondria, the organelles that produce energy in all our cells, usually portends a long healthy life whether in humans or in C. elegans, a tiny, short-lived nematode worm often used to study the aging process. Researchers at the Buck Institute have identified a new drug-like molecule that keeps mitochondria healthy via mitophagy, a process that removes and recycles damaged mitochondria in multicellular organisms. The compound, dubbed MIC, is a natural compound that extended lifespan in C. elegans, ameliorated pathology in neurodegenerative disease models of C. elegans, and improved mitochondrial function in mouse muscle cells. Results are published in the November 13, 2023, edition of Nature Aging.

The impact of mitochondrial dysfunction in age-related disease

Defective mitophagy is implicated in many age-related diseases. It's tied to neurodegenerative disorders such as Parkinson's and Alzheimer's; it plays a role in cardiovascular diseases including heart failure; it influences metabolic disorders including obesity and type 2 diabetes; it is implicated in muscle wasting and sarcopenia and has a complex relationship with cancer progression. Even though interventions that restore mitophagy and facilitate the elimination of damaged mitochondria hold great promise for addressing these conditions, not one treatment has been approved for human use despite advances in the field.

What's MIC?

MIC (Mitophagy-Inducing Compound) is a coumarin, which are naturally bioactive compounds that have anticoagulant, antibacterial, antifungal, antiviral, anticancer, and antihyperglycemic properties (among others) as well as being an antioxidant with neuroprotective effects. Coumarin is found in many plants and is found in high concentrations in certain types of cinnamon, which is one of the most frequent sources for human exposure to the substance.

A new mechanism of action in mitophagy

The project started in a mouse model of Parkinson's disease where researchers in the laboratory of Julie Andersen, PhD, a senior author of the paper, were looking at known enhancers of mitophagy, including rapamycin. "Co-author Shankar Chinta, PhD, started screening natural compounds in neuronal cells and MIC came up as a major hit," she said. "Rather than taking MIC immediately into a mouse model we wanted to understand its impact on overall aging and identify its mechanism of action, so we took the work into the worm where we found that MIC is in a different class of molecules that enhance the expression of a key protein, TFEB."

In an effort spearheaded by Andersen and research scientist Manish Chamoli, PhD, lead author of the study, researchers found that MIC enhanced the activity of transcription factor TFEB, which is a master regulator of genes involved in autophagy and lysosomal functions. Autophagy is the intracellular recycling process whereby cells clean up damaged proteins; it derives its abilities from the lysosome. Researchers found that MIC robustly increased the lifespan of C. elegans while also preventing mitochondrial dysfunction in mammalian cells.

"This paper helps support the overall notion of TFEB being a key autophagy regulator that extends lifespan, "said Buck professor and Chief Scientific Officer Malene Hansen, PhD, who collaborated on the paper. She added, "Mitophagy is a selective and very significant form of autophagy. The field has recognized TFEB as a player when it comes to quality control in mitochondria. This study provides a possible translational route to induce mitophagy in a TFEB-dependent fashion."

A link to the brain/gut connection

Mechanistically MIC works upstream of TFEB by inhibiting ligand-induced activation of the nuclear hormone receptor DAF-12 (in worms)/FXR (in humans), which in turn induces mitophagy and extends lifespan. FXR is best known for its ability to act in the liver and gut to maintain lipid homeostasis, where it acts to regulate levels of TFEB as part of a feed-fast cycle, but recently TFEB was shown to also be present in brain neurons. This provided Andersen with the clue needed to piece together MIC's potential mechanism of action in the latter. "This study provides another piece of the puzzle when it comes to understanding the brain/gut connection in terms of health and disease," said Andersen.

FXR is regulated by bile salts which are formed in the gut microbiome. "The gut microbiome impacts the body's use of bile acids. Aging impacts our microbiome," said Chamoli. "If levels of bile acids aren't correct it hinders mitophagy. That's how FXR can impact neuronal health. Neurons have a lot of mitochondria which makes mitophagy important in terms of neurodegeneration," he said, noting that experiments are underway to explore neuronal FXR as a therapeutic target for Alzheimer's disease as part of a jointly funded grant shared by the Andersen and Lithgow labs.

MIC as a general geroprotective therapeutic

"There's a bottleneck in efforts to develop potential therapeutics in the field of geroscience, and the bottleneck is that we don't have enough molecules in the pipeline," said Gordon Lithgow, PhD, Buck Professor and Vice President of Academic Affairs and senior co-author. "MIC is a great candidate to bring forward given its therapeutic effect across multiple models and the fact that it is a naturally occurring molecule."

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Yeast with an over half synthetic genome is created in the lab

Researchers have combined over seven synthetic chromosomes that were made in the lab into a single yeast cell, resulting in a strain with more than 50% synthetic DNA that survives and replicates similarly to wild yeast strains. The team present the half-synthetic yeast November 8 in the journal Cell as part of a collection of papers across Cell, Molecular Cell,and Cell Genomics that showcase the Synthetic Yeast Genome Project (Sc2.0), a global consortium working to develop the first synthetic eukaryote genome from scratch. The team has now synthesized and debugged all sixteen yeast chromosomes.

"Our motivation is to understand the first principles of genome fundamentals by building synthetic genomes," says co-author and synthetic biologist Patrick Yizhi Cai of the University of Manchester, who is also senior author of two other papers in the collection. "The team has now re-written the operating system of the budding yeast, which opens up a new era of engineering biology -- moving from tinkering a handful of genes to de novo design and construction of entire genomes."

Though bacterial and viral genomes have been synthesized previously, this would be the first synthetic eukaryote genome, which introduces the complication of multiple chromosomes. The synthetic yeast is also a "designer" genome that differs substantially from the natural Saccharomyces cerevisiae (brewer's or baker's yeast) genome on which it is based.

"We decided that it was important to produce something that was very heavily modified from nature's design," says senior author and Sc2.0 leader Jef Boeke, a synthetic biologist at NYU Langone Health. "Our overarching aim was to build a yeast that can teach us new biology."

To this end, the researchers removed chunks of non-coding DNA and repetitive elements that could be considered "junk," added new snippets of DNA to help them more easily distinguish between synthesized and native genes, and introduced a built-in diversity generator called "SCRaMbLE" that shuffles the order of genes within and between chromosomes.

To increase genome stability, the team also removed many of the genes that encode transfer RNA (tRNA) and relocated them to an entirely new "neochromosome" consisting only of tRNA genes. "The tRNA neochromosome is the world's first completely de novo synthetic chromosome," says Cai. "Nothing like this exists in nature."

Since the yeast genome is organized into sixteen chromosomes, the researchers began by assembling each chromosome independently to create sixteen partially synthetic yeast strains that each contained 15 natural chromosomes and one synthetic chromosome. The next challenge was to begin combining these synthetic chromosomes into a single yeast cell.

To do this, Boeke's team started by using a method reminiscent of Mendel's peas: essentially, the researchers interbred different partially synthetic yeast strains and then searched amongst their progeny for individuals carrying both synthetic chromosomes. Though effective, this method is very slow, but the team gradually consolidated all previously synthesized chromosomes -- six full chromosomes and one chromosome arm -- into a single cell. The resulting yeast strain was more than 31% synthetic, had normal morphology, and showed only slight growth defects compared to wild-type yeast.

To more efficiently transfer specific chromosomes between yeast strains, the researchers developed a new method called chromosome substitution that is discussed in another paper in the new collection. As a proof of concept, they used chromosome substitution to transfer a newly synthesized chromosome (chromosome IV, the largest of all the synthetic chromosomes), resulting in a yeast cell with 7.5 synthetic chromosomes that is more than 50% synthetic.

When the synthetic chromosomes were consolidated into a single yeast strain, the team detected several genetic defects or "bugs" that were invisible in yeast strains that only carried one synthetic chromosome. "We knew in principle that this might happen -- that we might have a huge number of things that had tiny little effects and that, when you put them all together, it might result in death by a thousand cuts," says Boeke.

Some of these bugs were simply due to the additive impact of having many tiny defects within the genome, while others involved genetic interactions between genes on the different synthetic chromosomes. The researchers were able to map and fix several of these bugs and increase the synthetic yeast's fitness by using a method based on CRISPR/Cas9.

"We've now shown that we can consolidate essentially half of the genome with good fitness, which suggests that this is not going to be a big problem," says Boeke. "And from debugging, we learn new twists on the rules of life."

The next step will be to integrate the remaining synthetic chromosomes. "Now we're just this far from the finish line of having all 16 chromosomes in a single cell," says Boeke. "I like to call this the end of the beginning, not the beginning of the end, because that's when we're really going to be able to start shuffling that deck and producing yeast that can do things that we've never seen before."

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Epigenetic changes are paramount in cancer progression

The path a cell takes from healthy to metastatic cancer is mostly driven by epigenetic changes, according to a new computational study. Dr. Eduard Porta, group leader of the Cancer Immunogenomics group at the Josep Carreras Leukaemia Research Institute, participated in the new analysis that has been recently published in the journal Nature.

Every cell makes its own proteins by accessing the genetic information on its genes. Changes in this information, called mutations, may ruin the function of the affected proteins. In oncology, this is regarded as the genetics of cancer. The last decades, however, have seen the rise of a new field: the epigenetics of cancer.

Epigenetic modifications do not change the information but transiently modifies the cell's ability to read some of its own genes and produce the associated proteins instead. There is a vast epigenetic programme controlling in such way the general working of the cell and, when altered, it may put it at the starting line of malignant transformation. Is there a way to track these changes and understand the epigenetics of cancer transition?

An international team of researchers has started to unlocked this long-awaited milestone. In a tour de force, they analysed 1.7 million cells from 225 samples from primary and metastatic origin, from 205 patients of 11 different cancer types. For each cell, the team obtained the full transcriptome, exome and epigenome. This covers virtually all gene mutations, gene accessibility and its consequences. Using vast computational power, they could deduce the whole functional status of each analysed cell and link it to its particular cancer type.

The results of the work, published in the scientific journal Nature, demonstrate that many regions in the DNA are differentially activated or inactivated in a cancer-specific manner, creating a signature for each tumour. These differences are relevant for cancer progression and many correspond to already identified hallmarks of cancer, the steps a cell must undergo to become malignant. Dr. Eduard Porta, group leader at the Josep Carreras Leukaemia Research Institute (IJC-CERCA), is part of the team and contributed with his experience in the analysis of large amounts of biological data.

Epigenetic changes at the DNA level stand out as an underlying cause of cancer, according to the new publication. Particularly, the accessibility of enhancer regions, a kind of master regulator acting upon many genes at once. Taken together, the results converges into a short list of genes that can be used as markers for good or poor prognosis, valuable information for the clinical management of patients.

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Mature sperm lack intact mitochondrial DNA

New research provides insight about the bedrock scientific principle that mitochondrial DNA -- the distinct genetic code embedded in the organelle that serves as the powerplant of every cell in the body -- is exclusively passed down by the mother.

The study, a collaboration among Oregon Health & Science University and other institutions, published today in the journal Nature Genetics.

Scientists have long recognized the fact that mitochondrial DNA, or mtDNA, comes exclusively from egg cells in humans, meaning only the mother contributes the genetic code carried by thousands of mitochondria necessary for energy production in every cell in the body.

Previously, it was believed that paternal mtDNA was eliminated soon after a sperm fuses with an oocyte, or developing egg, during fertilization, possibly through an immune-like search-and-destroy response.

However, the study found that while mature sperm do carry a small number of mitochondria, they lack intact mtDNA.

"We found that each sperm cell does bring 100 or so mitochondria as organelles when it fertilizes an egg, but there is no mtDNA in them," said co-author Shoukhrat Mitalipov, Ph.D., director of the Center for Embryonic Cell and Gene Therapy at OHSU.

Researchers found that sperm cells are not only devoid of intact mtDNA, but they also lacked a protein essential for mtDNA maintenance, known as mitochondrial transcription factor A, or TFAM.

Scientists aren't sure why sperm are not allowed to contribute mtDNA, but Mitalipov theorizes that it may relate to the fact that a sperm uses a lot of mitochondrial energy in its biological impetus to fertilize an egg. It would thus accumulate mutations in mtDNA. The developing eggs known as oocytes, by contrast, draw energy primarily from surrounding cells, not from their own mitochondria, so maintain relatively pristine mtDNA.

"Eggs pass on really good mtDNA at least partly because they don't use mitochondria as a source of energy," Mitalipov said.

The 100 or so organelles in sperm are swamped by hundreds of thousands of mitochondria embedded in each egg cell -- each carrying the 37 genes in mitochondrial DNA. The contribution of only maternal mtDNA is believed to confer an evolutionary advantage by limiting the risk of accumulations of mtDNA mutations that cause disease in offspring.

Mitochondria control respiration and energy production within every cell of the body, so mutations in mtDNA can cause a range of potentially fatal disorders affecting organs with high-energy demands, such as the heart, muscle and brain.

To help mothers prevent passing on known mtDNA disorders to their children, Mitalipov pioneered a method called mitochondrial replacement therapy to replace mutant mtDNA through in vitro fertilization using healthy mtDNA from donor eggs.

Congress has prevented the Food and Drug Administration from overseeing clinical trials using the procedure in the U.S., so clinical trials are instead being conducted overseas, including clinical trials in the United Kingdom to prevent disease and in Greece to treat infertility.

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Exposure to air pollution while in the womb is linked to adverse changes in cell processes in new-born babies

Exposure to air pollution while in the womb is linked to alterations in proteins that can be detected after a baby is born, and which affect cell processes such as autophagy, the "self-eating" of damaged cells that occurs in response to stress.

Dr Olga Gorlanova, a research physician at the University Children's Hospital, University of Basel, Switzerland, told the European Respiratory Society International Congress in Milan, Italy, that her study also showed that healthy, new-born babies had individual and different responses to their mothers' exposure to air pollution during pregnancy. This might mean that some babies were more vulnerable to it than others. This was the case even if they were born into households in areas with relatively low levels of pollution.

Earlier work by Dr Gorlanova and her colleagues had shown that exposure to air pollution during pregnancy could affect lung function and the immune system in new-borns. In the current study, they looked at proteins involved in autophagy, ageing and cell remodelling to see how prenatal exposure to air pollution could affect them.

The researchers measured 11 proteins found in the cord blood of 449 healthy new-born babies from the Bern Basel Infant Lung Development (BILD) cohort study. The BILD study, started in 1999 in Bern, aims to recruit 1000 babies by 2025. It is investigating the effects of genetics and the environment (particularly air pollution) on lung development in babies and children.

Dr Gorlanova and colleagues measured the mothers' exposure to nitrogen dioxide (NO2) and tiny particles called PM10,which areparticulate matter measuring 10 microns or less in diameter. Vehicle emissions, tyre and brake wear, and smoke are some of the sources of these pollutants. They found that NO2 and PM10 were both linked to changes in proteins involved in autophagy. Exposure to NO2 was linked to a decrease in the activity of the proteins SIRT1 and IL-8, and an increase in levels of the Beclin-1 protein.

"Our results indicate that NO2, a pollutant formed mainly from traffic emissions, is associated with increased levels of Beclin-1 protein, which is central to initiating autophagy. Exposure to higher NO2 was also linked to decreased levels of SIRT1, which is a protein that plays a protective role in stress resistance, inflammation and aging. IL-8 is a protein active in certain inflammatory cells," said Dr Gorlanova.

"We grouped the babies into four distinct clusters according to the levels of air pollution they were exposed to while in the womb. The four clusters all had similar concentrations of the proteins being studied but had differences their exposure to NO2 and PM10 air pollution. One cluster had low concentrations of nine proteins, while another cluster, consisting of seven percent of all the babies, had higher levels of proteins that are involved in inflammatory and remodelling processes: IL-8 and IL-1B. Both these groups of new-borns had been exposed to lower, although differing, levels of prenatal air pollution than the other two groups. Our findings suggest that healthy new-borns have an individual response pattern to air pollution. We think that this may be an indication that some babies are more vulnerable to it than others.

"Additionally, our work adds to the growing body of evidence that autophagy-related mechanisms may be involved in how human cells react to air pollution. The findings are consistent with evidence from tissue and animal research. Further exploration of these mechanisms may help to better understand the deleterious effects of pollution on infants."

The researchers plan to examine whether babies with distinct protein response patterns to air pollution will suffer from more breathing problems during infancy and childhood compared to those that do not show the same protein responses.

Professor Marielle Pijnenburg, associate professor of pediatric pulmonology and head of the Department of Pediatric Respiratory Medicine and Allergology at Erasmus Medical Center, Rotterdam, The Netherlands, is head of the ERS group on paediatrics and was not involved with the research. She commented: "This study adds to the growing body of evidence that air pollution can affect the health of children before and after they are born. It contributes to other research showing that autophagy-related mechanisms may be involved in how human cells react to air pollution. We need to know more about how these mechanisms can affect the health of lungs, and we need to understand why some new-borns seem to be more susceptible to air pollution than others.

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Unraveling the long history of breast cancer formation

From the early stages of cell mutations starting in puberty to their manifestations as breast cancer in later years, the entire process has remained shrouded in mystery.

Now, a team of researchers at Kyoto University has revealed the mechanism by which breast cancer is formed in the cells of the mammalian epithelium, whose main function is to secrete milk.

According to the team's first analysis, approximately 20 mutations accumulate annually in each epithelial cell until menopause. After menopause, however, the mutation rate significantlydecreases.

"Additionally, our results suggest that estrogen influences mutation accumulation in mammary epithelium, which correlates with our discovery of decreased accumulation after childbirth," says corresponding author Seishi Ogawa of KyotoU's Graduate School of Medicine.

As 70% of breast cancers are understood to be estrogen-sensitive, Ogawa's team may shed light on estrogen's role in the initiation of breast cancer.

Further investigation of the genetic relationship between breast cancer, its surrounding lesions, and normal epithelial cells led to mapping breast cancer's translocation-positive expansion. During this expansion process, cells of multiple origins that would subsequently develop breast cancer manifested themselves at the average age of 30. Previous studies have focused on driver mutations -- the genetic changes in cells that are already cancerous -- leading to abnormal growth. But these findings only paint a partial picture of the process and do not reveal the timing and order of driver mutations or cancer formation.

"Normal-looking tissues may already contain numerous populations of non-cancer cells -- or clones -- that have acquired mutations in cancer-related genes," says co-author author Tomomi Nishimuraof KyotoU's Graduate School of Medicine.

After examining the similarities and differences in the mutations of both cancer and non-cancer lesions originating from the clones, the team reconstructed an evolutionary tree to visualize the unique pattern of cancer evolution.

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The physics of fat droplets reveal DNA danger

Fat is a normal and necessary part of the body. Fat cells store and release energy, as well as play significant roles in hormonal regulation and immunity.

In recent decades, a concerning rise in metabolic illnesses -- such as cardiovascular disease, high blood pressure and diabetes -- has focused scientific attention on the biology and chemistry of fat, resulting in a wealth of information about how fat cells work.

But fat cells and their metabolic activities are only part of the story.

Fat-filled lipid droplets, tiny spheres of fat many times smaller than fat cells, are a growing subject of scientific interest. Found inside many different cell types, these lipid particles have long been little understood. Studies have begun to illuminate these droplets' participation in metabolic functions and cellular protection, but we still know next to nothing about the physical nature of fat.

Now, researchers at the University of Pennsylvania School of Engineering and Applied Science have looked beyond biochemistry to publish groundbreaking work on the physics of these droplets, revealing them to be a potential threat to a cell's nucleus. In the August issue of the Journal of Cell Biology, they are the first to discover fat-filled lipid droplets' surprising capability to indent and puncture the nucleus, the organelle which contains and regulates a cell's DNA.

The stakes of their findings are high: a ruptured nucleus can lead to elevated DNA damage that is characteristic of many diseases, including cancer.

The study was led by Dennis E. Discher, Robert D. Bent Professor in the Department of Chemical and Biomolecular Engineering, Irena Ivanovska, Ph.D. Research Associate in Penn's Molecular and Cell Biophysics Lab, and Michael Tobin, Ph.D. Candidate in the Department of Bioengineering.

"Intuitively, people think of fat as soft," says Discher. "And on a cellular level it is. But at this small size of droplet -- measuring just a few microns rather than the hundreds of microns of a mature fat cell -- it stops being soft. Its shape has a much higher curvature, bending other objects very sharply. This changes its physics in the cell. It can deform. It can damage. It can rupture."

"Imagine," adds Ivanovska, "trying to pop a balloon with your fist. Impossible. You can deform the balloon, but you won't puncture it. Now imagine trying to pop it with a pen. That's the difference between a fat cell and a cell with small fat droplets in the body. It's a fundamental physical difference, not a metabolic one."

The team's research reframes scientific inquiry into fat, underlining that fat's role in the body is much more than just a number on the scales.

"This isn't fat canonically conceived," says Tobin. "This is about how fat works at scales smaller than a cell and poses physical risks to cellular components, even at the level of DNA."

The team's work builds on a decade of foundational research, including leading contributions by Ivanovska, into the behaviors of nuclear proteins that give the nucleus its protective structural qualities. These proteins are dynamic, shifting levels to respond to their mechanical environments and provide what the nucleus needs to maintain its integrity.

"There's a constant process of repair to DNA damage that goes on in cells," says Ivanovska. "For this to happen, the nucleus needs to have enough DNA repair proteins. If a nucleus is ruptured, these proteins scatter and cannot repair damage in a timely manner. This causes DNA damage accumulation and can potentially result in a cancer cell."

A cell lives in a dynamic physical and mechanical environment where things can and do go wrong. But it also has an army of molecular helpers always working to maintain and repair it.

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Novel molecules fight viruses by bursting their bubble-like membranes

Antiviral therapies are notoriously difficult to develop, as viruses can quickly mutate to become resistant to drugs. But what if a new generation of antivirals ignores the fast-mutating proteins on the surface of viruses and instead disrupts their protective layers?

"We found an Achilles heel of many viruses: their bubble-like membranes. Exploiting this vulnerability and disrupting the membrane is a promising mechanism of action for developing new antivirals," said Kent Kirshenbaum, professor of chemistry at NYU and the study's senior author.

In a new study published Aug. 2 in the journal ACS Infectious Diseases, the researchers show how a group of novel molecules inspired by our own immune system inactivates several viruses, including Zika and chikungunya. Their approach may not only lead to drugs that can be used against many viruses, but could also help overcome antiviral resistance.

The urgent need for new antivirals

Viruses have different proteins on their surfaces that are often the targets of therapeutics like monoclonal antibodies and vaccines. But targeting these proteins has limitations, as viruses can quickly evolve, changing the properties of the proteins and making treatments less effective. These limitations were on display when new SARS-CoV-2 variants emerged that evaded both the drugs and the vaccines developed against the original virus.

"There is an urgent need for antiviral agents that act in new ways to inactivate viruses," said Kirshenbaum. "Ideally, new antivirals won't be specific to one virus or protein, so they will be ready to treat new viruses that emerge without delay and will be able to overcome the development of resistance."

"We need to develop this next generation of drugs now and have them on the shelves in order to be ready for the next pandemic threat -- and there will be another one, for sure," added Kirshenbaum.

Drawing inspiration from our immune systems

Our innate immune system combats pathogens by producing antimicrobial peptides, the body's first line of defense against bacteria, fungi, and viruses. Most viruses that cause disease are encapsulated in membranes made of lipids, and antimicrobial peptides work by disrupting or even bursting these membranes.

While antimicrobial peptides can be synthesized in the lab, they are rarely used to treat infectious diseases in humans because they break down easily and can be toxic to healthy cells. Instead, scientists have developed synthetic materials called peptoids, which have similar chemical backbones to peptides but are better able to break through virus membranes and are less likely to degrade.

"We began to think about how to mimic natural peptides and create molecules with many of the same structural and functional features as peptides, but are composed of something that our bodies won't be able to rapidly degrade," said Kirshenbaum.

The researchers investigated seven peptoids, many originally discovered in the lab of Annelise Barron at Stanford, a co-author of the study. The NYU team studied the antiviral effects of the peptoids against four viruses: three enveloped in membranes (Zika, Rift Valley fever, and chikungunya) and one without (coxsackievirus B3).

"We were particularly interested in studying these viruses as they have no available treatment options," said Patrick Tate, a chemistry PhD student at NYU and the study's first author.

How peptoids disrupt viral membranes and avoid other cells

The membranes surrounding viruses are made of different molecules than the virus itself, as lipids are acquired from the host to form membranes. One such lipid, phosphatidylserine, is present in the membrane on the outside of viruses, but is sequestered towards the interior of human cells under normal conditions.

"Because phosphatidylserine is found on the exterior of viruses, it can be a specific target for peptoids to recognize viruses, but not recognize -- and therefore spare -- our own cells," said Tate. "Moreover, because viruses acquire lipids from the host rather than encoding from their own genomes, they have better potential to avoid antiviral resistance."

The researchers tested seven peptoids against the four viruses. They found that the peptoids inactivated all three enveloped viruses -- Zika, Rift Valley fever, and chikungunya -- by disrupting the virus membrane, but did not disrupt coxsackievirus B3, the only virus without a membrane.

Moreover, chikungunya virus containing higher levels of phosphatidylserine in its membrane was more susceptible to the peptoids. In contrast, a membrane formed exclusively with a different lipid named phosphatidylcholine was not disrupted by the peptoids, suggesting that phosphatidylserine is crucial in order for peptoids to reduce viral activity.

"We're now starting to understand how peptoids actually exert their antiviral effect -- specifically, through the recognition of phosphatidylserine," said Tate.

The researchers are continuing pre-clinical studies to evaluate the potential of these molecules in fighting viruses and to understand if they can overcome the development of resistance. Their peptoid-focused approach may hold promise for treating a wide range of viruses with membranes that can be difficult to treat, including Ebola, SARS-CoV-2, and herpes.

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'Mind controlling' parasitic worms are missing genes found in every other animal

In a world full of bizarre animals, hairworms are some of the strangest: parasitic worms that manipulate the behavior of their hosts in what's sometimes called "mind control." A new study in the journal Current Biology reveals another strange trait shared by different hairworm species: they're missing about 30% of the genes that researchers expected them to have. What's more, the missing genes are responsible for the development of cilia, the hair-like structures present in at least some of the cells of every other animal known.

Hairworms are found all over the world, and they look like skinny strands of spaghetti, a couple inches long. Their simple bodies hint at their parasitic lifestyle -- they have no excretory, respiratory, or circulatory systems, and they spend almost their entire lives inside the bodies of other animals. "One of the coolest things, maybe the thing that they are most known for, is that they can affect the behavior of their hosts and make them do things that they wouldn't do otherwise," says Tauana Cunha, a postdoctoral researcher at Chicago's Field Museum and lead author of the study done in collaboration with Harvard University and the University of Copenhagen.

There are a few hundred species of freshwater hairworms. Their eggs hatch in water, and the hairworm larvae get eaten by tiny water-dwelling predators like mayfly larvae, which in turn get eaten by bigger, land-dwelling predators like crickets. After growing into adulthood inside of their new hosts' bodies, the hairworms manipulate the hosts' behavior, causing them to jump into water. There, the worms swim out of their hosts' butts and seek out mates, knotting themselves together, to begin the cycle anew. (There are also five species of hairworms that live in marine environments and parasitize water-dwelling creatures like lobsters, but it's not clear if those ones also have host manipulation capabilities -- there's no pressure for the worms to get back to the water, since the hosts already live there.)

As strange as hairworms' behavior is, Cunha's research interest in the animals has more to do with their DNA. "We set out to sequence their genomes, because nothing like them has ever been sequenced before at that level," she says of the study conducted with her co-authors Bruno de Medeiros, Arianna Lord, Martin Sørensen, and Gonzalo Giribet. "The goal was to produce those genomes and eventually use them to understand the evolutionary relationships between hairworms and other kinds of animals."

She and her colleagues took DNA samples from two hairworm species -- one freshwater and one saltwater -- and sequenced them. But when they compared the hairworms' genetic codes to those of other animals, they found something striking.

"What we found, which was very surprising, was that both hairworm genomes were missing about 30% of a set of genes that are expected to be present across basically all groups of animals," says Cunha.

Results like that often make scientists wonder if they've made a mistake. But there was a connection between the missing genes in the two worm species. "The large majority of the missing genes were exactly the same between the two species. This was just implausible by chance," says Cunha.

By looking at what functions these missing genes are responsible for in other animal groups, Cunha and colleagues showed that they give the instructions for producing cilia. "Cilia are organelles, small structures at the cellular level, that are basically present across all animals and even more broadly, in protists and some plants and fungi. So they're present across a large diversity of life on Earth," says Cunha. They're present in many of the cells in the human body: for instance, the tails of sperm cells are cilia, and cells in the retinas of our eyes have cilia too.

Previously, scientists had found that hairworms seemed to be missing cilia where they'd normally be found. Hairworm sperm, for example, do not have tails. But while no one had ever seen a ciliated cell from a hairworm, that wasn't considered definitive proof that they didn't have them. It's hard to prove something with negative evidence. "Without the genomes, this would require looking at all cells in all life stages in all species," says Bruno de Medeiros, Curator of Pollinating Insects at the Field Museum and co-author of the paper.

"Based on previous observations, it didn't seem like hairworms had any cilia, but we didn't really know for sure," says Cunha. "Now with the genomes, we saw that they actually lack the genes that produce cilia in other animals -- they don't have the machinery to make cilia in the first place."

What's more, the fact that both the freshwater and marine hairworm species had lost the genes for cilia indicates that this evolutionary change happened in the deep past to the two species' common ancestor. "It is likely that the loss happened early on in the evolution of the group, and they just have been carrying on like that," says Cunha.

The finding opens the door to several new questions. It's not clear how the lack of cilia have affected hairworms, or if the hairworms' parasitic behavior could be related to the missing cilia. "There are plenty of other parasitic organisms that aren't missing these specific genes, so we cannot say that the genes are missing because of their parasitic lifestyle," says Cunha. "But parasitic organisms in general are often missing lots of genes. It's hypothesized that because parasites are not using certain structures and instead rely on their hosts, they end up losing those structures."

Read more at Science Daily