Breakthrough for 'smart cell' design

 Rice University bioengineers have developed a new construction kit for building custom sense-and-respond circuits in human cells. The research, published in the journal Science, represents a major breakthrough in the field of synthetic biology that could revolutionize therapies for complex conditions like autoimmune disease and cancer.

"Imagine tiny processors inside cells made of proteins that can 'decide' how to respond to specific signals like inflammation, tumor growth markers or blood sugar levels," said Xiaoyu Yang, a graduate student in the Systems, Synthetic and Physical Biology Ph.D. program at Rice who is the lead author on the study. "This work brings us a whole lot closer to being able to build 'smart cells' that can detect signs of disease and immediately release customizable treatments in response."The new approach to artificial cellular circuit design relies on phosphorylation -- a natural process cells use to respond to their environment that features the addition of a phosphate group to a protein. Phosphorylation is involved in a wide range of cellular functions, including the conversion of extracellular signals into intracellular responses -- e.g., moving, secreting a substance, reacting to a pathogen or expressing a gene.

In multicellular organisms, phosphorylation-based signaling often involves a multistage, cascading effect like falling dominoes. Previous attempts at harnessing this mechanism for therapeutic purposes in human cells have focused on re-engineering native, existing signaling pathways. However, the complexity of the pathways makes them difficult to work with, so applications have remained fairly limited.

Thanks to Rice researchers' new findings, however, phosphorylation-based innovations in "smart cell" engineering could see a significant uptick in the coming years. What enabled this breakthrough was a shift in perspective:

Phosphorylation is a sequential process that unfolds as a series of interconnected cycles leading from cellular input (i.e. something the cell encounters or senses in its environment) to output (what the cell does in response). What the research team realized -- and set out to prove -- was that each cycle in a cascade can be treated as an elementary unit, and these units can be linked together in new ways to construct entirely novel pathways that link cellular inputs and outputs.

"This opens up the signaling circuit design space dramatically," said Caleb Bashor, an assistant professor of bioengineering and biosciences and corresponding author on the study. "It turns out, phosphorylation cycles are not just interconnected but interconnectable -- this is something that we were not sure could be done with this level of sophistication before.

"Our design strategy enabled us to engineer synthetic phosphorylation circuits that are not only highly tunable but that can also function in parallel with cells' own processes without impacting their viability or growth rate."

While this may sound straightforward, figuring out the rules for how to build, connect and tune the units -- including the design of intra- and extracellular outputs -- was anything but. Moreover, the fact that synthetic circuits could be built and implemented in living cells was not a given.

"We didn't necessarily expect that our synthetic signaling circuits, which are composed entirely of engineered protein parts, would perform with a similar speed and efficiency as natural signaling pathways found in human cells," Yang said. "Needless to say, we were pleasantly surprised to find that to be the case. It took a lot of effort and collaboration to pull it off."

The do-it-yourself, modular approach to cellular circuit design proved capable of reproducing an important systems-level ability of native phosphorylation cascades, namely amplifying weak input signals into macroscopic outputs. Experimental observations of this effect verified the team's quantitative modelling predictions, reinforcing the new framework's value as a foundational tool for synthetic biology.

Another distinct advantage of the new approach to sense-and-respond cellular circuit design is that phosphorylation occurs rapidly in only seconds or minutes, so the new synthetic phospho-signaling circuits could potentially be programmed to respond to physiological events that occur on a similar timescale. In contrast, many previous synthetic circuit designs were based on different molecular processes such as transcription, which can take many hours to activate.

Source: ScienceDaily

Fossil predator is the oldest known animal with 'saber teeth'

 The first true mammals evolved roughly 200 million years ago, during the early days of the dinosaurs. But mammals are the last surviving members of an older group, called the therapsids. At first glance, many therapsids weren't obviously mammal-like , but they also had subtle features that we recognize in mammals today, like a hole on the sides of their skull for the jaw muscle to attach and structures on their jaw bones that would eventually evolve into mammals' distinctive middle ear bones. In a new paper in the journal Nature Communications, scientists announce the discovery of a fossil therapsid that's the oldest of its kind, and maybe the oldest therapsid ever discovered: a vaguely dog-like saber-toothed predator.

The new fossil, which doesn't have a species name yet, is a member of a group called the gorgonopsians. "Gorgonopsians are more closely related to mammals than they are to any other living animals," says Ken Angielczyk, the Field Museum's MacArthur Curator of Paleomammalogy in the Negaunee Integrative Research Center and a co-author of the paper. "They don't have any modern descendents, and while they're not our direct ancestors, they're related to species that were our direct ancestors."

Until now, the oldest known gorgonopsians lived roughly 265 million years ago. However, the new fossil is from 270-280 million years ago. "It is most likely the oldest gorgonopsian on the planet," says Josep Fortuny, senior author of the article and head of the Computational Biomechanics and Evolution of Life History group at the Institut Català de Paleontologia Miquel Crusafont (ICP) in Spain.

The fossils were found in Mallorca (also sometimes spelled Majorca), a Spanish island in the Mediterranean Sea. But in the time of the gorgonopsians, Mallorca was part of the supercontinent of Pangea.

"The large number of bone remains is surprising. We have found everything from fragments of skull, vertebrae, and ribs to a very well-preserved femur. In fact, when we started this excavation, we never thought we would find so many remains of an animal of this type in Mallorca," explains Rafel Matamales, curator of the Museu Balear de Ciències Naturals (MUCBO | MBCN), research associate at the ICP, and first author of the article.

These bones allowed the researchers to reconstruct what the animal looked like and a little about its life. "If you saw this animal walking down the street, it would look a little bit like a medium-sized dog, maybe about the size of a husky, but it wouldn't be quite right. It didn't have any fur, and it wouldn't have had dog-like ears," says Angielczyk. "But it's the oldest animal scientists have ever found with long, blade-like canine teeth." These saber teeth suggest that this gorgonopsian was a top predator in its day.

The fact that this gorgonopsian predates its closest relatives by tens of millions of years changes scientists' understanding of when therapsids evolved, an important milestone on the way to the emergence of mammals, and in turn it tells us something about where we come from.

"Before the time of dinosaurs, there was an age of ancient mammal relatives. Most of those ancient mammal relatives looked really different from what we think of mammals looking like today," says Angielczyk. "But they were really diverse and played lots of different ecological roles. The discovery of this new fossil is another piece of the puzzle for how mammals evolved."

Source: ScienceDaily

The carbon in our bodies probably left the galaxy and came back on cosmic 'conveyer belt'

 Life on Earth could not exist without carbon. But carbon itself could not exist without stars. Nearly all elements except hydrogen and helium -- including carbon, oxygen and iron -- only exist because they were forged in stellar furnaces and later flung into the cosmos when their stars died. In an ultimate act of galactic recycling, planets like ours are formed by incorporating these star-built atoms into their makeup, be it the iron in Earth's core, the oxygen in its atmosphere or the carbon in the bodies of Earthlings.

A team of scientists based in the U.S. and Canada recently confirmed that carbon and other star-formed atoms don't just drift idly through space until they are dragooned for new uses. For galaxies like ours, which are still actively forming new stars, these atoms take a circuitous journey. They circle their galaxy of origin on giant currents that extend into intergalactic space. These currents -- known as the circumgalactic medium -- resemble giant conveyer belts that push material out and draw it back into the galactic interior, where gravity and other forces can assemble these raw materials into planets, moons, asteroids, comets and even new stars.

"Think of the circumgalactic medium as a giant train station: It is constantly pushing material out and pulling it back in," said team member Samantha Garza, a University of Washington doctoral candidate. "The heavy elements that stars make get pushed out of their host galaxy and into the circumgalactic medium through their explosive supernovae deaths, where they can eventually get pulled back in and continue the cycle of star and planet formation."

Garza is lead author on a paper describing these findings that was published Dec. 27 in the Astrophysical Journal Letters.

"The implications for galaxy evolution, and for the nature of the reservoir of carbon available to galaxies for forming new stars, are exciting," said co-author Jessica Werk, UW professor and chair of the Department of Astronomy. "The same carbon in our bodies most likely spent a significant amount of time outside of the galaxy!"

In 2011, a team of scientists for the first time confirmed the long-held theory that star-forming galaxies like ours are surrounded by a circumgalactic medium -- and that this large, circulating cloud of material includes hot gases enriched in oxygen. Garza, Werk and their colleagues have discovered that the circumgalactic medium of star-forming galaxies also circulates lower-temperature material like carbon.

"We can now confirm that the circumgalactic medium acts like a giant reservoir for both carbon and oxygen," said Garza. "And, at least in star-forming galaxies, we suggest that this material then falls back onto the galaxy to continue the recycling process."

Studying the circumgalactic medium could help scientists understand how this recycling process subsides, which will happen eventually for all galaxies -- even ours. One theory is that a slowing or breakdown of the circumgalactic medium's contribution to the recycling process may explain why a galaxy's stellar populations decline over long periods of time.

"If you can keep the cycle going -- pushing material out and pulling it back in -- then theoretically you have enough fuel to keep star formation going," said Garza.

For this study, the researchers used the Cosmic Origins Spectrograph on the Hubble Space Telescope. The spectrograph measured how light from nine distant quasars -- ultra-bright sources of light in the cosmos -- is affected by the circumgalactic medium of 11 star-forming galaxies. The Hubble readings indicated that some of the light from the quasars was being absorbed by a specific component in the circumgalactic medium: carbon, and lots of it. In some cases, they detected carbon extending out almost 400,000 light years -- or four times the diameter of our own galaxy -- into intergalactic space.

Future research is needed to quantify the full extent of the other elements that make up the circumgalactic medium and to further compare how their compositions differ between galaxies that are still making large amounts of stars and galaxies that have largely ceased star formation. Those answers could illuminate not just when galaxies like ours transition into stellar deserts, but why.

Co-authors on the paper are Trystyn Berg, research fellow at the Herzberg Astronomy and Astrophysics Research Centre in British Columbia; Yakov Faerman, a UW postdoctoral researcher in astronomy; Benjamin Oppenheimer, a research fellow at the University of Colorado Boulder; Rongmon Bordoloi, assistant professor of physics at North Carolina State University; and Sara Ellison, professor of physics and astronomy at the University of Victoria. The research was funded by NASA and the National Science Foundation.

Source: ScienceDaily

Loneliness linked to higher risk of heart disease

Interactions with friends and family may keep us healthy because they boost our immune system and reduce our risk of diseases such as heart disease, stroke and type 2 diabetes, new research suggests.

Researchers from the UK and China drew this conclusion after studying proteins from blood samples taken from over 42,000 adults recruited to the UK Biobank. Their findings are published today in the journal Nature Human Behaviour.

Social relationships play an important role in our wellbeing. Evidence increasingly demonstrates that both social isolation and loneliness are linked to poorer health and an early death. Despite this evidence, however, the underlying mechanisms through which social relationships impact health remain elusive.

One way to explore biological mechanisms is to look at proteins circulating in the blood. Proteins are molecules produced by our genes and are essential for helping our bodies function properly. They can also serve as useful drug targets, allowing researchers to develop new treatments to tackle diseases.

A team led by scientists at the University of Cambridge, UK, and Fudan University, China, examined the 'proteomes' -- the suite of proteins -- in blood samples donated by over 42,000 adults aged 40-69 years who are taking part in the UK Biobank. This allowed them to see which proteins were present in higher levels among people who were socially isolated or lonely, and how these proteins were connected to poorer health.

The team calculated social isolation and loneliness scores for individuals. Social isolation is an objective measure based on, for example, whether someone lives alone, how frequently they have contact with others socially, and whether they take part in social activities. Loneliness, on the other hand, is a subjective measure based on whether an individual feels lonely.

When they analysed the proteomes and adjusted for factors such as age, sex and socioeconomic background, the team found 175 proteins associated with social isolation and 26 proteins associated with loneliness (though there was substantial overlap, with approximately 85% of the proteins associated with loneliness being shared with social isolation). Many of these proteins are produced in response to inflammation, viral infection and as part of our immune responses, as well as having been linked to cardiovascular disease, type 2 diabetes, stroke, and early death.

The team then used a statistical technique known as Mendelian randomization to explore the causal relationship between social isolation and loneliness on the one hand, and proteins on the other. Using this approach, they identified five proteins whose abundance was caused by loneliness.

Dr Chun Shen from the Department of Clinical Neurosciences at the University of Cambridge and the Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, said: "We know that social isolation and loneliness are linked to poorer health, but we've never understood why. Our work has highlighted a number of proteins that appear to play a key role in this relationship, with levels of some proteins in particular increasing as a direct consequence of loneliness.

Professor Jianfeng Feng from the University of Warwick said: "There are more than 100,000 proteins and many of their variants in the human body. AI and high throughput proteomics can help us pinpoint some key proteins in prevention, diagnosis, treatment and prognosis in many human diseases and revolutionise the traditional view of human health.

"The proteins we've identified give us clues to the biology underpinning poor health among people who are socially isolated or lonely, highlighting why social relationships play such an important part in keeping us healthy."

One of the proteins produced in higher levels as a result of loneliness was ADM. Previous studies have shown that this protein plays a role in responding to stress and in regulating stress hormones and social hormones such as oxytocin -- the so-called 'love hormone' -- which can reduce stress and improve mood.

The team found a strong association between ADM and the volume of the insula, a brain hub for interoception, our ability to sense what's happening inside our body -- the greater the ADM levels, the smaller the volume of this region. Higher ADM levels were also linked to lower volume of the left caudate, a region involved in emotional, reward, and social processes. In addition, higher levels of ADM were linked to increased risk of early death.

Another of the proteins, ASGR1, is associated with higher cholesterol and an increased risk of cardiovascular disease, while other identified proteins play roles in the development of insulin resistance, atherosclerosis ('furring' of the arteries) and cancer progression, for example.

Professor Barbara Sahakian from the Department of Psychiatry at the University of Cambridge said: "These findings drive home the importance of social contact in keeping us well. More and more people of all ages are reporting feeling lonely. That's why the World Health Organization has described social isolation and loneliness as a 'global public health concern'. We need to find ways to tackle this growing problem and keep people connected to help them stay healthy."

The research was supported by the National Natural Sciences Foundation of China, China Postdoctoral Science Foundation, Shanghai Rising-Star Program, National Key R&D Program of China, Shanghai Municipal Science and Technology Major Project, 111 Project, Shanghai Center for Brain Science and Brain-Inspired Technology, and Zhangjiang Lab. 

Source: ScienceDaily

ome bacteria evolve like clockwork with the seasons

 Like Bill Murray in the movie "Groundhog Day," bacteria species in a Wisconsin lake are in a kind of endless loop that they can't seem to shake. Except in this case, it's more like Groundhog Year.

According to a new study in Nature Microbiology, researchers found that through the course of a year, most individual species of bacteria in Lake Mendota rapidly evolved, apparently in response to dramatically changing seasons. Gene variants would rise and fall over generations, yet hundreds of separate species would return, almost fully, to near copies of what they had been genetically prior to a thousand or so generations of evolutionary pressures. (Individual microbes have lifespans of only a few days -- not whole seasons -- so the scientists' work involved comparing bacterial genomes to examine changes in species over time.) This same seasonal change played out year after year, as if evolution was a movie run back to the beginning each time and played over again, seemingly getting nowhere.

"I was surprised that such a large portion of the bacterial community was undergoing this type of change," said Robin Rohwer, a postdoctoral researcher at The University of Texas at Austin in the lab of co-author Brett Baker. "I was hoping to observe just a couple of cool examples, but there were literally hundreds."

Rohwer led the research, first as a doctoral student working with Trina McMahon at the University of Wisconsin-Madison and then at UT.

Lake Mendota changes greatly from season to season -- during the winter, it's covered in ice, and during the summer, it's covered in algae. Within the same bacterial species, strains that are better adapted to one set of environmental conditions will outcompete other strains for a season, while other strains will get their chance to shine during different seasons.

The team used a one-of-a-kind archive of 471 water samples collected over 20 years from Lake Mendota by McMahon, Rohwer and other UW-Madison researchers as part of National Science Foundation-funded long-term monitoring projects. For each water sample, they assembled a metagenome, all of the genetic sequences from fragments of DNA left behind by bacteria and other organisms. This resulted in the longest metagenome time series ever collected from a natural system.

"This study is a total game changer in our understanding of how microbial communities change over time," Baker said. "This is just the beginning of what these data will tell us about microbial ecology and evolution in nature."

This archive also revealed longer-lasting genetic changes.

In 2012, the lake experienced unusual conditions: The ice cover melted early, the summer was hotter and drier than usual, the flow of water from a river that feeds into the lake dwindled, and algae, which are an important source of organic nitrogen for bacteria, were more scarce than usual. As Rohwer and the team discovered, many of the bacteria in the lake that year experienced a major shift in genes related to nitrogen metabolism, possibly due to the scarcity of algae.

"I thought, out of hundreds of bacteria, I might find one or two with a long-term shift," Rohwer said. "But instead, 1 in 5 had big sequence changes that played out over years. We were only able to dig deep into one species, but some of those other species probably also had major gene changes."

Climate scientists predict more extreme weather events -- like the hot, dry summer experienced at Lake Mendota in 2012 -- for the midwestern U.S. during the coming years.

"Climate change is slowly shifting the seasons and average temperatures, but also causing more abrupt, extreme weather events," Rohwer said. "We don't know exactly how microbes will respond to climate change, but our study suggests they will evolve in response to both these gradual and abrupt changes."

Unlike another famous bacterial evolution experiment at UT, the Long-Term Evolution Experiment, Rohwer and Baker's study involved bacterial evolution under complex and constantly changing conditions in nature. The researchers used the supercomputing resources at the Texas Advanced Computing Center (TACC) to reconstruct bacterial genomes from short sequences of DNA in the water samples. The same work that took a couple of months to complete at TACC would have taken 34 years with a laptop computer, Rohwer estimated, involving over 30,000 genomes from about 2,800 different species.

Source: ScienceDaily

Researchers discover class of anti-malaria antibodies

 A novel class of antibodies that binds to a previously untargeted portion of the malaria parasite could lead to new prevention methods, according to a study from researchers at the National Institutes of Health (NIH) published in Science. The most potent of the new antibodies was found to provide protection against malaria parasites in an animal model. The researchers say antibodies in this class are particularly promising because they bind to regions of the malaria parasite not included in current malaria vaccines, providing a potential new tool for fighting this dangerous disease.

Malaria is a life-threatening disease caused by Plasmodium parasites, which are spread through the bites of infected mosquitoes. Although malaria is not common in the United States, its global impact is devastating, with 263 million cases and 597,000 deaths estimated by the World Health Organization in 2023. Of the five species of Plasmodium that cause malaria, Plasmodium falciparum is the most common in African countries where the burden of malaria is largest and where young children account for the majority of malaria deaths. Safe and effective countermeasures are critical for reducing the immense burden of this disease.

In recent years, new interventions have been developed against malaria, including vaccines that currently are being rolled out for young children in regions where the disease is prevalent. Anti-malarial monoclonal antibodies (mAbs) are another promising new tool that have been shown to be safe and efficacious against infection with P. falciparum in adults and children in early clinical trials. The anti-malarial mAbs evaluated in trials in malaria-endemic regions target the P. falciparum sporozoite -- the life stage of the parasite that is transmitted from mosquitoes to people. By binding to and neutralizing the sporozoite, the mAbs prevent sporozoites from infecting the liver, where they otherwise develop into blood-stage parasites that infect blood cells and cause disease and death.

The most promising anti-malarial mAbs tested in humans to date bind to a protein on the sporozoite surface called the circumsporozoite protein (PfCSP) at locations near to or containing amino acid repeats in a region called the central repeat region. This portion of PfCSP also is included in the two available malaria vaccines. The researchers in the current study aimed to find mAbs that target new sites on the sporozoite surface.

Led by scientists at NIH's National Institute of Allergy and Infectious Diseases (NIAID), the research team used a novel approach to find new portions -- or epitopes -- on the sporozoite surface where antibodies bind. They isolated human mAbs produced in response to whole sporozoites, rather than to specific parts of the parasite, and then tested the mAbs to see if they could neutralize sporozoites in a mouse model of malaria. One mAb, named MAD21-101, was found to be the most potent, providing protection against P. falciparum infection in mice.

This new mAb binds to an epitope on PfCSP outside of the central repeat region that is conserved -- or similar -- between different strains of P. falciparum. Notably, the epitope, called pGlu-CSP, is exposed only after a specific step in the development of the sporozoite, but it is widely accessible on the sporozoite surface -- a scenario that the researchers say could mean pGlu-CSP would be effective at eliciting a protective immune response if used in a vaccine. As pGlu-CSP is not included in currently used malaria vaccines, mAbs targeting this epitope are unlikely to interfere with the efficacy of these vaccines if the vaccines and mAbs are co-administered. According to the scientists, this could provide an advantage because this new class of antibodies may be suitable to prevent malaria in at-risk infants who have not yet received a malaria vaccine, but may receive one in the future.

Findings from the study will inform future strategies for the prevention of malaria and may facilitate the development of new antibodies and vaccines against the disease, the researchers indicate. The scientists also note that more research is needed to examine the activity and effectiveness of the newly identified antibody class and epitope, according to their paper. The approach used in this study could also aid the development of a new generation of countermeasures against other pathogens, in addition to malaria.

Source: ScienceDaily

Study reveals that sleep prevents unwanted memories from intruding

 The link between poor sleep and mental health problems could be related to deficits in brain regions that keep unwanted thoughts out of mind, according to research from the University of East Anglia (UEA).

Sleep problems play an important role in the onset and maintenance of many mental health problems, but the reason for this link is elusive.

A new study, published in Proceedings of the National Academy of Sciences (PNAS), offers fresh insight into the cognitive and neural mechanisms underlying the connection between sleep and mental health. These findings could support the development of novel treatments and prevention strategies for mental health problems such as depression and anxiety.

Dr Marcus Harrington, a Lecturer in UEA's School of Psychology, is lead author of the paper 'Memory control deficits in the sleep-deprived human brain'. He worked with colleagues at the universities of York, Cambridge, Sussex, and Queen's University (Canada).

Functional neuroimaging was used to reveal for the first time that deficits in memory control after sleep deprivation are related to difficulties in engaging brain regions that support the inhibition of memory retrieval, and that the overnight rejuvenation of these brain regions is associated with rapid eye movement (REM) sleep.

Dr Harrington said: "Memories of unpleasant experiences can intrude into conscious awareness, often in response to reminders.

"While such intrusive memories are an occasional and momentary disturbance for most people, they can be recurrent, vivid and upsetting for individuals suffering from mental health disorders such as depression, anxiety and post-traumatic stress disorder.

"Given that memories play a central role in our affective perception of the external world, memory control failures may go a long way towards explaining the relationship between sleep loss and emotional dysregulation.

"A better understanding of the mechanisms that precipitate the occurrence of intrusive memories is vital to improving emotional wellbeing and reducing the global burden of mental illness."

Eighty-five healthy adults attempted to suppress unwanted memories while images of their brain were taken using functional MRI. Half of the participants enjoyed a restful night of sleep in the sleep lab before the task, whereas the other half stayed awake all night.

During memory suppression, the well-rested participants showed more activation in the right dorsolateral prefrontal cortex -- a brain region that controls thoughts, actions, and emotions -- compared to those who stayed awake all night. The rested participants also showed reduced activity in the hippocampus -- a brain region involved in memory retrieval -- during attempts to suppress unwanted memories.

Among the participants who slept in the lab, those who spent more time in REM sleep were better able to engage the right dorsolateral prefrontal cortex during memory suppression, pointing to a role for REM sleep in restoring prefrontal control mechanisms underpinning the ability to prevent unwanted memories from entering conscious thought.

Dr Harrington said: "Taken together, our findings highlight the critical role of sleep in maintaining control over both our memories and ongoing thoughts."

Source:ScienceDaily