There are four “letters” in the linear DNA code: A, C, G and T. Through the complex processes of transcription, followed by protein synthesis and finally protein folding, those four, two-dimensional letters turn into a 20-letter, three-dimensional recipe for proteins. Most of the time, this process works flawlessly, and our cells can build and reproduce themselves smoothly. But when something goes awry, the results can be catastrophic. Luckily, cells rely on a rigorous quality control to offset the devastating consequences.

The protein folding process, during which a chain of amino acids assumes its final shape as a protein, can be especially fraught. Researchers have long known that special molecules called chaperones help shepherd the protein into its final, correct shape. These “chaperones” can figure out which proteins are at risk of being deformed and can then lend that protein additional help. But how exactly they do their work has been poorly understood: “The chaperones do some kind of magic,” says Alexandra Pozhidaeva, co-lead author of the paper who contributed to this study as a postdoctoral research associate at UMass Amherst and is currently a postdoctoral fellow at UConn Health. “What we’ve done is to reveal the mechanics behind the trick.”

The trick is that, though there are tens of thousands of different proteins in our cells, each with a different shape and function, there are far fewer chaperones. “How is it,” asks Lila Gierasch, Distinguished Professor of biochemistry and molecular biology at UMass Amherst and the paper’s senior author, “that the same chaperones can help many different proteins?” The answer lies in what the authors call the chaperones’ “selective promiscuity.”

The team relied on the cutting-edge, in-house resources of UMass Amherst’s Institute for Applied Life Sciences for a novel combination of x-ray crystallography, which yields an incredibly detailed high-resolution but static snapshot of the chaperone’s interaction with its protein client, and nuclear magnetic resonance, which can capture a fuller, more dynamic picture of this complex process. The team focused their efforts on a specific chaperone family known as the Hsp70s. Hsp70s, according to co-lead author Rachel Jensen, a UMass undergraduate at the time she conducted this research and now a graduate student at Berkeley, are among the most important of chaperones because “they carry out a wide range of critical roles within the cell and help execute many crucial cellular functions.”

Whereas previous researchers used artificially shortened protein chains, the team used much longer chains to study how Hsp70’s interaction with their clients. “We studied a much more complex system,” says Eugenia Clerico, co-lead author and research professor of biochemistry and molecular biology at UMass. “We were able to study in the lab something that mimics what happens in our bodies.”

What they discovered is that Hsp70s are both promiscuous — they can service many different proteins — but also selective: the range of proteins they can work with is limited. Additionally, Hsp70s “read” ambidextrously: they can identify which protein chains to help by reading their sequences either from left to right, or right to left.

Not only is this breakthrough an advance in our understanding of how cells stay healthy, it has real-world applications. “Hsp70s,” says Gierasch, “are involved in so many pathological diseases, from cancer to Alzheimer’s, and host Hsp70s are exploited by parasites and viruses. Understanding how Hsp70s work can help us develop therapeutic strategies against these terrible diseases.”

Story Source:

Materials provided by University of Massachusetts Amherst. Note: Content may be edited for style and length.

“We show experimentally for the first time the potential that direct photon measurements are sensitive to the transverse motion of gluons and that we can use such measurements to start constraining things — to reduce the huge uncertainties in our knowledge of how gluons behave,” said Alexander Bazilevsky, deputy spokesperson of the PHENIX Collaboration and a physicist at the U.S. Department of Energy’s (DOE) Brookhaven National Laboratory.

The data, published in Physical Review Letters, come from collisions between beams of polarized protons at RHIC, a DOE Office of Science user facility for nuclear physics research located at Brookhaven Lab. RHIC is the only facility in the world capable of colliding protons with their spin directions aligned in a controlled way.

“RHIC’s spin polarization is a crucial requirement for this research. It gives us a way to establish which way is up so we can measure the motions of other particles relative to that reference direction,” explained Brookhaven Lab physicist Nicole Lewis, whose work on this analysis formed the basis of her Ph.D. thesis.

As Lewis explained in an invited talk at the 2021 Fall Meeting of the American Physical Society’s Division of Nuclear Physics on October 12, understanding the origin of proton spin is also one of the main research goals.

A proton’s spin, or intrinsic angular momentum, makes it act like a tiny bar magnet with two poles. This property is used every day in magnetic resonance imaging (MRI), where a powerful external magnet changes the alignment of protons’ spins in our bodies so doctors can see features inside. But where spin comes from is still a mystery.

Studies at RHIC and elsewhere show that quark spins and gluon spins both make substantial contributions to proton spin, but not enough. The motions of these fundamental particles within protons are expected to also play a role. Using direct photons to measure how gluons’ transverse motion is correlated with overall proton spin is expected to help solve this puzzle.

In addition, studying the motion of quarks and gluons within a proton will help reveal details of the interactions between these particles. Those interactions are governed by the strong nuclear force — the strongest force in nature — which is carried by gluons and binds the quarks within the protons and neutrons of atomic nuclei. So, studying gluons and the strong force is really about understanding the “glue” that binds visible matter — everything made of atoms.

The newly analyzed data from PHENIX reveal that direct photons can be used to study gluons’ motions inside a proton.

The PHENIX measurements are 50 times more precise than the only previously published direct photon data — about 30 years ago from an experiment at DOE’s Fermi National Accelerator Laboratory.

“Our results help to validate the use of this approach for future studies at RHIC — including at an upgraded sPHENIX detector currently being installed in the location of the original PHENIX detector, which ended its experimental run in 2016. sPHENIX is expected to be operational in 2023 and will have even better capabilities to detect direct photons,” Bazilevsky said.

The direct photon data from proton-proton collisions will also provide important cross-checking for experiments using electrons to probe the inner structure of protons at the future Electron-Ion Collider (EIC).

“Proton-proton and electron-proton collisions give us different, complementary ways to ‘see’ inside a proton to construct the final picture of how things look,” Bazilevsky said.

How to peer inside a proton

Proton-proton collisions can produce a range of interactions. A quark in one proton can interact with either a quark or gluon in the other. And a gluon also can interact with a quark or gluon. So, these collisions produce a mixture of quark-quark, gluon-gluon, and quark-gluon events.

But only one of those possible interactions — quark-gluon scattering — is a major source of photons (quantized particles of light) emitted directly from the collision zone. And because photons have no electric charge or “color” charge (the type of charge carried by quarks and gluons) they don’t interact with anything on their way out. By measuring these direct photons, scientists can zero in on the gluons involved in these interactions.

To tell whether the gluons are moving, the scientists align the spins in one proton beam transversely — that is, pointing “up” relative to their forward direction of motion. Then they measure whether there are more photons emerging to the left or the right of the forward-going proton’s up point of reference.

“The up is the spin, and the left or right gives you the momentum of the gluons in the transverse direction,” Lewis explained. That helps physicists expand beyond a one-dimensional view of quarks or gluons only moving in the same direction as the proton they are in.

“From this we are able to probe a more three-dimensional picture of the proton and study internal transverse dynamics of the quarks and gluons. If we were to measure a very large left to right asymmetry, that would indicate that there are large internal dynamics going on inside the proton, which would in turn contribute to the proton’s spin.”

Picking out direct photons

Figuring out which photons come directly from a quark-gluon interaction isn’t so simple.

“There are so many other photons present in these collisions that come from the decays of other particles or radiative processes,” Lewis said. “Trying to isolate the photons that came directly from the collision, that’s the hard part.”

The scientists use a process of elimination. If a photon picked up in the detector is surrounded by other particles with similar energy, it likely came from radiative processes that happened after the collision — so those photons are not direct. Likewise, if the energy and angles of a pair of photons can be reconstructed to have originated from the decay of a parent particle — a pi zero meson, say — then those photons are also not direct photons. After all the eliminations, the photons with no other obvious source are assumed to have originated from a quark-gluon scattering event.

“PHENIX has the resolution and other characteristics that enable it to do these measurements,” Bazilevsky said.

“Another reason why this is hard is because direct photon production is a pretty rare process,” said Lewis. “It doesn’t happen frequently, and it has a large background — which makes the signal hard to detect. We need many collisions to have enough occurrences to be able to do the analysis.”

Now for the first time, Bazilevsky said, “we show that a collider like RHIC can produce enough collisions for such measurements.”

Coming into focus

But even with the detector and collider capabilities, the PHENIX results did not show an asymmetry in the number of direct photons emerging left or right of the transversely polarized proton. “We got something that was consistent with zero,” Lewis said.

But that does not mean that the gluons involved in these interactions were not moving, because the uncertainties in the measurements are still somewhat large.

“The models based on previous measurements give only a blurry picture,” Bazilevsky said. “Within the large uncertainties of these models, we show that direct photons are starting to be sensitive to gluon motions and reducing the uncertainties. So, our picture is still blurry, but we are zooming in a bit.”

“We are looking forward to the next step — building and using the sPHENIX detector, which will be able to track many more collisions and pick out direct photons emerging from wider angles around the collision zone. Then we may start to see something that’s not zero,” he said.

The study focused on two traits previously linked to the risk of dementia: neuroticism, which measures a predisposition for negative emotions, and conscientiousness, which measures the tendency to be careful, organized, goal-directed and responsible.

“We have done studies showing who’s at risk of developing dementia, but those other studies were looking at the clinical diagnosis,” said Antonio Terracciano, professor of geriatrics at the College of Medicine. “Here, we are looking at the neuropathology; that is, the lesions in the brain that tell us about the underlying pathological change. This study shows that even before clinical dementia, personality predicts the accumulation of pathology associated with dementia.”

The findings, published as an article-in-press online with Biological Psychiatry and also available through FSU’s open access research repository, combine data from the Baltimore Longitudinal Study of Aging (BLSA) and previously published work in a meta-analysis that summarized 12 studies on personality and Alzheimer’s neuropathology. The studies combined included more than 3,000 participants. Combining results across studies provides more robust estimates of the associations between personality and neuropathology than a single individual study can typically provide.

In both the BLSA and meta-analysis, the researchers found more amyloid and tau deposits (the proteins responsible for the plaques and tangles that characterize Alzheimer’s disease) in participants who scored higher in neuroticism and lower in conscientiousness.

The team also found associations to be stronger in studies of cognitively normal people compared to studies that included people with cognitive problems.

The findings suggest that personality can help protect against Alzheimer’s and other neurological diseases by delaying or preventing the emergence of neuropathology for those strong in conscientiousness and low in neuroticism.

“Such protection against neuropathology may derive from a lifetime difference in people’s emotions and behaviors,” Terracciano said. “For example, past research has shown that low neuroticism helps with managing stress and reduces the risk of common mental health disorders. Similarly, high conscientiousness is consistently related to healthy lifestyles, like physical activity. Over time, more adaptive personality traits can better support metabolic and immunological functions, and ultimately prevent or delay the neurodegeneration process.”

The BLSA is a scientific study of human aging conducted by the National Institute on Aging (NIA), part of the National Institutes of Health (NIH), that began in 1958. Personality was measured using a five-factor personality test, the most common personality assessment tool. At the time of their enrollment in the BLSA neuroimaging sub-study, all participants were free of dementia or other severe medical conditions.

Advances in brain scan technology used to assess in vivo amyloid and tau neuropathology made it possible for researchers to complete this work.

“Until recently, researchers measured amyloid and tau in the brain through autopsy — after people died,” Terracciano said. “In recent years, advances in medical imaging have made it possible to assess neuropathology when people are still alive, even before they show any symptoms.”

Story Source:

Materials provided by Florida State University. Original written by Doug Carlson. Note: Content may be edited for style and length.

This ability is key to our survival, enabling us to safely navigate our surroundings and quickly understand and respond to new situations. It is perhaps unsurprising that the brain devotes considerable space to these sensitive skin surfaces that are specialized for fine, discriminative touch and continually gather detailed information via the sensory neurons that innervate them.

But how does the connection between sensory neurons and the brain result in such exquisitely sensitive skin?

A new study led by researchers at Harvard Medical School has unveiled a mechanism that may underlie the greater sensitivity of certain skin regions.

The research, conducted in mice and published Oct. 11 in Cell, shows that the overrepresentation of sensitive skin surfaces in the brain develops in early adolescence and can be pinpointed to the brain stem. Moreover, the sensory neurons that populate the more sensitive parts of the skin and relay information to the brain stem form more connections and stronger ones than neurons in less sensitive parts of the body.

“This study provides a mechanistic understanding of why more brain real estate is devoted to surfaces of the skin with high touch acuity,” said senior author David Ginty, the Edward R. and Anne G. Lefler Professor of Neurobiology at Harvard Medical School. “Basically, it’s a mechanism that helps explain why one has greater sensory acuity in the parts of the body that require it.”

While the study was done in mice, the overrepresentation of sensitive skin regions in the brain is seen across mammals — suggesting that the mechanism may be generalizable to other species. From an evolutionary perspective, mammals have dramatically varied body forms, which translates into sensitivity in different skin surfaces. For example, humans have highly sensitive hands and lips, while pigs explore the world using highly sensitive snouts. Thus, Ginty thinks this mechanism could provide the developmental flexibility for different species to develop sensitivity in different areas.

Moreover, the findings, while fundamental, could someday help illuminate the touch abnormalities seen in certain neurodevelopmental disorders in humans.

Scientists have long known that certain body parts are overrepresented in the brain — as depicted by the brain’s sensory map, called the somatosensory homunculus, a schematic of human body parts and the corresponding areas in the brain where signals from these body parts are processed. The striking illustration includes cartoonishly oversized hands and lips. Previously, it was thought that the overrepresentation of sensitive skin regions in the brain could be attributed to a higher density of neurons innervating those skin areas. However, earlier work by the Ginty lab revealed that while sensitive skin does contain more neurons, these extra neurons are not sufficient to account for the additional brain space.

“We noticed that there was a rather meager number of neurons that were innervating the sensitive skin compared to what we’d expect,” said co-first author Brendan Lehnert, a research fellow in neurobiology, who led the study with Celine Santiago, also a research fellow in the Ginty lab.

“It just wasn’t adding up,” Ginty added.

To investigate this contradiction, the researchers conducted a series of experiments in mice that involved imaging the brain and neurons as neurons were stimulated in different ways. First, they examined how different skin regions were represented in the brain throughout development. Early in development, the sensitive, hairless skin on a mouse’s paw was represented in proportion to the density of sensory neurons. However, between adolescence and adulthood, this sensitive skin became increasingly overrepresented in the brain, even though the density of neurons remained stable — a shift that was not seen in less sensitive, hairy paw skin.

“This immediately told us that there’s something more going on than just the density of innervation of nerve cells in the skin to account for this overrepresentation in the brain,” Ginty said.

“It was really unexpected to see changes over these postnatal developmental timepoints,” Lehnert added. “This might be just one of many changes over postnatal development that are important for allowing us to represent the tactile world around us and helping us gain the ability to manipulate objects in the world through the sensory motor loop that touch is such a special part of.”

Next, the team determined that the brain stem — the region at the base of the brain that relays information from sensory neurons to more sophisticated, higher-order brain regions — is the location where the enlarged representation of sensitive skin surfaces occurs. This finding led the researchers to a realization: The overrepresentation of sensitive skin must emerge from the connections between sensory neurons and brain stem neurons.

To probe even further, the scientists compared the connections between sensory neurons and brain stem neurons for different types of paw skin. They found that these connections between neurons were stronger and more numerous for sensitive, hairless skin than for less sensitive, hairy skin. Thus, the team concluded, the strength and number of connections between neurons play a key role in driving overrepresentation of sensitive skin in the brain. Finally, even when sensory neurons in sensitive skin weren’t stimulated, mice still developed expanded representation in the brain — suggesting that skin type, rather than stimulation by touch over time, causes these brain changes.

“We think we’ve uncovered a component of this magnification that accounts for the disproportionate central representation of sensory space.” Ginty said. “This is a new way of thinking about how this magnification comes about.”

Next, the researchers want to investigate how different skin regions tell the neurons that innervate them to take on different properties, such as forming more and stronger connections when they innervate sensitive skin. “What are the signals?” Ginty asked. “That’s a big, big mechanistic question.”

And while Lehnert describes the study as purely curiosity-driven, he noted that there is a prevalent class of neurodevelopmental disorders in humans called developmental coordination disorders that affect the connection between touch receptors and the brain — and thus might benefit from elucidating further the interplay between the two.

“This is one of what I hope will be many studies that explore on a mechanistic level changes in how the body is represented over development,” Lehnert says. “Celine and I both think this might lead, at some point in the future, to a better understanding of certain neurodevelopmental disorders.”

Co-investigators included Erica L. Huey, Alan J. Emanuel, Sophia Renauld, Nusrat Africawala, Ilayda Alkislar, Yang Zheng, Ling Bai, Charalampia Koutsioumpa, Jennifer T. Hong, Alexandra R. Magee,Christopher D. Harvey of Harvard Medical School.

The research was supported by the National Institutes of Health (F32 NS095631-01, F32-NS106807, K99 NS119739, DP1 MH125776, R01 NS089521, and R01 NS97344), a William Randolph Hearst Fellowship, a Goldenson Fellowship, a Harvard Medical School Dean’s Innovation Grant in the Basic and Social Sciences, and the Edward R. and Anne G. Lefler Center for the Study of Neurodegenerative Disorders.