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A rare and controversial mutation in the phospholipase D3 (PLD3) protein — previously linked to Alzheimer’s disease — interferes with PLD3’s vital recycling function inside neurons. Matthew Schrag of Vanderbilt University Medical Center and colleagues report these new findings in a paper published April 8th in PLOS Genetics.
About 1 percent of people with Alzheimer’s disease carry a specific mutation in their PLD3 gene. The question of whether or not this mutation leads to Alzheimer’s disease has remained controversial, however, due to its rarity and because the protein’s function was previously unknown. In the new study, Schrag’s team delved deeper into the function of this gene and its link to the disease. The researchers found that PLD3 is located in lysosomes inside neurons. Lysosomes are highly acidic sacs of enzymes that act as the recycling system of the cell. PLD3 produces an important component of the membrane of these acidic organelles, and this function is lost in the mutant form. In the brains of people with Alzheimer’s disease, PLD3 occurred near buildups of toxic proteins called β-amyloid plaques. Furthermore, people with high levels of PLD3 had fewer β-amyloid plaques and less cognitive decline, suggesting that normal PLD3 helps protect against the disease.
Together, these discoveries establish the PLD3 mutation places a person at higher risk of developing Alzheimer’s disease, most likely by disrupting its role in the lysosome. The researchers propose that future studies should focus on investigating whether boosting PLD3 can have a protective effect that reduces the effects of the disease. Ultimately, these findings may yield new drug targets for Alzheimer’s disease therapies and improve our understanding of the role of the lysosome in this common and burdensome disease.
“The discovery of Phospholipase D3 as a genetic risk factor for Alzheimer’s disease points to the critically important role of the lysosome in dementia,” the authors add. “Targeting experimental therapies to these lysosomes could lead us to new approaches to treat this disease.”
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Materials provided by PLOS. Note: Content may be edited for style and length.

Six years ago, Michael Niederweis, Ph.D., described the first toxin ever found for the deadly pathogen Mycobacterium tuberculosis. This toxin, tuberculosis necrotizing toxin, or TNT, became the founding member of a novel class of previously unrecognized toxins present in more than 600 bacterial and fungal species, as determined by protein sequence similarity. The toxin is released as M. tuberculosis bacteria survive and grow inside their human macrophage host, killing the macrophage and allowing the escape and spread of the bacteria.
For 132 years, the lack of an identified toxin in M. tuberculosis had contrasted with nearly all other pathogenic bacteria whose toxins contribute to illness or death. M. tuberculosis infects 9 million people a year and kills more than 1 million.
Now, in another groundbreaking work, the University of Alabama at Birmingham researcher and colleagues describe how two small ESX proteins made by the M. tuberculosis bacteria mediate secretion of TNT by pore formation in the membranes that envelop the bacteria. This finding may have broad application because a distinctive three-amino acid motif found on EsxE and EsxF — tryptophan/any-amino-acid/glycine, known in shorthand as WXG — is also found on many other small mycobacterium proteins and on the large WXG100 superfamily of bacterial proteins that resemble EsxE and EsxF.
“Here, we show for the first time that small Esx proteins of the WXG100 family have an important molecular function inside the Mtb cell by mediating toxin secretion,” said Niederweis, a professor in the UAB Department of Microbiology. “Our results suggest a dynamic mechanism of pore formation by small Esx proteins that might be applicable to other members of the large WXG100 protein family. Thus, our study not only represents a major advancement in our understanding of secretion of TNT and likely of other proteins in M. tuberculosis, but also describes a biological function for Esx-paralogs in M. tuberculosis and their homologs in the large WXG100 protein family in Gram-positive bacteria.”
TNT is one of two domains in the M. tuberculosis outer membrane protein CpnT; activity of the TNT domain of CpnT in the cytosol of the macrophage induces macrophage death by hydrolyzing NAD+. M. tuberculosis has an inner membrane and an outer membrane, and a protein needs to get through each layer to be secreted outside of the bacterium. How CpnT gets to the outer membrane was unknown.
EsxE and EsxF are part of the same gene segment as CpnT, and the UAB researchers hypothesized that the two small proteins might be involved in secretion of the toxin.

Alzheimer’s disease is known for its slow attack on neurons crucial to memory and cognition. But why are these particular neurons in aging brains so susceptible to the disease’s ravages, while others remain resilient?
A new study led by researchers at the Yale School of Medicine has found that susceptible neurons in the prefrontal cortex develop a “leak” in calcium storage with advancing age, they report April 8 in the journal Alzheimer’s & Dementia, The Journal of the Alzheimer’s Association. This disruption of calcium storage in turns leads to accumulation of phosphorylated, or modified, tau proteins which cause the neurofibrillary tangles in the brain that are a hallmark of Alzheimer’s.
These changes occur slowly, building over many years, and can be seen within neurons in the brains of very old monkeys, the researchers report.
“Altered calcium signaling with advancing age is linked to early-stage tau pathology in the neurons that subserve higher cognition,” said corresponding author Amy Arnsten, the Albert E. Kent Professor of Neuroscience and professor of psychology and member of the Kavli Institute of Neuroscience at Yale University.
These vulnerable neurons face another problem. As they age, they tend to lose a key regulator of calcium signaling, a protein called calbindin, which protects neurons from calcium overload, and is abundant in the neurons of younger individuals.
“With age, these neurons face a double whammy, with an excessive calcium leak that initiates toxic actions, as well as diminished levels of the protectant, calbindin,” said Arnsten.
Neurons in the prefrontal cortex require relatively high levels of calcium to perform their cognitive operations, but the calcium must be tightly regulated. However, as regulation is lost with increasing age, neurons become susceptible to tau pathology and degeneration. Essentially, neurons “eat” themselves from within.
“Understanding these early pathological changes may provide strategies to slow or prevent disease progression,” Arnsten said.
The study is a collaboration between the labs of Arnsten and Angus Nairn at Yale; Dibyadeep Datta and Shannon N. Leslie are co-first authors of the research.
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Materials provided by Yale University. Original written by Bill Hathaway. Note: Content may be edited for style and length.

When you think of ways to treat opioid use disorder, you might think methadone clinics and Narcotics Anonymous meetings. You probably don’t imagine stretches and strengthening exercises.
But Anne Swisher — professor at the West Virginia University School of Medicine — is working to address opioid misuse in an unconventional way: through physical therapy. She and her colleagues have enhanced physical therapy instruction at WVU to emphasize the profession’s role in preventing and treating opioid use disorder.
“Students have different interests and passions within the profession, and they find their niche,” said Swisher, a researcher and director of scholarship in the Division of Physical Therapy. “No matter what their passion is, there is a way they can make a difference, whether it’s by preventing people from starting down the road of opioids — by minimizing pain medication and doing movement interventions — or whether it’s by helping people in the recovery process become healthier overall.”
Swisher and her team devised a model to show doctor of physical therapy students how key topics in their curriculum — such as women’s health, pediatric care and sports therapy — could all address opioid use disorder in various ways.
Their model — which was published in rehabilitation journal Physical Therapy — is innovative because it goes beyond musculoskeletal issues and addresses how physical therapists can assist people across the lifespan, from neonatal to hospice settings. It also illustrates how physical therapists can help improve human movement across what Swisher calls the “whole addiction spectrum.”
“In our curriculum, our students learn about all of these different aspects — what to do with somebody who’s critically ill, the appropriate developmental milestones for children, how to help older people stay active — but it was really just a matter of connecting it all together,” she said.

Scientists could be a step closer to finding a way to reduce the impact of traumatic memories, according to a Texas A&M University study published recently in the journal Nature Neuroscience.
The report details a study by researchers from the Department of Psychological and Brain Sciences and the Institute for Neuroscience. Stephen Maren, professor of psychological and brain sciences, said the group’s findings suggest that procedures used by clinicians to indirectly reactivate traumatic memories render a window whereby those memories can be altered, or even erased completely.
In therapy, imaginal reminders are often used to safely retrieve traumatic memories of experiences. For example, Maren said a military veteran wounded by an improvised explosive device may be asked to re-experience trauma cues — like the lights and sounds of the explosion — without the negative consequences. The idea is that the fear responses can be dampened through this exposure therapy.
“The one major challenge is when you do the extinction procedures, it doesn’t erase the original trauma memory,” Maren said. “It’s always there and can bubble back up, which is what causes relapse for people who re-experience fear.”
With this in mind, the researchers hoped to answer whether they could isolate a memory and drive fear responses by reactivating it artificially — and potentially disrupt the original memory itself. Maren said their findings suggest that procedures currently used by clinicians to indirectly reactivate traumatic memories create an opportunity to change or eliminate them.
To do this, the researchers used a conditioning procedure in which a cue becomes indirectly associated with a fearful event. When the cue is presented later, it indirectly reactivates a memory of the event and increases activity in the hippocampus, a brain area important for memory.
The study showed that indirectly reactivating a contextual fear memory through re-exposure to the cue can make the memory vulnerable to disruption. Maren said further research is needed to answer if scientists can produce a permanent loss of the traumatic information.
Authors on the study are Maren, Reed L. Ressler, Travis D. Goode, Sohmee Kim and Karthik R. Ramanathan. This research was funded by the National Institutes of Health.
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Materials provided by Texas A&M University. Original written by Caitlin Clark. Note: Content may be edited for style and length.

Damage to the autism-associated gene Dyrk1a, sets off a cascade of problems in developing mouse brains, resulting in abnormal growth-factor signaling, undergrowth of neurons, smaller-than-average brain size, and, eventually, autism-like behaviors, a new study from Scripps Research, Florida, finds.
The study from neuroscientist Damon Page, PhD, describes a new mechanism underlying the brain undergrowth seen in individuals with Dyrk1a mutations. Page’s team used those insights to target the affected pathway with an existing medicine, a growth hormone. It restored normal brain growth in the Dyrk1a mutant mice, Page says.
“As of now, there’s simply no targeted treatments available for individuals with autism spectrum disorders caused by DYRK1A mutations,” Page says. “This represents a first step in evaluating a potential treatment that could be used in the clinic.”
Their study appears Thursday in the journal Biological Psychiatry.
To track the effects of missing Dyrk1a genes, Jenna Levy, the paper’s first author and a graduate student in Page’s lab, engineered mice to have one or two broken copies of Dyrk1a in their developing brain tissue. The brains of both sets of mice developed abnormally, she found, displaying decreased brain size and number of neurons, as well as reduced number of other brain cells.
Downstream effects
The scientists also conducted “unbiased” proteomic studies, to see if the mutant mice had abnormally high or low levels of other unknown proteins that might impact brain development. Using a technique called “high-resolution tandem mass spectrometry coupled to liquid chromatography,” they found that the Dyrk1a mutant mice had reduced levels of 56 cellular proteins, and increased levels of 33. Many of those were known autism risk genes, some implicated in sending growth signals, Levy says.

It’s one thing to decide among two or three snacks available at a friend’s house. But what do people do when they’re faced with a vending machine offering 36 different options?
A new study using eye-tracking technology suggests that the amount of time people spend looking at individual items may actually help them decide. Findings showed that people tended to choose snacks they spent more time looking at, sometimes even over snacks that they rated more highly.
“We could do pretty well predicting what people would choose based just on their ratings of the snacks available to them. But we could do an even better job by accounting for how much they looked at each item,” said Ian Krajbich, co-author of the study and associate professor of psychology and economics at The Ohio State University.
But the amount of time people spend looking at individual items isn’t the whole story of how people decide when they have many alternatives, Krajbich said.
“It’s a little more complicated than that,” he said.
Krajbich conducted the study with lead author Armin Thomas of Technische Universität Berlin and Felix Molter of Freie Universität Berlin. The research was published this week in the journal eLife.

The full assembly of human chromosome 8 is reported this week in Nature. While on the outside this chromosome looks typical, being neither short nor long or distinctive, its DNA content and arrangement are of interest in primate and human evolution, in several immune and developmental disorders, and in chromosome sequencing structure and function generally.
This linear assembly is a first for a human autosome — a chromosome not involved in sex determination. The entire sequence of chromosome 8 is 146,259,671 bases. The completed assembly fills in the gap of more than 3 million bases missing from the current reference genome.
The Nature paper is titled “The structure, function and evolution of a complete chromosome 8.”
One of several intriguing characteristics of chromosome 8 is a fast-evolving region, where the mutation rate appears to be highly accelerated in humans and human-like species, in contrast to the rest of the human genome.
While chromosome 8 offers some insights into evolution and human biology, the researchers point out that the complete assembly of all human chromosomes would be necessary to acquire a fuller picture.
An international team of scientists collaborated on the chromosome 8 assembly and analysis. The lead author of the paper is Glennis Logsdon, a postdoctoral fellow in genome sciences at the University of Washington School of Medicine in Seattle.

Powerful algorithms used by Netflix, Amazon and Facebook can ‘predict’ the biological language of cancer and neurodegenerative diseases like Alzheimer’s, scientists have found.
Big data produced during decades of research was fed into a computer language model to see if artificial intelligence can make more advanced discoveries than humans.
Academics based at St John’s College, University of Cambridge, found the machine-learning technology could decipher the ‘biological language’ of cancer, Alzheimer’s, and other neurodegenerative diseases.
Their ground-breaking study has been published in the scientific journal PNAS today (April 8 2021) and could be used in the future to ‘correct the grammatical mistakes inside cells that cause disease’.
Professor Tuomas Knowles, lead author of the paper and a Fellow at St John’s College, said: “Bringing machine-learning technology into research into neurodegenerative diseases and cancer is an absolute game-changer. Ultimately, the aim will be to use artificial intelligence to develop targeted drugs to dramatically ease symptoms or to prevent dementia happening at all.”
Every time Netflix recommends a series to watch or Facebook suggests someone to befriend, the platforms are using powerful machine-learning algorithms to make highly educated guesses about what people will do next. Voice assistants like Alexa and Siri can even recognise individual people and instantly ‘talk’ back to you.

Pioneering research led by experts from the University of Exeter’s Living Systems Institute has provided new insight into formation of the human embryo.
The team of researchers discovered an unique regenerative property of cells in the early human embryo.
The first tissue to form in the embryo of mammals is the trophectoderm, which goes on to connect with the uterus and make the placenta. Previous research in mice found that trophectoderm is only made once.
In the new study, however, the research team found that human early embryos are able to regenerate trophectoderm. They also showed that human embryonic stem cells grown in the laboratory can similarly continue to produce trophectoderm and placental cell types.
These findings show unexpected flexibility in human embryo development and may directly benefit assisted conception (IVF) treatments. In addition, being able to produce early human placental tissue opens a door to finding causes of infertility and miscarriage.
The study is published in the leading international peer-review journal Cell Stem Cell on Wednesday, April 7th 2021.
Dr Ge Guo, lead author of the study from the Living Systems Institute said: “We are very excited to discover that human embryonic stem cells can make every type of cell required to produce a new embryo.”
Professor Austin Smith, Director of the Living Systems Institute and co-author of the study added, said: “Before Dr Guo showed me her results, I did not imagine this should be possible. Her discovery changes our understanding of how the human embryo is made and what we may be able do with human embryonic stem cells”
Human naïve epiblast cells possess unrestricted lineage potential is published in Cell Stem Cell. The research was funded by the Medical Research Council (MRC) .
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Materials provided by University of Exeter. Note: Content may be edited for style and length.