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Tuberculosis, caused by the bacterium Mycobacterium tuberculosis (Mtb) kills upwards of 1.6 million people a year, making it one of the leading causes of death by an infectious agent worldwide — and that number is only growing larger. How, exactly, Mtb evades the immune system isn’t yet known, but a collaborative team of researchers from the University of Massachusetts Amherst and Seattle Children’s Research Institute recently discovered something surprising: prior exposure to a genus of bacteria called Mycobacterium seems to remodel the first-line defenders in the body’s immune system. Furthermore, how those cells are remodeled depends on exactly how the body is exposed. These results, published recently in PLOS Pathogens, suggest that a more integrated treatment approach that targets all aspects of the immune response could be a more effective strategy in the fight against tuberculosis.
“We breathe in thousands of liters of air every day,” says Alissa Rothchild, assistant professor in the Veterinary and Animal Sciences Department at UMass Amherst and the paper’s senior author. “This essential process makes us incredibly vulnerable to inhalation of all sorts of potentially infectious pathogens that our immune systems have to respond to.”
Systems, plural. When we think of immunity, we typically think of the adaptive immune system, which is when prior exposure to a pathogen — say, a weakened version of chickenpox — teaches the immune system what to guard against. Vaccination is the most common tool that we use to teach our adaptive immune systems what to look out for.
While the adaptive immune system is the major focus of most vaccine research (think protective antibodies induced by COVID-19 vaccines), it is not the body’s first responder — that would be the innate immune system and its ranks of macrophages. The macrophages are the first-line defenders in the tissues that recognize and destroy pathogens and also call for backup. One way they do this by turning on different inflammatory programs that can change the tissue environment.
In the case of the lungs, these macrophages are called alveolar macrophages (AMs). They live in the lung’s alveoli, the tiny air sacs where oxygen passes into the bloodstream — but, as Rothchild has shown in a previous paper, AMs don’t mount a robust immune response when they’re initially infected by Mtb. This lack of response seems to be a chink in the body’s armor that Mtb exploits to such devastating effect. “Mtb takes advantage of the immune response,” says Rothchild, “and when they infect an AM, they can replicate inside of it for a week or longer. They effectively turn the AM into a Trojan Horse in which the bacteria can hide from the body’s defenses.”
“But what if we could change this first step in the chain of infection?” Rothchild continues. “What if the AMs responded more effectively to Mtb? How could we change the body’s innate immune response? Studies over the last 10 years or so have demonstrated that the innate immune system is capable of undergoing long-term changes, but we are only beginning to understand the underlying mechanisms behind them.”
To test conditions where the innate immune response might be remodeled, Dat Mai, a research associate at Seattle Children’s Research Instituteand the first author of the paper, Rothchild and their colleagues designed an experiment using two different mouse models. The first model used the BCG vaccination, one of the world’s most widely distributed vaccines and the only vaccine used for tuberculosis. In the second model, the researchers induced a contained Mtb infection, which they previously showed protects against subsequent infections in a form of concomitant immunity.
Weeks after exposure, the researchers challenged the mice with aerosolized Mtb and infected macrophages were taken from each mouse model for RNA sequencing. There were striking differences in the RNA from each set of models.
While both sets of AMs showed a stronger pro-inflammatory response to Mtb than AMs from unexposed mice, the BCG-vaccinated AMs strongly turned on one type of inflammatory program, driven by interferons, while the AMs from the contained Mtb infection turned on a qualitatively different inflammatory program. Other experiments showed that the different exposure scenarios changed the AMs themselves, and that some of these changes seem to be dependent on the greater lung environment.
“What this tells us,” says Rothchild, “is that there’s a great deal of plasticity in the macrophage response, and that there’s potential to therapeutically harness this plasticity so that we can remodel the innate immune system to fight tuberculosis.”

Halfway through a true crime podcast, a morning commuter jerks the wheel to narrowly avoid a collision. When discussing the podcast with a coworker later that day, the driver can easily recall the details of the episode’s second half but retains only a blurry recollection of how it began.
A new study from psychologists at the Beckman Institute for Advanced Science and Technology suggests that we remember the moments immediately following a distressing episode more sharply than the moments leading up to it. Clarifying the relationship between trauma and memory can improve how we evaluate eyewitness testimonies, inform therapies to treat PTSD, and help clinicians combat memory decline in brain disorders like Alzheimer’s disease.
This study appears in the journal Cognition and Emotion.
“It’s a clean finding, and it opens up an entirely new dimension for understanding emotion’s impacts on memory,” said lead author Paul Bogdan, whose Ph.D. research at the University of Illinois Urbana-Champaign formed the basis for this study.
Bogdan’s research was conducted within the Dolcos Lab headed by psychology professors Florin Dolcos and Sanda Dolcos. For more than 15 years, the Dolcoses have studied the relationship between mental health and memory — specifically, unwanted memories that intrude into our daily lives, degrading mental health and aggravating anxiety, depression, and PTSD. The result of their research is an emotional security system, crafted with cognitive therapies that protect emotional security and preserve focus in the face of troublesome recollections.
Studying traumatic memories is tricky, the researchers say, because our brains tend to auto-edit negative experiences. Big ideas trump details, peripheral features concede to central ones, and specific moments are cut loose from their context: the where, when, and “what else,” Florin Dolcos said.
So far, there is little evidence to explain how negative emotion impacts the when: our ability to situate a sequence of memories along a timeline.

“Suppose your partner unexpectedly insults you in the middle of an otherwise neutral discussion. Later, when you are trying to make sense of the encounter …, will you more accurately remember what happened before or after the insult?” Bogdan said. “Existing research does not give us a clear answer.”
But Bogdan’s new research might. His team orchestrated two identical experiments: an initial study of 72 participants to pin down their procedures and predictions, and a replication study with 150 participants to confirm the results.
First, participants viewed a series of images simulating a string of memories. Half of the images elicited negative emotional responses, and half were emotionally neutral. To contextualize the images — and make them more memory-like — the participants were asked to privately imagine themselves traveling among the locations pictured and to craft a creative story arc to bind them together. This “promoted the feeling that pairs of sequential images are meaningfully related,” the researchers wrote.
An hour later, participants viewed pairs of images from the series. For each pair, they were asked whether the second picture occurred immediately before or immediately after the first. (They were also offered a “neither” option and could indicate if they did not remember the order.)
Results were consistent across both studies. The participants’ ability to accurately place the second image improved when the negative memories occurred before the neutral ones on the timeline. If participants were shown a negative image first, they did a better job of recalling neutral images that followed it; inversely, if participants were first shown a neutral image, they could more consistently place the negative images that came before.
In other words, memory flows from negative to neutral.

“So, our results suggest that if insulted in a conversation, one would better retrieve what was said immediately afterward than what was said immediately beforehand,” Bogdan said.
This is unintuitive, the researchers say.
“You might imagine that humans evolved to have a good memory for what led to negative things,” Bogdan said. “If you got bit by a snake, what foolhardy thing were you doing beforehand?”
One explanation is that negative emotional spikes (for example, upon sustaining a snake bite) cause a rush of focus and alertness, telling our brains to take exhaustive notes about what happens next and squirrel them away for future use.
But the prelude to trauma employs a much less diligent notetaker. This casts a dubious eye on scenarios like witness testimonies, where contextual details are paramount.
“Knowing that people are more likely to miss details leading to something negative that happened, we can be more cautious about statements related to events that have led to a crime, compared to memories of what happened after, which we know will be sharper,” Florin Dolcos said.
As relevant in a clinic as it is in a courtroom, these results help clarify the mechanisms behind PTSD, where an objectively neutral activity can trigger an involuntary surge of negative emotions.
“For example, a war veteran hearing a loud noise and inferring that their building will soon collapse due to an explosion,” Florin Dolcos said. “This happens because there is a rupture between the memory of the traumatic experience and its original context: the what breaks from the where and the when.”
Taking back control over traumatic memories, then, requires reattaching them to their context — their original place and time. The researchers hope to incorporate this strategy into cognitive therapies for people with PTSD.
In addition to muting the maelstrom of negative memories, another therapeutic avenue may entail using positive emotions to reconstruct sturdier, sharper memories for those who need them, according to Sanda Dolcos.
“As people age, problems with memories become more serious, especially conditions like Alzheimer’s,” she said. “The memory for context suffers the most. If we know exactly what’s happening, we can build future strategies to better encode information that will help us help others with those conditions.”

A team of physicians, neuroscientists and engineers at Duke University has demonstrated two new strategies that use deep brain stimulation to improve the symptoms of Parkinson’s disease.
By simultaneously targeting two key brain structures and using a novel self-adjusting device, the team showed that they can efficiently target and improve disruptive symptoms caused by the movement disorder.
The research appears online in the journal Brain.
For the past 20 years physicians have prescribed deep brain stimulation, or DBS, to treat the symptoms of advanced Parkinson’s disease when medication alone will no longer work. The technique uses a device similar to a pacemaker to deliver electric impulses to key areas within the brain. This targeted stimulation can reduce tremors and stiffness and limit the involuntary, writhing movements that develop after years of medication.
While DBS has proven to be an effective therapy to address these symptoms, it isn’t perfect, and physicians and researchers continue to explore ways to make improvements.
“Physicians place the electrodes for DBS in either the subthalamic nucleus or the globus pallidus, which are two structures in the brain closely associated with movement,” said senior author Dennis Turner, professor of neurosurgery, neurobiology, and biomedical engineering at the Duke University School of Medicine, who conceived and organized the research and assembled the interdisciplinary team.
“There are benefits to both locations on their own depending on the patient’s symptoms,” Turner said, “but we believed placing the electrodes at both locations could be complementary and help reduce medication doses and side effects, as well as implement a completely new approach to adaptive DBS.”
Beyond increasing the area of stimulation, the team wanted to explore whether a technique called adaptive DBS could make their system more efficient. In traditional DBS, a physician sets key electrical parameters, like the amplitude, pulse frequency and pulse duration, to best treat symptoms while minimizing side effects. Those parameters may stay the same for days, weeks, months and even years, depending on the patient’s response.

But according to Warren Grill, the Edmund T. Pratt, Jr. School Distinguished Professor of Biomedical Engineering at Duke, these unchanging parameters are far from optimal.
“The amount of stimulation a person living with Parkinson’s needs changes, depending on their medications or activity levels. A patient will need more stimulation if they are walking their daughter down the aisle at her wedding than if they are just watching TV,” Grill said. An adaptive system is “like a smart thermostat in your office that makes adjustments based on the temperature outside.”
To implement their bespoke approach, the team worked with experimental technology provided by the medical device company Medtronic to create their own adaptive DBS techniques. By programming the device to sense and record key biomarkers and brain activity in the patient, the researchers developed a system that can adjust the parameters of stimulation automatically to provide optimal symptom relief throughout the day.
The team tested their strategies in a clinical trial at Duke University Medical Center with six patients between the ages of 55 and 65. Each had varying symptoms of Parkinson’s disease.
First, the researchers spent two years observing and testing the efficacy of stimulating both the subthalamic nucleus and the globus pallidus with the standard, continuous DBS. The results were measured using a combination of patient feedback, tracking the amount of time a patient could move without experiencing involuntary movements and recording how much a patient could reduce their medication without experiencing symptoms.
During this period, the team also ran experiments to establish the parameters for an adaptable DBS system. The team studied a specific frequency of brain activity, called beta oscillations, in the subthalamic nucleus. Previous research had shown that a high level of beta oscillations is linked to the slow, halting movement seen in most cases of Parkinson’s.

“We were able to test different levels of stimulation to determine the optimal levels of beta oscillations that would improve symptoms under different circumstances,” said Stephen Schmidt, a research and development engineer in the Grill lab. “This helped us establish the initial settings for the adaptive DBS and allowed us to compare how the adaptive and standard DBS operated in a home setting.”
After two years of study with the adaptive system, the team had their results.
They found that targeting the subthalamic nucleus and the globus pallidus at the same time improved motor symptoms more than targeting either region alone. And they found that the adaptive DBS applied less stimulation but was just as effective as dual-target continuous DBS in both clinical and home settings.
“Clinically, the patients are doing phenomenally. Looking at their rating scales, they are doing better than the average DBS patient when both target areas are stimulated,” said Kyle Mitchell, Assistant Professor of Neurology at DUSM. “We’re not only seeing excellent clinical responses to dual target stimulation, but we’re also able to integrate this adaptive, smart tool into the brain that can at least match this clinical response. It’s very exciting.”
Spurred on by their initial success, the team plans to further optimize adaptive deep brain stimulation and pursue additional testing for the next stage of their clinical trials.
“This tool has great potential down the road for making DBS a more tailored and elegant therapy,” said Grill. “This is very promising research for the field of DBS, and it couldn’t have been done without the six participants who agreed to undergo this experimental work, as well as their families and caregivers. We are grateful for their significant contribution to this effort.”

Published33 minutes agocommentsCommentsShareclose panelShare pageCopy linkAbout sharingImage source, PA MediaBy Aurelia FosterHealth reporter, BBC NewsRemoving the largest glass of wine from sale cuts the total amount people drink by 7.6%, a four-week trial in 21 pubs, bars and restaurants suggests.With the largest measure, 250ml – equal to a third of a bottle – off the menu, more 125ml and 175ml glasses of wine were sold.Customers bought the same amount of wine by the bottle, but overall, less volume of wine was sold daily.Sales of beer and cider stayed the same as did the venues’ overall takings.”Value for money” was likely to have been a factor in the drop in the amount of wine sold, the University of Cambridge researchers say.However, they believe the policy should now be “considered” for trial by licensing authorities.’Value for money’The study’s lead author, Prof Dame Theresa Marteau, said: “What it tells us is that people are very sensitive to cues in their environment.” And the results were “in keeping” with existing evidence people ate less if served smaller portions of food.”People are sensitive to the size of containers and serving size,” Dame Theresa said.”And these have tended to get bigger and so we’ve consumed more. “So the focus of my research group is on whether or not we can reverse-engineer our environments to see whether we can reduce our consumption to improve everybody’s health.But, Dame Theresa said financial constraints were also likely to have affected drinkers’ behaviour.”A 250ml glass of wine usually costs less than the cost of two 125 ml glasses. Value for money is therefore likely to be one factor influencing a decision to buy larger rather than smaller glasses of wine.”No safe level of alcohol consumption, study says She added she believed the strategy “merits consideration” to added to licensing regulations.”It does seem quite a relatively simple way of reducing the amount of alcohol that that we’re consuming, often without our awareness.”This, in turn, might “shift our social norm” and make people drink less at home.Image source, Charlotte LysterCharlotte Lyster, licensee of the Prince Albert pub in Stroud, Gloucs, told BBC News most of her customers had been “fine”.”They said, ‘I’ll just have another one,’ but actually they didn’t,” she said.”People drink in rounds – so when they finished one, they would wait for someone else to go to the bar.”And many had stuck to the smaller measures even after the trial had ended.Customers ‘happy’All the venues were in England – most in London. Lauren Johns, licensee of the Three Compasses in Dalston, said most of her customers had also been happy with smaller glasses of wine. Those who did complain tended to be over the age of 50, she said.”There was no major reaction.” “I was interested to do this study as I thought people might buy a bottle instead – but it turns out people would just buy a medium glass.”Regular or heavy drinking is a contributing factor in many diseases, causing three million deaths worldwide each year, according to the World Health Organization.A Department of Health and Social Care official said: “The UK chief medical officer’s low-risk drinking guidelines recommend not regularly exceeding 14 units of alcohol a week.”And we continue to promote the guidelines in England, online and by encouraging producers to include them on alcoholic-drinks labels.”More on this storyServing size labelling leaves many confused- surveyPublished28 July 2023No alcohol safe to drink, study confirmsPublished24 August 2018Does glass size matter to wine drinkers?Published14 December 2017Wine drinkers urged to drop glass sizePublished25 November 2015Smaller portions call to tackle obesityPublished15 September 2015Related Internet LinksDepartment of Health and Social Care – GOV.UKSchool of Clinical MedicineThe BBC is not responsible for the content of external sites.

She documented the powerful role that education, income and self-perceived social status play in a person’s health and longevity.Nancy E. Adler, a health psychologist whose work helped transform the public understanding of the relationship between socioeconomic status and physical health, died on Jan. 4 at her home in San Francisco. She was 77.The cause was pancreatic cancer, her husband, Arnold Milstein, said.Dr. Adler was instrumental in documenting the powerful role that education, income and self-perceived status in society play in predicting health and longevity.Today, the connection is well known — a truism among public health experts is that life expectancy is determined more by your ZIP code than your genetic code. But it was an obscure notion as recently as 30 years ago.“It’s thanks to the decades of Nancy’s work and leadership that we now recognize socioeconomic status as one of the biggest and most consistent predictors of morbidity and mortality that we know of,” said Elissa Epel, a health psychologist at the University of California, San Francisco, and a mentee of Dr. Adler’s.Beginning in 1997, Dr. Adler led the MacArthur Foundation Research Network on Socioeconomic Status and Health, a group of health economists, epidemiologists, physicians, public health experts, psychologists and sociologists that studied the relationship between socioeconomic status and health. The group has been credited with bringing into the mainstream the concept of social determinants of health, along with their implications for health and social policy.“They looked at the question, ‘How does inequity or poverty or stress get under your skin?’” said Claire Brindis, a public health and policy researcher at U.C.S.F. “How does it affect your life? How many years are you going to live?”We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? 

The federal Emergency Medical Treatment and Labor Act, known as EMTALA, requires hospitals to provide medically necessary care to stabilize patients in emergency situations.One of the newest battlefields in the abortion debate is a decades-old federal law called the Emergency Medical Treatment and Labor Act, known by doctors and health policymakers as EMTALA.The issue involves whether the law requires hospital emergency rooms to provide abortions in urgent circumstances, including when a woman’s health is threatened by continuing her pregnancy. But, as with many abortion-related arguments, this one could have broader implications. Some legal experts say it could potentially determine how restrictive state abortion laws are allowed to be and whether states can prevent emergency rooms from providing other types of medical care, such as gender-affirming treatments.The Biden administration is in the middle of legal battles over the law with the states of Texas and Idaho. The Supreme Court has agreed to hear the Idaho case.What does the law do?Enacted by Congress in 1986, EMTALA (pronounced em-TAHL-uh) requires hospitals across the country to guarantee all patients a standard of emergency care, regardless of whether they have insurance or can pay. The law, which was passed to address concerns that hospitals were failing to screen, treat or correctly transfer patients, applies to any hospital that receives Medicare funding and has an emergency department — most hospitals in the United States.Specifically, the law says that if a patient goes to an emergency room with an “emergency medical condition,” hospitals must either provide treatment to stabilize the patient or transfer the patient to a medical facility that can. Hospitals that violate the law can face consequences including fines and exclusion from further Medicare funding.What does that have to do with abortion?The law does not mention abortion or name specific treatments for any emergency medical condition. It requires only that hospitals use accepted medical approaches for each patient. But soon after the Supreme Court overturned the national right to abortion in June 2022, the Biden administration issued a memorandum saying that EMTALA applies in cases where abortion is necessary to stabilize a patient.We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? 

An international clinical trial led by Professor Dr med. Achim Kaasch, Head of the Institute for Medical Microbiology and Hospital Hygiene at the Otto von Guericke University of Magdeburg and Professor Dr med. Harald Seifert, former deputy director of the Institute for Medical Microbiology, Immunology and Hygiene at the University Hospital Cologne, was able to gain decisive new insights into the treatment of bloodstream infections with the pathogen Staphylococcus aureus (SAB). The research shows that in patients with a low risk of developing infectious complications, an early switch to oral antibiotic therapy is as effective and safe as continuing the intravenous standard treatment. This new therapy approach enables easier treatment and faster discharge from hospital for patients.
The results of the study, in which researchers from Magdeburg and Cologne as well as scientists from the Heinrich-Heine-University Düsseldorf and the German Center for Infection Research (DZIF) were involved, have been published under the title ‘Efficacy and safety of an early oral switch in low-risk Staphylococcus aureus bloodstream infection (SABATO): An international, open-label, randomized, controlled, non-inferiority trial’ in the journal The Lancet Infectious Diseases.
The bacterium Staphylococcus aureus is one of the most common pathogens worldwide, which can cause severe bloodstream infections — also called sepsis or blood poisoning. An estimated 30,000 people in Germany fall ill each year from this infection alone, and about 25 per cent of those affected die within the first three months. Professor Kaasch explained: “If SAB is not adequately treated, there is a serious risk that the infection will spread to other parts of the body. Even after successful treatment, an infection can often have a negative effect on the recovery process for several months.”
The standard intravenous treatment of SAB with antibiotics is carried out in hospital for at least 14 days. The research group focused on the question whether oral therapy with pills is as effective as conventional intravenous treatment in patients with SAB. “We found that an early switch to oral antibiotic therapy after 5 to 7 days of intravenous treatment is as safe and effective as the established standard intravenous therapy,” said Kaasch. Nevertheless, according to the microbiologist, a careful assessment of patients for signs and symptoms is necessary to clarify whether infectious complications already exist. Only if these are excluded can oral switch therapy be considered.
The results of this groundbreaking study mark a significant advance in the treatment of Staphylococcus aureus bloodstream infections and give rise to hope for better treatment for patients worldwide. “With these findings, it is possible to simplify treatment and to discharge patients more quickly,” Kaasch emphasized.
In further studies, the researchers want to investigate various questions regarding the diagnosis and treatment of SAB. “The evaluation of a switch to oral antibiotic therapy after initial intravenous treatment is now particularly relevant in patients with complicated Staphylococcus aureus bloodstream infections,” explained Professor Seifert from the University Hospital Cologne and initiator of the study. “There are no findings on this yet.”
The study is a multi-centric, controlled, non-inferiority clinical trial. It was conducted at 31 study sites in Germany, France, the Netherlands and Spain. The goal of such a study is to show that a new treatment method achieves equivalent results to the standard therapy. In total, data from over 5,000 patients were collected. The study included 213 participants, with 108 randomly assigned to the oral group and 105 to the intravenous group. It was funded by the German Research Foundation.

Researchers at Karolinska Institutet in Sweden have used DNA origami, the art of folding DNA into desired structures, to show how an important cell receptor can be activated in a previously unknown way. The result opens new avenues for understanding how the Notch signalling pathway works and how it is involved in several serious diseases. The study is published in Nature Communications.
Notch is a cell receptor that is of great importance to a wide range of organisms and plays a crucial role in many different processes, including early embryonic development in both flies and humans. Notch regulates the development of stem cells into different cell types in the body. Defects in this signalling pathway can result in serious diseases, including cancer.
The prevailing view of the receptor’s function has so far been that it is activated purely mechanically, by a neighbouring cell pulling on it, meaning that signalling only occurs as a result of direct communication between cells.
However, researchers at Karolinska Institutet now report that the activation of Notch can also be achieved ‘on demand’ with the help of a protein called Jag1. The researchers placed the protein on a DNA structure created by so-called DNA origami, a technique that makes it possible to build structures of any shape at the nanoscale using DNA as a building material. In this case, the DNA structure was moulded into a nano-sized stick that can carry the protein to the cell surface.
“This is a technique that allows us to place molecules of the Jag1 protein at very small distances from each other in different patterns, and then we have exposed these patterns to stem cells with Notch receptors,” says Björn Högberg, professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, who led the study together with KI researcher Ioanna Smyrlaki at the same department.
The results show that the Notch receptor can be activated to different degrees, depending on the shape of the pattern and the local concentration of the protein. However, several questions remain about how exactly this signalling takes place.
“We are now collaborating with other researchers to see if we can make this method work in vivo as well, i.e. in a mouse model and not just in test tubes,” says Björn Högberg. “This is basic research, but Notch is an important component in several diseases, including a form of leukaemia and the developmental disorder Alagille Syndrome. We therefore hope that the results will also lead to a better understanding of these diseases.”
The research was mainly funded by the Knut and Alice Wallenberg Foundation, the Swedish Research Council and the European Research Council (ERC).

10.1038/s41467-023-44465-8Alzheimer’s disease, which is expected to have affected about 6.7 million patients in the U.S. in 2023, results in a substantial loss of brain cells. But the events that cause neuron death are poorly understood.
A new Northwestern Medicine study shows that RNA interference may play a key role in Alzheimer’s. For the first time, scientists have identified short strands of toxic RNAs that contribute to brain cell death and DNA damage in Alzheimer’s and aged brains. Short strands of protective RNAs are decreased during aging, the scientists report, which may allow Alzheimer’s to develop.
The study also found that older individuals with a superior memory capacity (known as SuperAgers) have higher amounts of protective short RNA strands in their brain cells. SuperAgers are individuals aged 80 and older with a memory capacity of individuals 20 to 30 years younger.
“Nobody has ever connected the activities of RNAs to Alzheimer’s,” said corresponding study author Marcus Peter, the Tom D. Spies Professor of Cancer Metabolism at Northwestern University Feinberg School of Medicine. “We found that in aging brain cells, the balance between toxic and protective sRNAs shifts toward toxic ones.”
The paper will be published Jan.18 in Nature Communications.
Relevance beyond Alzheimer’s disease
The Northwestern discovery may have relevance beyond Alzheimer’s. “Our data provide a new explanation for why, in almost all neurodegenerative diseases, affected individuals have decades of symptom free life and then the disease starts to set in gradually as cells lose their protection with age,” Peter said.

New avenue for treatment
The findings also point to a new way for treating Alzheimer’s and potentially other neurodegenerative diseases.
Alzheimer’s is characterized by a progressive occurrence of amyloid-beta plaques, tau neurofibrillary tangles, scarring and ultimate brain cell death.
“The overwhelming investment in Alzheimer’s drug discovery has been focused on two mechanisms: reducing amyloid plaque load in the brain — which is the hallmark of Alzheimer’s diagnosis and 70 to 80% of the effort — and preventing tau phosphorylation or tangles,” Peter said. “However, treatments aimed at reducing amyloid plaques have not yet resulted in an effective treatment that is well tolerated.
“Our data support the idea that stabilizing or increasing the amount of protective short RNAs in the brain could be an entirely new approach to halt or delay Alzheimer’s or neurodegeneration in general.”
Such drugs exist, Peter said, but they would need to be tested in animal models and improved.

The next step in Peter’s research is to determine in different animal and cellular models (as well as in brains from Alzheimer’s patients) the exact contribution of toxic sRNAs to the cell death seen in the disease and screen for better compounds that would selectively increase the level of protective sRNAs or block the action of the toxic ones.
What are toxic and protective short RNAs?
All our gene information is stored in form of DNA in the nucleus of every cell. To turn this gene information into the building blocks of life, DNA needs to be converted into RNA which is used by cell machinery to produce proteins. RNA is essential for most biological functions.
In addition to these long coding RNAs, there are large numbers of short RNAs (sRNAs), which do not code for proteins. They have other critical functions in the cell. One class of such sRNAs suppresses long coding RNAs through a process called RNA interference that results in the silencing of the proteins that the long RNAs code for.
Peter and colleagues have now identified very short sequences present in some of these sRNAs that when present can kill cells by blocking production of proteins required for cells to survive resulting in cell death. Their data suggest that these toxic sRNAs are involved in the death of neurons which contributes to the development of Alzheimer’s disease.
The toxic sRNAs are normally inhibited by protective sRNAs. One type of sRNA is called microRNAs. While microRNAs play multiple important regulatory roles in cells, they are also the main species of protective sRNAs. They are the equivalent of guards that prevent the toxic sRNAs from entering the cellular machinery that executes RNA interference. But the guards’ numbers decrease with aging, thus allowing the toxic sRNAs to damage the cells.
Key findings
· The amount of protective sRNAs is reduced in the aging brain.
· Adding back protective miRNAs partially protects brain cells engineered to produce less protective sRNAs from cell death induced by amyloid beta fragments (which trigger Alzheimer’s).
· Enhancing the activity of the protein that increases the amount of protective microRNAs partially inhibits cell death of brain cells induced by amyloid beta fragments and completely blocks DNA damage (also seen in Alzheimer’s patients.)
How the study worked:
Scientists analyzed the brains of Alzheimer’s disease mouse models, the brains of young and old mice, induced pluripotent stem cell-derived neurons from normal individuals (both young and aged) and from Alzheimer’s patients, the brains of a group of older individuals over 80 with memory capacity equivalent to individuals 50 to 60 years old, and multiple human brain-derived neuron-like cell lines treated with amyloid beta fragments, a trigger of Alzheimer’s.
Northwestern co-authors on the study include first author Bidur Paudel, Si-Yeon Jeong, Ashley Haluck-Kangas, Elizabeth T. Bartom, Kristina Fredriksen, Amira Affaneh, John A. Kessler, Joseph R. Mazzulli, Andrea E. Murmann, Emily Rogalski (formerly of Northwestern), Changiz Geula, Adriana Ferreira, Katherine R. Sadleir and Robert Vassar.
This work was supported by National Institutes of Health grants R35CA197450, R35CA231620, R01NS090993, R01AG030142, R01AG045571, R56AG045571, R01AG067781, U19AG073153, P30AG072977, P30AG13854 and R01NS124783 and L40CA231423.

New research has been published that identifies positive steps towards a better understanding of antimicrobial resistance (AMR), specifically in hospital-acquired pneumonia (HAP).
Antimicrobial, or antibiotic resistance, is a growing global issue, yet little is known about how to dose antibiotics to minimise bacteria developing resistance in patients. However, the University of Liverpool is playing a key role in contributing to international efforts to better understand AMR.
In a paper published today (Thursday 18 January), Dr Christopher Darlow, from the Antimicrobial Pharmacology & Therapeutics (APT) group at the University of Liverpool details a new experimental animal model of HAP. The model tests both the effect of meropenem — a commonly used antibiotic for HAP — and crucially determines how resistance to meropenem emerges.
Infections of the lungs are quite common in hospitals, with HAP accounting for approximately 10% of deaths in hospital. Because of the types of bacteria causing HAP and the large numbers of bacteria in the lungs during HAP, development of resistance to administered antibiotics to treat it is common. This is partly because doses of antibiotics are determined by drug developers to treat HAP effectively, but without consideration to the dose needed to prevent resistance emerging.
The team at the APT group, including Dr Darlow, have developed a new experimental model of HAP and used it to test the effects of meropenem. This model has allowed the team to detect both the amount of bacteria in the lungs as the antibiotic is given (i.e. is the antibiotic working to treat the infection) and also to detect the emergence of resistance, including by measuring the mutations in the genes of the bacteria that drive this.
In this work, the team demonstrated that too low doses of meropenem do treat HAP, but also cause a greater emergence of resistance. Conversely, resistance can be reduced by increasing the meropenem dose or by giving a second type of antibiotic (amikacin) at the same time. Both strategies may be used in clinical settings to reduce antimicrobial resistance. The team also mapped how the bacteria mutates and adapts to develop this resistance, giving insight into the underlying mechanisms.
Dr Christopher Darlow said: “Through this work we have highlighted the problem of resistance development in HAP when treated by meropenem and demonstrated potential strategies to prevent this i.e. increasing the meropenem or using a second antibiotic in combination. Beyond the implications for HAP, this is also a new experimental platform to allow antibiotics (both new and old) to be assessed for their ability to cause development of resistance and identify strategies to mitigate against this. We hope to use this platform for other antibiotics in the future to improve the use of antibiotics and prevent antibiotic resistance development.”
This pioneering research is being delivered through the Infection Innovation Consortium: iiCON, a global collaborative infectious disease R&D programme led by Liverpool School of Tropical Medicine, of which the University of Liverpool is a core partner.