How cells repair their power plants

 Damage to the genetic material of mitochondria -- the mitochondrial DNA or mtDNA for short -- can lead to diseases such as Parkinson's, Alzheimer's, amyotrophic lateral sclerosis (ALS), cardiovascular diseases and type 2 diabetes. Such damage also speeds up the ageing process. However, the cells are normally capable of identifying such damage and reacting.

Scientists from University Hospital Düsseldorf and HHU have -- in collaboration with the University of Cologne and the Center for Molecular Medicine Cologne (CMMC) -- discovered a mechanism, which protects and repairs the mitochondria.The research team, headed by Professor Pla-Martín from the Institute of Biochemistry and Molecular Biology I at HHU, has identified a specialised recycling system, which cells activate when they identify damage to the mtDNA.

According to the authors in Science Advances, this mechanism relies on a protein complex known as retromer and the lysosomes -- cell organelles containing digestive enzymes.

These special cellular compartments act like recycling centres, eliminating the damaged genetic material.

This process is one of the mechanisms, which prevent the accumulation of faulty mtDNA, thus maintaining cellular health and potentially preventing diseases.

"We have identified a previously unknown cellular pathway, which is important for mitochondrial health and thus for the natural defences of our cells," explains Professor Pla-Martín, continuing: "By understanding this mechanism, we can explain how mitochondrial damage can trigger diseases like Parkinson's and Alzheimer's. This could in turn form the basis for developing preventive therapies."

In collaboration with the cell biologist Dr Parisa Kakanj from the University of Cologne, who is also a member of the CEPLAS Cluster of Excellence, Professor Pla-Martín was able to verify and extend the findings using fruit flies (Drosophila) as a model organism.

Dr Kakanj showed that damaged mitochondrial DNA are eliminated much more quickly and that mitochondrial function improves significantly when the activity of the retromer complex -- in particular the protein VPS35 -- is increased.

Dr Kakanj: "Using Drosophila allowed us to confirm our initial findings in human cells and demonstrate clear improvements in mitochondrial health. This opens up exciting possibilities for therapeutic strategies for treating mitochondrial diseases and age-related conditions."

Source: ScienceDaily

How specialized diet can improve gut disorders

 A new study from Cedars-Sinai examined whether a specialized diet could improve symptoms of gastrointestinal disorders linked to an imbalance in gut microbiota.

The research tested the elemental diet's effectiveness and explored whether improving its unappealing taste -- a major barrier -- could help patients adhere to the diet's stringent protocol. The investigators' findings were published in the peer-reviewed journal Clinical Gastroenterology and Hepatology.he elemental diet is a special low-fat liquid formulation that is designed to be easily digested and contains all the essential nutrients necessary for a healthy diet. A few prior studies have shown that the diet has the potential to improve challenging symptoms associated with digestive issues like small intestinal bacterial overgrowth (SIBO), intestinal methanogen overgrowth (IMO), Crohn's disease, eosinophilic esophagitis and other gut ailments. The diet likely works by reducing inflammation, balancing the gut microbiome, healing the gut lining, and providing complete nutrition without additives and allergens that typically irritate the gut. Historically, elemental diet has had a low adherence rate because of the strict protocol and unpleasant taste.

SIBO and IMO typically occur when harmful bacteria or methane-producing microbes grow out of control in the gut. While antibiotics are often used to treat these conditions, they don't always work.

"Elemental diets are designed to give the digestive system a break by providing easily absorbed nutrients," said Ali Rezaie, MD, the study's corresponding author and medical director of the GI Motility Program and director of Bioinformatics at the Medically Associated Science and Technology (MAST) Program at Cedars-Sinai. "This reduces stress on the gut, helping it heal and function better."

In this study, 30 adults ages 18 to 85 diagnosed with SIBO or IMO strictly adhered to only a more palatable version of the elemental diet for two weeks. This was followed by two weeks during which study participants resumed their normal diet. The researchers analyzed changes in the gut microbiome, how well the diet was tolerated, symptom relief and breath test results, along with tracking any side effects.

The results were encouraging. Most participants reported tolerating the diet well, with no serious side effects. A key finding was a reduction in unfavorable microbes linked to gut issues. Methane levels also dropped significantly, with many returning to normal.

In addition, 83% of participants reported feeling better, with significant relief from common symptoms like bloating and discomfort. These findings suggested that a tastier version of the elemental diet helped restore balance in the gut and eased symptoms of SIBO and IMO.

"The study's positive results suggest that enhancing the palatability of the elemental diet could make it more accessible and practical for patients, improving adherence and quality of life for those who face significant challenges with traditional therapies," said Mark Pimentel, MD, study author and executive director of the MAST Program at Cedars-Sinai.

Rezaie and his team of investigators plan to conduct larger studies to better understand the long-term effects of elemental diets and further address the socioeconomic barriers.

Other Cedars-Sinai authors include: Bianca W. Chang, Juliana de Freitas Germano, Gabriela Leite, Ruchi Mathur, Krystyna Houser, Ava Hosseini, Daniel Brimberry, Mohamad Rashid, Sepideh Mehravar, MJ Villanueva-Millan, Maritza Sanchez, Stacy Weitsman, Cristina M. Fajardo, Ignacio G. Rivera, LiJin Joo, Yin Chan and Gillian M. Barlow.

Funding: This study was in part supported by a research grant from Good LFE and John and Geraldine Cusenza Foundation. These sponsors played no role in the study design or in the collection, analysis, and interpretation of data.

Conflict of interest: Mark Pimentel, MD, is a consultant for Ferring Pharmaceuticals, Inc, Salvo Health, Dieta Health, and Cylinder Health, Inc has received grant support from Bausch Health, and has equity in Gemelli Biotech, Salvo Health, Cylinder Health, and Good LFE. Ali Rezaie, MD, is a consultant/speaker for Bausch Health and has equity in Gemelli Biotech and Good LFE. Cedars-Sinai has licensing agreements with Hobbs Medical and Gemelli Biotech.

Source: ScienceDaily

Some gut bacteria could make certain drugs less effective

 A new study, published today in Nature Chemistry by researchers from the University of Pittsburgh and Yale University, shows how common gut bacteria can metabolize certain oral medications that target cellular receptors called GPCRs, potentially rendering these important drugs less effective.

Drugs that act on GPCRs, or G protein-coupled receptors, include more than 400 medications approved by the U.S. Food and Drug Administration (FDA) for treatment of many common conditions such as migraines, depression, type 2 diabetes, prostate cancer and more.

"Understanding how GPCR-targeted drugs interact with human gut microbiota is critical for advancing personalized medicine initiatives," said first author Qihao Wu, Ph.D., assistant professor in the Pitt School of Pharmacy, who started this project as a postdoctoral researcher at Yale. "This research could help open up new avenues for drug design and therapeutic optimization to ensure that treatments work better and safer for every individual."

The effectiveness of a drug varies from person to person, influenced by age, genetic makeup, diet and other factors. More recently, researchers discovered that microbes in the gut can also metabolize orally administered drugs, breaking down these compounds into different chemical structures and potentially altering their efficacy.

To learn more about which gut bacteria metabolize which drugs, Wu and the team at Yale, including the labs of Jason Crawford, Ph.D., Noah Palm, Ph.D., and Andrew Goodman, Ph.D., built a pipeline to rapidly and efficiently test this in the lab. They started by building a synthetic microbial community composed of 30 common bacterial strains found in the human gut. To tubes containing the bacteria, they added each of 127 GPCR-targeting drugs individually. Then they measured whether these drugs were chemically transformed and, if so, which compounds were produced.

The experiment showed that the bacterial mix metabolized 30 of the 127 tested drugs, 12 of which were heavily metabolized, meaning that concentrations of the original drug were greatly depleted because they were transformed into other compounds.

Next, the researchers looked more closely at one heavily metabolized drug called iloperidone, which is often used to treat schizophrenia and bipolar I disorder. One bacterial strain in particular, Morganella morganii, inactivated iloperidone by transforming it a range of different compounds, both in the lab and in mice.

Overall, the findings suggest that specific gut bacteria could make GPCR-targeting drugs less effective by transforming them into other compounds.

However, Wu cautioned that more research is needed to understand potential impacts in people and that patients shouldn't stop taking or change their medication without consulting their provider.

Although the study focused on a subset of GPCR drugs, the approaches could be applied more broadly to any orally administered chemicals, according to Wu.

"Another potential application of this pipeline is investigating interactions between gut bacteria and compounds found in food," he said. "For example, we identified a couple of phytochemicals in corn that may affect gut barrier function. Notably, we observed that the gut microbiome could potentially protect us from these phytochemicals by detoxifying them."

The next goal of the Wu Lab is to decode the metabolic pathway underlying these biotransformations, which could potentially identify strategies for improving therapeutic efficacy and enhancing food and drug safety.

Other authors on the study were Deguang Song, Ph.D., Yanyu Zhao, Andrew Verdegaal, Ph.D., Tayah Turocy, Ph.D., and Brianna Duncan-Lowey, Ph.D., all of Yale University.

This research was primarily supported by the National Institute of General Medical Sciences (1RM1GM141649). It was also supported by the National Institutes of Health (DP2DK125119 and R01AT010014).

Source: ScienceDaily

Feeling the future: New wearable tech simulates realistic touch

 When it comes to haptic feedback, most technologies are limited to simple vibrations. But our skin is loaded with tiny sensors that detect pressure, vibration, stretching and more.

Now, Northwestern University engineers have unveiled a new technology that creates precise movements to mimic these complex sensations.

The study will be published on March 28 in the journal Science.

While sitting on the skin, the compact, lightweight, wireless device applies force in any direction to generate a variety of sensations, including vibrations, stretching, pressure, sliding and twisting. The device also can combine sensations and operate fast or slow to simulate a more nuanced, realistic sense of touch.

Powered by a small rechargeable battery, the device uses Bluetooth to wirelessly connect to virtual reality headsets and smartphones. It also is small and efficient, so it could be placed anywhere on the body, combined with other actuators in arrays or integrated into current wearable electronics.

The researchers envision their device eventually could enhance virtual experiences, help individuals with visual impairments navigate their surroundings, reproduce the feeling of different textures on flat screens for online shopping, provide tactile feedback for remote health care visits and even enable people with hearing impairments to "feel" music.

"Almost all haptic actuators really just poke at the skin," said Northwestern's John A. Rogers, who led the device design. "But skin is receptive to much more sophisticated senses of touch. We wanted to create a device that could apply forces in any direction -- not just poking but pushing, twisting and sliding. We built a tiny actuator that can push the skin in any direction and in any combination of directions. With it, we can finely control the complex sensation of touch in a fully programmable way."

A pioneer in bioelectronics, Rogers is the Louis A. Simpson and Kimberly Querrey Professor of Materials Science and Engineering, Biomedical Engineering, and Neurological Surgery, with appointments in the McCormick School of Engineering and Northwestern University Feinberg School of Medicine. He also directs the Querrey Simpson Institute for Bioelectronics. Rogers co-led the work with Northwestern's Yonggang Huang, the Jan and Marcia Achenbach Professor in Mechanical Engineering and professor of civil and environmental engineering at McCormick. Northwestern's Kyoung-Ho Ha, Jaeyoung Yoo and Shupeng Li are the study's co-first authors.

The study builds on previous work from Rogers' and Huang's labs, in which they designed a programmable array of miniature vibrating actuators to convey a sense of touch.

The haptic hang-up

In recent years, visual and auditory technologies have experienced explosive growth, delivering unprecedented immersion through devices like high-fidelity, deeply detailed surround-sound speakers and fully immersive virtual-reality goggles. Haptics technologies, however, mostly have plateaued. Even state-of-the-art systems only offer buzzing patterns of vibrations.

This developmental gap stems largely from the extraordinary complexity of human touch. The sense of touch involves different types of mechanoreceptors (or sensors) -- each with its own sensitivity and response characteristics -- located at varying depths within the skin. When these mechanoreceptors are stimulated, they send signals to the brain, which are translated as touch.

Replicating that sophistication and nuance requires precise control over the type, magnitude and timing of stimuli delivered to the skin. This presents a massive challenge, which current technologies have struggled -- and failed -- to overcome.

"Part of the reason haptic technology lags video and audio in its richness and realism is that the mechanics of skin deformation are complicated," said Northwestern's J. Edward Colgate, a haptics pioneer and study co-author. "Skin can be poked in or stretched sideways. Skin stretching can happen slowly or quickly, and it can happen in complex patterns across a full surface, such as the full palm of the hand."

Actuator unleashed

To simulate that complexity, the Northwestern team developed the first actuator with full freedom of motion (FOM). This means the actuator is not constrained to a single type of movement or limited set of movements. Instead, it can move and apply forces in all directions along the skin. These dynamic forces engage all mechanoreceptors in the skin, both individually and in combination with one another.

"It's a big step toward managing the complexity of the sense of touch," said Colgate, Walter P. Murphy Professor of Mechanical Engineering at McCormick. "The FOM actuator is the first small, compact haptic device that can poke or stretch skin, operate slow or fast, and be used in arrays. As a result, it can be used to produce a remarkable range of tactile sensations."

Source: ScienceDaily

Study strengthens link between shingles vaccine and lower dementia risk

 An unusual public health policy in Wales may have produced the strongest evidence yet that a vaccine can reduce the risk of dementia. In a new study led by Stanford Medicine, researchers analyzing the health records of Welsh older adults discovered that those who received the shingles vaccine were 20% less likely to develop dementia over the next seven years than those who did not receive the vaccine.

The remarkable findings, to be published April 2 in Nature, support an emerging theory that viruses that affect the nervous system can increase the risk of dementia. If further confirmed, the new findings suggest that a preventive intervention for dementia is already close at hand.Lifelong infection

Shingles, a viral infection that produces a painful rash, is caused by the same virus that causes chicken pox -- varicella-zoster. After people contract chicken pox, usually in childhood, the virus stays dormant in the nerve cells for life. In people who are older or have weakened immune systems, the dormant virus can reactivate and cause shingles.

Dementia affects more than 55 million people worldwide, with an estimated 10 million new cases every year. Decades of dementia research has largely focused on the accumulation of plaques and tangles in the brains of people with Alzheimer's, the most common form of dementia. But with no breakthroughs in prevention or treatment, some researchers are exploring other avenues -- including the role of certain viral infections.

Previous studies based on health records have linked the shingles vaccine with lower dementia rates, but they could not account for a major source of bias: People who are vaccinated also tend to be more health conscious in myriad, difficult-to-measure ways. Behaviors such as diet and exercise, for instance, are known to influence dementia rates, but are not included in health records.

"All these associational studies suffer from the basic problem that people who get vaccinated have different health behaviors than those who don't," said Pascal Geldsetzer, MD, PhD, assistant professor of medicine and senior author of the new study. "In general, they're seen as not being solid enough evidence to make any recommendations on."

A natural experiment

But two years ago, Geldsetzer recognized a fortuitous "natural experiment" in the rollout of the shingles vaccine in Wales that seemed to sidestep the bias. The vaccine used at that time contained a live-attenuated, or weakened, form of the virus.

The vaccination program, which began Sept. 1, 2013, specified that anyone who was 79 on that date was eligible for the vaccine for one year. (People who were 78 would become eligible the next year for one year, and so on.) People who were 80 or older on Sept. 1, 2013, were out of luck -- they would never become eligible for the vaccine.These rules, designed to ration the limited supply of the vaccine, also meant that the slight difference in age between 79- and 80-year-olds made all the difference in who had access to the vaccine. By comparing people who turned 80 just before Sept. 1, 2013, with people who turned 80 just after, the researchers could isolate the effect of being eligible for the vaccine.

The circumstances, well-documented in the country's health records, were about as close to a randomized controlled trial as you could get without conducting one, Geldsetzer said.

The researchers looked at the health records of more than 280,000 older adults who were 71 to 88 years old and did not have dementia at the start of the vaccination program. They focused their analysis on those closest to either side of the eligibility threshold -- comparing people who turned 80 in the week before with those who turned 80 in the week after.

"We know that if you take a thousand people at random born in one week and a thousand people at random born a week later, there shouldn't be anything different about them on average," Geldsetzer said. "They are similar to each other apart from this tiny difference in age."

The same proportion of both groups likely would have wanted to get the vaccine, but only half, those almost 80, were allowed to by the eligibility rules.

"What makes the study so powerful is that it's essentially like a randomized trial with a control group -- those a little bit too old to be eligible for the vaccine -- and an intervention group -- those just young enough to be eligible," Geldsetzer said.

Protection against dementia

Over the next seven years, the researchers compared the health outcomes of people closest in age who were eligible and ineligible to receive the vaccine. By factoring in actual vaccination rates -- about half of the population who were eligible received the vaccine, compared with almost none of the people who were ineligible -- they could derive the effects of receiving the vaccine.

Source: ScienceDaily

New study links lower proportions of certain sleep stages to brain changes associated with Alzheimer's disease

 New research reveals that lower proportions of specific sleep stages are associated with reduced brain volume in regions vulnerable to the development of Alzheimer's disease over time.

Results show that individuals with lower proportions of time spent in slow wave sleep and rapid eye movement sleep had smaller volumes in critical brain regions, particularly the inferior parietal region, which is known to undergo early structural changes in Alzheimer's disease.The results were adjusted for potential confounders including demographic characteristics, smoking history, alcohol use, hypertension, and coronary heart disease.

"Our findings provide preliminary evidence that reduced neuroactivity during sleep may contribute to brain atrophy, thereby potentially increasing the risk of Alzheimer's disease," said lead author Gawon Cho, who has a doctorate in public health and is a postdoctoral associate at Yale School of Medicine in New Haven, Connecticut.

"These results are particularly significant because they help characterize how sleep deficiency, a prevalent disturbance among middle-aged and older adults, may relate to Alzheimer's disease pathogenesis and cognitive impairment."

The study was published March 31 as an accepted paper in the Journal of Clinical Sleep Medicine, the official publication of the American Academy of Sleep Medicine.

According to the Alzheimer's Association, Alzheimer's disease is a degenerative brain disease and the most common cause of dementia.

An estimated 6.7 million Americans aged 65 and older are living with Alzheimer's disease, and this number is projected to double by 2060, pending medical developments to prevent, slow or cure the disease.

The study involved an analysis of data from 270 participants who had a median age of 61 years.

Fifty-three percent were female, and all participants were white.

Individuals were excluded from the analysis if they previously had a stroke or probable dementia or other significant brain pathology.

The research utilized polysomnography to assess baseline sleep architecture.

Advanced brain imaging techniques were used to measure brain volumes 13 to 17 years later.

According to the authors, the study demonstrates an important association between sleep and long-term brain health, and it highlights potential opportunities to reduce the risk of Alzheimer's disease.

"Sleep architecture may be a modifiable risk factor for Alzheimer's disease and related dementias, posing the opportunity to explore interventions to reduce risk or delay Alzheimer's onset," said Cho.

The researchers emphasized that further investigation is needed to fully understand the causal relationships between sleep architecture and Alzheimer's disease progression.

Source: ScienceDaily

World's smallest pacemaker is activated by light

 Northwestern University engineers have developed a pacemaker so tiny that it can fit inside the tip of a syringe -- and be non-invasively injected into the body.

Although it can work with hearts of all sizes, the pacemaker is particularly well-suited to the tiny, fragile hearts of newborn babies with congenital heart defects.

Smaller than a single grain of rice, the pacemaker is paired with a small, soft, flexible, wireless, wearable device that mounts onto a patient's chest to control pacing. When the wearable device detects an irregular heartbeat, it automatically shines a light pulse to activate the pacemaker. These short pulses -- which penetrate through the patient's skin, breastbone and muscles -- control the pacing.Designed for patients who only need temporary pacing, the pacemaker simply dissolves after it's no longer needed. All the pacemaker's components are biocompatible, so they naturally dissolve into the body's biofluids, bypassing the need for surgical extraction.

The study will be published on April 2 in the journal Nature. The paper demonstrates the device's efficacy across a series of large and small animal models as well as human hearts from deceased organ donors.

"We have developed what is, to our knowledge, the world's smallest pacemaker," said Northwestern bioelectronics pioneer John A. Rogers, who led the device development. "There's a crucial need for temporary pacemakers in the context of pediatric heart surgeries, and that's a use case where size miniaturization is incredibly important. In terms of the device load on the body -- the smaller, the better."

"Our major motivation was children," said Northwestern experimental cardiologist Igor Efimov, who co-led the study. "About 1% of children are born with congenital heart defects -- regardless of whether they live in a low-resource or high-resource country. The good news is that these children only need temporary pacing after a surgery. In about seven days or so, most patients' hearts will self-repair. But those seven days are absolutely critical. Now, we can place this tiny pacemaker on a child's heart and stimulate it with a soft, gentle, wearable device. And no additional surgery is necessary to remove it."

Rogers is the Louis Simpson and Kimberly Querrey Professor of Materials Science and Engineering, Biomedical Engineering and Neurological Surgery at Northwestern -- where he has appointments in the McCormick School of Engineering and Feinberg School of Medicine -- and the director of the Querrey Simpson Institute of Bioelectronics. Efimov is a professor of biomedical engineering at McCormick and professor of medicine (cardiology) at Feinberg. Rogers and Efimov co-led the study with Yonggang Huang, the Jan and Marcia Achenbach Professor of Mechanical Engineering and Civil and Environmental Engineering at McCormick; Wei Ouyang, an assistant professor of engineering at Dartmouth College; and Rishi Arora, the Harold H. Hines Jr. Professor of Medicine at the University of Chicago.

Meeting an unmet clinical need

This work builds on a previous collaboration between Rogers and Efimov, in which they developed the first dissolvable device for temporary pacing. Many patients require temporary pacemakers after heart surgery -- either while waiting for a permanent pacemaker or to help restore a normal heart rate during recovery.

For the current standard of care, surgeons sew the electrodes onto the heart muscle during surgery. Wires from the electrodes exit the front of a patient's chest, where they connect to an external pacing box that delivers a current to control the heart's rhythm.

When the temporary pacemaker is no longer needed, physicians remove the pacemaker electrodes. Potential complications include infection, dislodgement, torn or damaged tissues, bleeding and blood clots.

"Wires literally protrude from the body, attached to a pacemaker outside the body," Efimov said. "When the pacemaker is no longer needed, a physician pulls it out. The wires can become enveloped in scar tissue. So, when the wires are pulled out, that can potentially damage the heart muscle."

In response to this clinical need, Rogers, Efimov and their teams developed their dissolvable pacemaker, which was introduced in Nature Biotechnology in 2021. The thin, flexible, lightweight device eliminated the need for bulky batteries and rigid hardware, including wires. Rogers' lab had previously invented the concept of bioresorbable electronic medicine -- electronics that provide a therapeutic benefit to the patient and then harmlessly dissolve in the body like absorbable sutures. By varying the composition and thickness of the materials in these devices, Rogers' team can control the precise number of days they remain functional before dissolving.

Source: ScienceDaily