A look into the heart of cellular waste disposal

Researchers reveal how a nanomachine takes care of cleaning up inside the cell

Peer-Reviewed Publication

MAX-PLANCK-GESELLSCHAFT

 

IMAGE: FLUORESCENT LIPIDS SHOW HOW THE NANOMACHINE ACCELERATES LIPID TRANSFER WHEN NECESSARY. view more 

CREDIT: ANH NGUYEN / MAX PLANCK INSTITUTE FOR MULTIDISCIPLINARY SCIENCES & POUYA HOSNANI / UNIVERSITY MEDICAL CENTRE GÖTTINGEN

To prevent our body’s cells from overflowing with garbage and to keep them healthy, the waste inside them is constantly being disposed of. This cleaning process is called autophagy. Scientists have now, for the first time, rebuilt the complex nanomachine in the laboratory that starts this process – and it works quite differently from other cellular machines. The researchers’ new insights could help open up new approaches for the treatment of cancer, immune disorders, and neurodegenerative diseases in the future, and possibly even delay aging.

Have you ever put off cleaning the house or decluttering the overflowing basement? Living cells cannot afford this procrastination when it comes to clearing the decks. Tiny garbage chutes are constantly active there to capture worn-out proteins, faulty cell components, or defective organelles. These garbage chutes, called autophagosomes, pick out the discarded components before they accumulate in the cell and cause damage. The cellular waste is then passed on to the cell’s own recycling machinery, the lysosome, where it is digested and recycled. Thus, building blocks for new cellular components are quickly available again. The autophagy process, literally self-eating, thus also helps cells to survive stress or periods of starvation.

Autophagy also serves another important purpose. It renders harmless viruses and bacteria that successfully bypass the immune system’s defenses and reach the cell plasma. The consequences are correspondingly fatal if the autophagy process is faulty, too slow, or too fast. Neurodegenerative diseases and cancer can develop or disorders of the immune system may occur. Aging processes also appear to accelerate.

“Autophagy is a highly complex process involving many different proteins and protein complexes. We know many of them, but there are still fundamental gaps in our knowledge,” reports Alex Faesen, research group leader at the Max Planck Institute for Multidisciplinary Sciences in Göttingen. “How do the protein components work together? How is the process of autophagy started and stopped? When and where is the autophagosome assembled? That is what we want to find out.”

Nanomachine at work

His team has now succeeded, for the first time, in producing all the proteins involved in the autophagy process in the laboratory and observing them directly as the autophagosomes assemble. This was a mammoth task for the entire research group, taking several years, for which they cooperated with the teams led by Björn Stork from the University of Düsseldorf and Michael Meinecke, previously at the University Medical Center Göttingen now at the Heidelberg University Biochemistry Center. “There were many challenges,” recalls Faesen. In the first step, the scientists produced each individual protein component in the laboratory. The standard approach is to use bacteria that are genetically reprogrammed to produce the desired protein in large quantities. “But protein production with bacteria did not work for any of our proteins,” the Göttingen biochemist says. Instead, the researchers switched to insect cells as molecular helpers – the breakthrough.

In the next step, the team brought the individual protein complexes together. “The complexes self-assembled into a protein supercomplex, the autophagy initiation complex. In fact, autophagy involves a sophisticated cellular nanomachine – and it works quite differently than previously thought,” the group leader says.

To make autophagosomes, the autophagy initiation complex first creates a junction between a particular structure of the cell, the endoplasmic reticulum, and the autophagosome that forms. Under stress or in times of starvation, such as during endurance sports, this occurs within just a few minutes. “From this point on, there is no turning back: The waste disposal is assembled and collects the cellular waste,” explains Anh Nguyen, one of the two first authors of the study. Co-first author Fancesca Lugarini adds, “Via the contact site, fat-like molecules called lipids are transported to a precursor stage of autophagosomes, where they are incorporated.” These grow and, in the process, enclose the cell material to be disposed of – the finished mini-organelle is formed. Within barely 20 minutes of its formation, the autophagosome is already delivering its waste to the lysosome by fusing with it.

Protein origami for “on” and “off”

But what starts the assembly of the autophagy machine, what starts it and what stops it? The researchers did not find a molecular “on” and “off” switch as in other molecular machines. Instead, the switch uses a highly unusual behavior of proteins: metamorphosis. ” Certain molecules, called ATG13 and ATG101, have the ability to fold in different 3D structures, thereby changing its ability to bind to proteins in the machine. “This protein metamorphosis also gives the go-ahead for the assembly of the autophagy initiation complex at the right time and in the right place,” says Faesen, describing the special features of the nanomachine. Without metamorphosis, the initiation machine does not assemble.

The scientists hope that the new findings will advance the development of future drugs that can be used to treat diseases that are based on a faulty autophagy process.

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JOURNAL

Molecular Cell

DOI

10.1016/j.molcel.2023.04.026 

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

Cells

ARTICLE TITLE

Metamorphic proteins at the basis of human autophagy initiation and lipid transfer.

Enhancing patient care by improving electronic health records: Plan outlines 3 'essential' steps

Peer-Reviewed Publication

UNIVERSITY OF VIRGINIA HEALTH SYSTEM

 

IMAGE: THE UNIVERSITY OF VIRGINIA SCHOOL OF MEDICINE’S DON DETMER, MD, MA, WAS AN EARLY ADVOCATE FOR THE ELECTRONIC HEALTH RECORDS NOW FOUND IN HOSPITALS ACROSS THE COUNTRY. HE HAS NOW DEVELOPED A PLAN TO IMPROVE THEIR USE, LIGHTEN CLINICIANS’ WORKLOAD AND ENHANCE PATIENT CARE. view more 

CREDIT: COURTESY DON DETMER

An early advocate for the electronic health records now found in hospitals across the country has developed a plan to improve their use, lighten clinicians’ workload and enhance patient care.

The University of Virginia School of Medicine’s Don Detmer, MD, MA, designed the improvement plan in collaboration with Andrew Gettinger, MD, of Dartmouth’s Geisel School of Medicine. Detmer oversaw UVA’s adoption of electronic physician order entry in the early 1990s while vice president for health sciences. That move made UVA one of the first academic health centers in the country to embrace electronic records.

In the new proposal, published in the Journal of American Medical Association, Detmer and Gettinger outline what they are calling “essential electronic health reforms for this decade.” 

Electronic health records, commonly called EHRs or EMRs, were introduced to improve record-keeping and assist doctors and other health professionals in providing the best care possible. But with their implementation came increased documentation responsibilities that added to an already heavily workload for clinicians and that can contribute to provider burnout. Further, many argue that the required documentation can distract from focusing on patients during visits.

Detmer and Gettinger seek to tackle these problems head-on. “Lack of action by national leaders saps the energy and motivation of health workers," Detmer said. "Health and safety should count for more, and action on our recommendations could improve both.”

Enhancing Electronic Health Records

The authors call for three key changes they say could be implemented fairly easily:

• Removing all administrative and regulatory documentation obligations for care providers during their “clinical time” with patients, except for matters pertaining directly to the reason for the patient’s visit. This would effectively separate care provision from payment and billing, cutting through red tape. For example, Detmer and Gettinger suggest streamlining all insurance approval and authorization practices to eliminate, as much as possible, the need to get “pre-approval” from insurers for treatments. 
• Adding the ability for patients to enter information in their electronic health record, making them more active participants in their care.
• Reinventing the “clinical note,” one of the most common records providers create, to better support patient care. These notes, Detmer and Gettinger say, should directly address expected or desired results from each visit and could include timelines, when possible.

“What will be the effect of these interventions?” the authors ask in their article. “A major move in these directions will allow far greater creativity and innovation between clinicians and patients to transcend the traditional boundaries of what constitutes care. The focus of care can broaden to consider all the social determinants of health [the external factors that affect outcomes] that may be relevant to a particular patient.”

In addition to those proposals, Detmer and Gettinger argue that the most urgently needed change is the least likely to be implemented. They say there is a desperate need for “unique personal safety identifiers” that would let hospitals, employers, health plans, insurance companies and other healthcare organizations streamline operations by jointly identifying individual patients. That idea was originally mandated in 1996’s Health Insurance Portability and Accountability Act (HIPAA) but has not been implemented at the national level because of concerns about patient privacy and other issues. The lack of such consistent identifiers, Detmer and Gettinger maintain, “presents a continuing threat to privacy, safety, cost reduction and administrative errors.”

Next Steps

While the doctors acknowledge that national identifiers are likely off the table, they say that enacting the other changes they suggest could make a big difference for both care providers and patients.

“Although addressing shortcomings in EHRs will not cure all that ails our current health care system, implementing these recommendations should positively affect patients and clinicians and move us toward the original vision of a patient-centered, technology-enhanced health care ecosystem that is designed to significantly improve outcomes at a lower cost, with more satisfied patients and clinicians,” the authors conclude.  

To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog.

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JOURNAL

JAMA

DOI

10.1001/jama.2023.3961 

UMD study finds brain connectivity, memory improves in older adults after walking

School of Public Health research adds to growing evidence that exercise slows cognitive impairment and may delay onset of Alzheimer’s disease.

Peer-Reviewed Publication

UNIVERSITY OF MARYLAND

A new University of Maryland School of Public Health study reveals how walking strengthens connections within and between three of the brain’s networks, including one associated with Alzheimer’s disease, adding to the growing evidence that exercise improves brain health.

Published this month in the Journal for Alzheimer’s Disease Reports, the study examined the brains and story recollection abilities of older adults with normal brain function and those diagnosed with mild cognitive impairment, which is a slight decline in mental abilities like memory, reasoning and judgment and a risk factor for Alzheimer’s.

“Historically, the brain networks we studied in this research show deterioration over time in people with mild cognitive impairment and Alzheimer’s disease,” said J. Carson Smith, a kinesiology professor with the School of Public Health and principal investigator of the study. “They become disconnected, and as a result, people lose their ability to think clearly and remember things. We're demonstrating that exercise training strengthens these connections.”

The study builds upon Smith’s previous research, which showed how walking may decrease cerebral blood flow and improve brain function in older adults with mild cognitive impairment.

Thirty-three participants, who ranged between 71 and 85 years old, walked while supervised on a treadmill four days a week for 12 weeks. Before and after this exercise regimen, researchers asked participants to read a short story and then repeat it out loud with as many details as possible.

Participants also underwent functional magnetic resonance imaging (fMRI) so researchers could measure changes in communication within and between the three brain networks that control cognitive function:

• Default mode network - Activates when a person isn’t doing a specific task (think daydreaming about the grocery list) and is connected to the hippocampus - one of the first brain regions affected by Alzheimer’s disease. It’s also where Alzheimer's and amyloid plaques, a prime suspect for Alzheimer's disease found around nerve cells, show up in tests.
• Frontoparietal network - Regulates decisions made when a person is completing a task. It also involves memory.
• Salience network - Monitors the external world and stimuli and then decides what deserves attention. It also facilitates switching between networks to optimize performance.

After 12 weeks of exercise, researchers repeated the tests and saw significant improvements in participants’ story recall abilities. 

“The brain activity was stronger and more synchronized, demonstrating exercise actually can induce the brain’s ability to change and adapt,” Smith said. “These results provide even more hope that exercise may be useful as a way to prevent or help stabilize people with mild cognitive impairment and maybe, over the long term, delay their conversion to Alzheimer's dementia.”

Researchers also observed stronger activity within the default mode network, within the salience network and in the connections between the three networks. 

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JOURNAL

Journal of Alzheimer s Disease Reports

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Large-Scale Network Connectivity and Cognitive Function Changes After Exercise Training in Older Adults with Intact Cognition and Mild Cognitive Impairment

Multivitamin improves memory in older adults, study finds

Taking a daily multivitamin may help slow age-related memory decline, a study has found.

Peer-Reviewed Publication

COLUMBIA UNIVERSITY IRVING MEDICAL CENTER

NEW YORK, NY (May 24, 2023)--Taking a daily multivitamin supplement can slow age-related memory decline, finds a large study led by researchers at Columbia University and Brigham and Women’s Hospital/Harvard.

“Cognitive aging is a top health concern for older adults, and this study suggests that there may be a simple, inexpensive way to help older adults slow down memory decline,” says study leader Adam M. Brickman, PhD, professor of neuropsychology at Columbia University Vagelos College of Physicians and Surgeons.

Many older people take vitamins or dietary supplements under the assumption that they will help maintain general health. But studies that have tested whether they improve memory and brain function have been mixed, and very few large-scale, randomized trials have been done. 

Study methods

In the current study, more than 3,500 adults (mostly non-Hispanic white) over age 60 were randomly assigned to take a daily multivitamin supplement or placebo for three years. At the end of each year, participants performed a series of online cognitive assessments at home designed to test memory function of the hippocampus, an area of the brain that is affected by normal aging. The COSMOS-Web study is part of a large clinical trial led by Brigham & Women’s Hospital and Harvard called the COcoa Supplement and Multivitamin Outcomes Study (COSMOS).

By the end of the first year, memory improved for people taking a daily multivitamin, compared with those taking a placebo. The researchers estimate the improvement, which was sustained over the three-year study period, was equivalent to about three years of age-related memory decline. The effect was more pronounced in participants with underlying cardiovascular disease. 

The results of the new study are consistent with another recent COSMOS study of more than 2,200 older adults that found that taking a daily multivitamin improved overall cognition, memory recall, and attention,  effects that were also more pronounced in those with underlying cardiovascular disease.

“There is evidence that people with cardiovascular disease may have lower micronutrient levels that multivitamins may correct, but we don’t really know right now why the effect is stronger in this group,” says Brickman.

Good nutrition important for aging brain

Though the researchers did not look at whether any specific component of the multivitamin supplement was linked to the improvement in memory, the findings support growing evidence that nutrition is important for optimizing brain health as we age.

“Our study shows that the aging brain may be more sensitive to nutrition than we realized, though it may not be so important to find out which specific nutrient helps slow age-related cognitive decline,” says Lok-Kin Yeung, PhD, a postdoctoral researcher in Columbia’s Taub Institute for Research on Alzheimer’s Disease and the Aging Brain and first author of the study.

“The finding that a daily multivitamin improved memory in two separate cognition studies in the COSMOS randomized trial is remarkable, suggesting that multivitamin supplementation holds promise as a safe, accessible, and affordable approach to protecting cognitive health in older adults,” says co-author JoAnn Manson, MD, chief of the Division of Preventive Medicine at Brigham and Women’s Hospital.

“Supplementation of any kind shouldn’t take the place of more holistic ways of getting the same micronutrients,” adds Brickman. “Though multivitamins are generally safe, people should always consult a physician before taking them.”

More information

The study, titled “Multivitamin supplementation improves memory in older adults: A randomized clinical trial,” was published in the American Journal of Clinical Nutrition. 

All authors: Lok-Kin Yeung (Columbia), Daniel M. Alschuler (New York State Psychiatric Institute), Melanie Wall (Columbia), Heike Luttman-Gibson (Brigham and Women’s Hospital/Harvard), Trisha Copeland (Brigham and Women’s/Harvard), Richard P. Sloan (Columbia), Howard D. Sesso (Brigham and Women’s/Harvard), JoAnn E. Manson (Brigham and Women’s/Harvard), and Adam M. Brickman (Columbia). 

Dr. Manson and Dr. Sesso are co-leaders of the parent COSMOS trial.

The study was supported by grants from Mars Edge, a segment of Mars Inc., and the National Institutes of Health (AG050657, AG071611, EY025623, and HL157665).

Multivitamins were supplied by Pfizer. Dr. Sesso reported receiving investigator-initiated grants from Pure Encapsulations and Pfizer and/or travel funds for lectures from the Council for Responsible Nutrition, BASF, NIH, and the American Society of Nutrition during the study.

No other conflicts have been reported.

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Columbia University Irving Medical Center

Columbia University Irving Medical Center (CUIMC) is a clinical, research, and educational campus located in New York City, and is one of the oldest academic medical centers in the United States. CUIMC is home to four professional colleges and schools (Vagelos College of Physicians and Surgeons, Mailman School of Public Health, College of Dental Medicine, and School of Nursing) that are global leaders in their fields. CUIMC is committed to providing inclusive and equitable health and medical education, scientific research, and patient care, and working together with our local upper Manhattan community—one of New York City's most diverse neighborhoods. For more information, please visit cuimc.columbia.edu.  

 

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JOURNAL

American Journal of Clinical Nutrition

DOI

10.1016/j.ajcnut.2023.05.011 

METHOD OF RESEARCH

Randomized controlled/clinical trial

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Multivitamin supplementation improves memory in older adults: A randomized clinical trial

ARTICLE PUBLICATION DATE

24-May-2023

COI STATEMENT

Multivitamins were supplied by Pfizer. Dr. Sesso reported receiving investigator-initiated grants from Pure Encapsulations and Pfizer and/or travel for lectures from the Council for Responsible Nutrition, BASF, NIH, and the American Society of Nutrition during the study. No other conflicts have been reported.

Fibromyalgia changes the brain

Neuroscience

Peer-Reviewed Publication

RUHR-UNIVERSITY BOCHUM

 

IMAGE: USING DATA FROM MAGNETIC RESONANCE IMAGING, THE RESEARCHERS WERE ABLE TO COMPARE THE BRAINS OF HEALTHY AND FIBROMYALGIA SUFFERERS. view more 

CREDIT: © BENJAMIN MOSCH

Changes in the pain network

The team surrounding Professor Martin Diers and Benjamin Mosch analysed the magnetic resonance imaging data of 23 female patients with fibromyalgia and 21 healthy control subjects. They wanted to examine the volume of the grey matter, i.e. the nerve cells, in various pain-processing areas of the brain, and the so-called white matter, which mainly consists of the fibre connections between the nerve cells through which signals are transmitted. “One of our goals was to find out whether the directionality of the diffusion of water molecules differs in certain areas of the brain, in other words: whether we can identify any regional differences in signal transmission,“ explains Benjamin Mosch.

The researchers found changes of the grey matter volume mainly in the pain network of the brain, i.e. in the regions responsible for processing and evaluating pain. “In certain regions responsible for the inhibition of pain, we found a decrease in grey matter in the patients compared to the healthy individuals,” explains Benjamin Mosch. “In patients, the volume of these regions was significantly reduced.”

Regarding the transmission of signals, changes were found in the thalamus. The thalamus is considered as an important node in neuronal pain processing. The deviations of the white matter in patients with fibromyalgia compared to healthy controls indicate an altered conduction of pain signals in patients with fibromyalgia.

Relationships between brain structure, perception and behaviour

The team finally related the results of the structural brain changes to perceptional and behavioural characteristics of the study participants. The amount of decreased volume in a number of relevant brain regions is inversely related with the amount of perceived pain the patients report. The researchers made an interesting observation when analysing the correlation between depressiveness or activity levels with the change in the volume of certain brain areas. The volume of the so-called putamen correlated negatively with the expression of depressive symptoms and positively with the activity level of the participants. “This indicates that changes in the brain may not be permanent, but that they can be influenced; in other words they might be reversible, for example through an active everyday life,” concludes Benjamin Mosch.

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JOURNAL

Arthritis Research & Therapy

DOI

10.1186/s13075-023-03064-0 

METHOD OF RESEARCH

Observational study

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Brain morphometric changes in fibromyalgia and the impact of psychometric and clinical factors: A volumetric and diffusion-tensor imaging study

Your thoughts can harm your neck and back during lifting tasks

In lab, contradictory feedback linked to increased spine loading

Peer-Reviewed Publication

OHIO STATE UNIVERSITY

COLUMBUS, Ohio – The mental distress of cognitive dissonance – encountering information that conflicts with how we act or what we believe – can lead to added pressure on the neck and low back during lifting and lowering tasks, new research suggests.

When study participants were told they were performing poorly in a precision lowering experiment in the lab, after initially being told they were doing well, their movements were linked to increased loads on vertebrae in their neck and low back.

Results showed that the higher the cognitive dissonance score, the greater the extent of loading on the upper and lower parts of the spine.

The finding suggests cognitive dissonance may be a previously unidentified risk factor for neck and low back pain, which could have implications for risk prevention in the workplace, according to researchers.

“This increased spine loading occurred under just one condition with a fairly light load – you can imagine what this would be like with more complex tasks or higher loads,” said senior author William Marras, executive director of the Spine Research Institute at The Ohio State University. “Basically, the study scratched the surface of showing there’s something to this.”

The research was published recently in the journal Ergonomics.

Marras’ lab has been studying daily living and occupational forces on the spine for decades. About 20 years ago, he found that psychological stress could influence spine biomechanics, using a study design that involved having a fake argument with a graduate student in front of research participants.

“We found that in certain personality types, the loads in the spine increased by up to 35%,” Marras said. “We ended up finding that when you’re under that kind of psychosocial stress, what you tend to do is what we call co-activate muscles in your torso. It creates this tug of war in the muscles because you’re always tense.

“In this study, to get at that mind-body connection, we decided to look at the way people think and, with cognitive dissonance, when people are disturbed by their thoughts.”

Seventeen research participants – nine men and eight women aged 19-44 – completed three phases of an experiment in which they placed a light-weight box within a square on a surface that was moved left and right, up and down. After a short practice run, researchers gave almost exclusively positive feedback during the first of two 45-minute trial blocks. During the second, the feedback increasingly suggested participants were performing in an unsatisfactory way.

To arrive at a cognitive dissonance score for each participant, changes during the experiment to blood pressure and heart rate variability were combined with responses to two questionnaires assessing discomfort levels as well as positive and negative affect – feeling strong and inspired versus distressed and ashamed.

Wearable sensors and motion-capture technology were used to detect peak spinal loads in the neck and low back: both compression of vertebrae and vertebral movement, or shear, from side to side (lateral) and forward and back (A/P).

Statistical modeling showed that, on average, peak spinal loads on cervical vertebrae in the neck were 11.1% higher in compression, 9.4% higher in A/P shear and 19.3% higher in lateral shear during the negative-feedback trial block compared to the baseline measures from the practice run. Peak loading in the lumbar region of the low back – an area that bears the brunt of any spinal loading – increased by 1.7% in compression and 2.2% in shear during the final trial block.

“Part of the motivation here was to see whether cognitive dissonance can manifest itself not only in the low back – we thought we’d find it there, but we didn’t know what we’d find in the neck. We did find a pretty strong response in the neck,” said Marras, a professor of integrated systems engineering with College of Medicine academic appointments in neurosurgery, orthopaedics and physical medicine and rehabilitation.

“Our tolerance to shear is much, much lower than it is to compression, so that’s why that’s important,” he said. “A small percentage of load is no big deal for one time. But think about when you’re working day in and day out, and you’re in a job where you’re doing this 40 hours a week – that could be significant, and be the difference between a disorder and not having a disorder.”

Marras is also principal investigator on a federally funded multi-institution clinical trial assessing different treatments for low back pain that range from medication to exercise to cognitive behavioral therapy.

“We’re trying to unravel this onion and understand all the different things that affect spine disorders because it’s really, really complex,” he said. “Just like the whole system has got to be right for a car to run correctly, we’re learning that that’s the way it is with the spine. You could be in physically great shape, but if you’re not thinking correctly or appropriately, or you have all these mental irregularities, like cognitive dissonance, that will affect the system. And until you get that right, you’re not going to be right.

“We’re looking for causal pathways. And now we can say cognitive dissonance plays a role and here’s how it works.”

This research was supported by internal Spine Research Institute funds. Co-authors included first author Eric Weston, a former integrated systems engineering graduate student at Ohio State; Afton Hassett of the University of Michigan; and Safdar Khan and Tristan Weaver of Ohio State.

#

Contact: William Marras, Marras.1@osu.edu

Written by Emily Caldwell, Caldwell.151@osu.edu; 614-292-8152

 

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JOURNAL

Ergonomics

DOI

10.1080/00140139.2023.2186323 

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Cognitive dissonance increases spine loading in the neck and low back

Sudden infant death syndrome may have biologic cause

Peer-Reviewed Publication

OXFORD UNIVERSITY PRESS USA

Sudden infant death syndrome is a case where the death of an apparently healthy infant before their first birthday remains unexplained even after thorough investigation. Death generally seems to occur when infants are sleeping. While rare, it is the leading post-neonatal infant death in the United States today, occurring in 103 out of 100,000 live births a year. Despite the initial success of national public health campaigns promoting safe sleep environments and healthier sleep positions in infants in the 1990s in the United States, rates of cases have remained the same over the last three decades.

Researchers here collected tissue from the San Diego Medical Examiner’s Office related to infant deaths between 2004 and 2011. Researchers examined the brain stems of 70 infants who died during the period and tested them for consistent abnormalities.

They find that the serotonin 2A/C receptor is altered in sudden infant death cases compared to control cases of infant deaths. Previous research in rodents has shown that 2A/C receptor signaling contributes to arousal and autoresuscitation, protecting brain oxygen status during sleep. This new research supports the idea that a biological abnormality in some infants makes them vulnerable to death under certain circumstances.

The investigators here believe that sudden infant death syndrome occurs when three things happen together: a child is in a critical period of cardiorespiratory development in their first year, the child faces an outside stressor like a face-down sleep position or sharing a bed, and the child has a biological abnormality that makes them vulnerable to respiratory challenges while sleeping.

“The work presented builds upon previous work by our laboratory and others showing abnormalities in the serotonergic system of some SIDS infants,” said the paper’s lead author, Robin Haynes. “Although we have identified abnormalities in the serotonin 2A/C receptor in SIDS, the relationship between the abnormalities and cause of death remains unknown. Much work remains in determining the consequence of abnormalities in this receptor in the context of a larger network of serotonin and non-serotonin receptors that protect vital functions in cardiac and respiratory control when challenged. Currently, we have no means to identify infants with biological abnormalities in the serotonergic system. Thus, adherence to safe-sleep practices remains critical.”

The paper, “Altered 5-HT2A/C receptor binding in the medulla oblongata in the sudden infant death syndrome (SIDS): part I. Tissue-based evidence for serotonin receptor signaling abnormalities in cardiorespiratory- and arousal-related circuits,” will be available (at midnight on May 25th) at: https://doi.org/10.1093/jnen/nlad030.

Direct correspondence to: 
Robin L. Haynes
CJ Murphy Laboratory for SIDS Research
Boston Children’s Hospital
300 Longwood Avenue
Boston, MA 02115
robin.haynes@childrens.harvard.edu

To request a copy of the study, please contact:
Daniel Luzer 
daniel.luzer@oup.com

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JOURNAL

Journal of Neuropathology & Experimental Neurology

DOI

10.1093/jnen/nlad030 

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Altered 5-HT2A/C receptor binding in the medulla oblongata in the sudden infant death syndrome (SIDS): part I. Tissue-based evidence for serotonin receptor signaling abnormalities in cardiorespiratory- and arousal-related circuits

ARTICLE PUBLICATION DATE

25-May-2023

Keeping time: Understanding the master clock in the brain

Researchers from the University of Tsukuba find a molecular pathway that controls sleep rhythms and homeostasis

Peer-Reviewed Publication

UNIVERSITY OF TSUKUBA

Tsukuba, Japan—Most living creatures exhibit a circadian rhythm, an internal clock that repeats around every 24 hours. Now, researchers from Japan have found new details about the molecular processes that govern sleep/wake rhythms in mice.

In a recently published study, researchers from the University of Tsukuba have revealed that a key molecule involved in sleep homeostasis (called SIK3 or salt-inducible kinase 3) also plays a critical role in circadian behavior.

Animals are able to adapt to the 24-hour cycle of light and dark in terms of both behavior and physiology via changes in the suprachiasmatic nucleus (SCN), which is the brain's master clock that synchronizes the various rhythms in the body. However, the biological activities within the SCN that induce time-specific wakefulness have not been fully characterized; the research team aimed to address this.

"Most animals show a peak in activity at a specific point in the circadian cycle," explains lead author of the study Professor Masashi Yanagisawa. "Because the SCN has been found to regulate sleep and wakefulness at certain times of the day, we wanted to investigate the distinct neurons that control this process."

To do this, the research team genetically manipulated levels of SIK3 in specific neuron groups in the SCN of mice. Then, they examined sleep and circadian behaviors in the mice, such as when and for how long the mice exhibited activity with respect to the light-dark cycle.

"We found that SIK3 in the SCN can influence circadian cycle length and the timing of peak arousal activity, without changing the daily sleep amount," says Professor Yanagisawa.

The research team previously reported that SIK3 interacts with LKB1 (an upstream molecule of SIK3) and HDAC4 (an important target of SIK3) in glutamatergic neurons to regulate the amount and depth of sleep. Now, they have found that the SIK3-HDAC4 pathway modulates the length of the circadian period through NMS-producing neurons, and contributes to the sleep/wake rhythm.

The length of the behavioral period and the timing of peak activity are important components of the circadian rhythm. Given the similarities between the circadian systems of different mammals, new information about how this system works in mice could lead to new treatments for sleep and circadian rhythm disorders in humans.

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This work was supported by the World Premier International Research Center Initiative (WPI) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (KAKENHI), Japan Science and Technology Agency (JST) Core Research for Evolutional Science and Technology (CREST), Japan Agency for Medical Research and Development (AMED), JSPS DC2 grant, University of Tsukuba Basic Research Support Program Type A, and Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program).
 

Original Paper

Title of original paper:
SIK3-HDAC4 in the suprachiasmatic nucleus regulates the timing of arousal at the dark onset and circadian period in mice

Journal:
PNAS

DOI:
10.1073/pnas.2218209120

Correspondence

Professor YANAGISAWA Masashi
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba

Related Link

International Institute for Integrative Sleep Medicine (WPI-IIIS)

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JOURNAL

Proceedings of the National Academy of Sciences

DOI

10.1073/pnas.2218209120 

ARTICLE TITLE

SIK3–HDAC4 in the suprachiasmatic nucleus regulates the timing of arousal at the dark onset and circadian period in mice

New study provides novel insights into the cosmic evolution of amino acids

Scientists perform computational simulations for biological molecules detected in meteorites to clarify the origin of life on Earth.

Peer-Reviewed Publication

UNIVERSITY OF TSUKUBA

All biological amino acids on Earth appear exclusively in their left-handed form, but the reason underlying this observation is elusive. Recently, scientists from Japan uncovered new clues about the cosmic origin of this asymmetry. Based on the optical properties of amino acids found on the Murchison meteorite, they conducted physics-based simulations, revealing that the precursors to the biological amino acids may have determined the amino acid chirality during the early phase of galactic evolution.

If you look at your hands, you will notice that they are mirror images of each other. However, no matter how hard you try to flip and rotate one hand, you will never be able to superimpose it perfectly over the other. Many molecules have a similar property called "chirality," which means that the "left-handed" (L) version of a molecule cannot be superimposed onto its "right-handed" (D) mirror image version. Even though both versions of a chiral molecule, called "enantiomers," have the same chemical formula, the way they interact with other molecules, especially with other chiral molecules, can vary immensely.

Interestingly, one of the many mysteries surrounding the origin of life as we know it has to do with chirality. It turns out that biological amino acids (AAs)—the building blocks of proteins—on Earth appear only in one of their two possible enantiomeric forms, namely the L-form. However, if you synthesize AAs artificially, both L and D forms are produced in equal amounts. This suggests that, at some early point in the past, L-AAs must have come to dominate a hetero-chiral world. This phenomenon is known as "chiral symmetry breaking."

Against this backdrop, a research team led by Assistant Professor Mitsuo Shoji from University of Tsukuba, Japan, conducted a study aimed at solving this mystery. As explained in their paper published in The Journal of Physical Chemistry Letters, the team sought to find evidence supporting the cosmic origin of the homochirality of AAs on Earth, as well as iron out some inconsistencies and contradictions in our previous understanding.

"The idea that homochirality may have originated in space was suggested after AAs were found in the Murchison meteorite that fell in Australia in 1969," explains Dr. Shoji. Curiously enough, in the samples obtained from this meteorite, each of the L-enantiomers was more prevalent than its D-enantiomer counterpart. One popular explanation for this suggests that the asymmetry was induced by ultraviolet circularly polarized light (CPL) in the star-forming regions of our galaxy. Scientists verified that this type of radiation can, indeed, induce asymmetric photochemical reactions that, given enough time, would favor the production of L-AAs over D-AAs. However, the absorption properties of the AA isovaline are opposite to those of the other AAs, meaning that the UV-based explanation alone is either insufficient or incorrect.

Against this backdrop, Dr. Shoji's team pursued an alternate hypothesis. Instead of far-UV radiation, they hypothesized that the chiral asymmetry was, in fact, induced specifically by the CP Lyman-α (Lyα) emission line, a spectral line of hydrogen atom that permeated the early Milky Way. Moreover, instead of focusing only on photoreactions in AAs, the researchers investigated the possibility of the chiral asymmetry starting in the precursors to the AAs, namely amino propanals (APs) and amino nitriles (ANs).

Through quantum mechanical calculations, the team analyzed Lyα-induced reactions for producing AAs along the chemical pathway adopted in Strecker synthesis. They then noted the ratios of L- to D-enantiomers of AAs, APs, and ANs at each step of the process.

The results showed that L-enantiomers of ANs are preferentially formed under right-handed CP (R-CP) Lyα irradiation, with their enantiomeric ratios matching those for the corresponding AAs. "Taken together, our findings suggest that ANs underlie the origin of the homochirality," remarks Dr. Shoji. "More specifically, irradiating AN precursors with R-CP Lyα radiation lead to a higher ratio of L-enantiomers. The subsequent predominance of L-AAs is possible via reactions induced by water molecules and heat."

The study thus brings us one step closer to understanding the complex history of our own biochemistry. The team emphasizes that more studies focused on ANs need to be conducted on future samples from asteroids and comets to validate their findings. "Further analyses and theoretical investigations of ANs and other prebiotic molecules related to sugars and nucleobases will provide new insights into the chemical evolution of molecules and, in turn, the origin of life," concludes an optimistic Dr. Shoji.

Be sure to stay tuned as scientists continue to piece together this one grand puzzle called life !

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This study has been supported by research projects (1) JST, PRESTO grant number JPMJPR19G6, Japan, and (2) JSPS KAKENHI grant numbers 19H00697, 20H05453, 20H05088, 22H00347, and 22H04916. Computational resources were partially supported by Multidisciplinary Cooperative Research Program in CCS, University of Tsukuba. The authors also thank the HPC Center at the University of Strasbourg funded by the Equipex Equip@Meso project and the CPER Alsacalcul/Big Data and the Grand Equipement National de Calcul Intensif (GENCI) under allocations DARI A0120906092 and A0140906092.
 

Original Paper

Title of original paper:
Enantiomeric Excesses of Aminonitrile Precursors Determine the Homochirality of Amino Acids

Journal:
The Journal of Physical Chemistry Letters

DOI:
10.1021/acs.jpclett.2c03862

Correspondence

Assistant Professor SHOJI Mitsuo
Center for Computational Sciences (CCS), University of Tsukuba

Related Link

Center for Computational Sciences (CCS)

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JOURNAL

The Journal of Physical Chemistry Letters

DOI

10.1021/acs.jpclett.2c03862 

ARTICLE TITLE

Enantiomeric Excesses of Aminonitrile Precursors Determine the Homochirality of Amino Acids