Publisher Health

Eating lots of fats increases the risk of metabolic disorders, but the mechanisms behind the problem have not been well understood. Now, University of California, Irvine biologists have made a key finding about how to ward off harmful effects caused by a high-fat diet. Their study appears in Nature Communications.
The UC Irvine research centered on a protein complex called AMPK, which senses the body’s nutrition and takes action to keep it balanced. For example, if AMPK detects that glucose is low, it can boost lipid breakdown to produce energy in its place. Scientists have known that consuming high amounts of fat blocks AMPK’s activity, leading the metabolism to go out of balance. However, until now, how cells block this mechanism has not been widely examined, especially in live models.
The UCI biologists decided to investigate, believing an AMPK component called SAPS3 serves a significant role. They eliminated SAPS3 from the genome of a group of mice and fed them meals with a 45 percent fat content. The results were startling even to the research team.
“Removing the SAPS3-inhibiting component freed the AMPK in these mice to activate, allowing them to maintain a normal energy balance despite eating a large amount of fat,” said Mei Kong, professor of molecular biology & biochemistry and the study’s corresponding author. “We were surprised by how well they maintained normal weight, avoiding obesity and development of diabetes.”
The discovery could eventually lead to a new way to approach metabolism-related conditions. “If we block this inhibition activity, we could help people reactivate their AMPK,” said first author Ying Yang, a project scientist in the Kong lab. “It could help in overcoming disorders such as obesity, diabetes, fatty liver disease and others. It’s important to recognize how important normal metabolic function is for every aspect of the body.”
The researchers are working on developing molecules that could inhibit SAPS3 and restore the metabolism’s balance. They plan to next study SAPS3’s role in other conditions with disturbed metabolic systems, such as cancer and aging.
The discovery comes as metabolic-related diseases such as obesity and diabetes continue to rise. More than half of the global population is expected to be overweight or obese by 2035, compared to 38 percent in 2020, according to the World Obesity Federation. The number of people worldwide with diabetes is expected to rise to 578 million by 2030, up 25 percent from 2019, reports the National Center for Biotechnology Information.
Support for the project was provided by the National Institutes of Health and the American Cancer Society.

Whether you’re afraid of dogs, needles or enclosed spaces, one of the most effective interventions for this type of anxiety disorder is exposure therapy in which you confront your fear in a safe environment. A new study led by researchers at Penn State College of Medicine finds that exposure therapy is also a promising treatment for adolescents with eating disorders. They found that exposure to feared foods — such as candy bars and pizza — helped kids who were in a partial hospitalization program for eating disorders experience decreased anxiety toward food.
“As a society that is so heavily influenced by diet culture, our relationships with our bodies can be dysfunctional,” said Jamal Essayli, assistant professor of pediatrics and of psychiatry and behavioral health. “I came out as gay in high school, and by the time I got to college, I noticed an increased emphasis on body image among gay men. That’s partly what inspired my interest in researching and working with patients with eating disorders.”
According to the National Eating Disorders Association, approximately 30 million Americans will struggle with eating disorders, including anorexia nervosa, bulimia nervosa, binge-eating disorder and others, at some point in their lives. In addition to the LGBTQ+ community, adolescents and young adults are particularly vulnerable, and the COVID-19 pandemic didn’t help. Recent research by co-author Jennifer Shook, assistant professor of pediatrics at the Penn State College of Medicine, and others demonstrated a significant increase in eating disorder-associated inpatient and outpatient visits to emergency departments among adolescents and young adults during the pandemic.
“While this is an active area of research, the causes of eating disorders are typically thought to be a combination of biological predisposition and environment,” said Essayli. “For example, having an anxious or perfectionistic predisposition and being teased about your body size or weight can both increase a person’s risk for developing an eating disorder.”
In the current study, which was published in the International Journal of Eating Disorders, Essayli and his colleagues recruited 54 adolescents with a median age of 14 years who were participating in a partial hospitalization program for eating disorders. The program ran five days a week for an average of eight weeks per individual. Each day, the clinical team exposed the patients to a feared food. For example, participants were given a full-sized candy bar on Mondays, a baked good such as a cookie on Tuesdays, pizza on Wednesdays, a dessert on Thursdays and a breakfast item such as pancakes on Fridays.
“Many of these patients were underweight or weight suppressed, and had intense anxiety about these foods,” said Essayli. “It was important for them to learn that there’s nothing horrible about having pizza and ice cream at a party, for example, that it’s actually part of a fulfilling life.”
Patients provided subjective units of distress (SUDS) ratings on a scale from 0 (no distress) to 10 (extremely high distress) immediately before and after each food exposure. In addition, patients were periodically given the Children’s Eating Attitudes Test and Fear of Food Measure, which are aimed at determining levels of anxiety about eating and food avoidance behaviors. Finally, the adolescents were encouraged to discuss their feelings about the exposure challenges in weekly therapy sessions.

“One of the things we wanted to test was whether within-session and between-session habituation were important for weight gain,” said Essayli. “Say, you’re afraid of dogs. If you’re doing exposure therapy by spending time around a dog, within-session habituation is when your anxiety decreases while you’re with the dog. Between-session habituation is when your anxiety decreases from session to session across days.”
This distinction is important, Essayli said, because the extent to which clinicians should emphasize or disregard fear-reduction during exposure therapy sessions for eating disorders was previously unknown.
Overall, the team found that SUDS decreased significantly over time prior to exposure to feared foods, providing some evidence that between-session habituation occurred. However, the difference between pre-exposure and post-exposure SUDS did not decrease over time, indicating that within-session habituation did not occur. Therefore, the team concluded that between-session habituation, but not within-session habituation, predicted favorable treatment outcomes, including weight gain and improvements on the Children’s Eating Attitudes Test and Fear of Food Measure.
“Our findings provide support for integrating food exposure into partial hospitalization programs for adolescents with eating disorders who are undergoing weight restoration,” said Essayli. “And while more research is needed, our results may begin to help clinicians determine how much emphasis to place on within-session habituation and between-session habituation.”
Other Penn State authors on the paper include Lauren Forrest, assistant professor of psychiatry and behavioral health; Kathleen Keller, professor of nutritional sciences and food science; and Susan Lane-Loney, associate professor of pediatrics and of psychiatry and behavioral health. Hana Zickgraf, assistant professor of pediatrics, Emory University, and Emily Stefano, assistant professor, Bariatric and Weight Management Center, Wake Forest University, also are authors.
The National Institutes of Health supported this research.

Infections of the middle ear, the air-filled space behind the eardrum that contains the tiny vibrating bones of hearing, annually affect more than 700 million people worldwide. Children are especially prone to ear infections, with 40% of them developing recurrent or chronic infections that can lead to complications like impaired hearing, speech and language delays, perforations in their eardrums, and even life-threatening meningitis.
As a treatment, doctors may surgically insert ear tubes knowns as “tympanostomy tubes” (TTs) into the eardrum to create an opening between the ear canal and middle ear. Ideally, these conduits ventilate the middle ear, provide a route for fluid to drain out, and allow antibiotic drops to reach the infection-causing bacteria. But in reality, these small hollow cylindrical devices made of plastic or metal function far from perfectly. Bacteria can lay down biofilms and local tissue can grow on their surfaces, which blocks TTs’ lumen and causes them to extrude. Also, antibiotic ear drops applied in the ear canal may not reach the site of infection anymore. These complications pose risks and result in the need for frequent replacement surgeries, producing sizeable economic costs to the health care system.
Importantly, problems affecting TTs also plague other fluid-transporting “implantable medical conduits” (IMCs), such as catheters, shunts, and various small tubes with use in the brain, liver, eyes, and other organs where a high-pressure barrier prevents fluids from flowing through the conduit. In the quest for superior devices, the fundamental challenge faced by biomedical engineers is rooted in the conflict that reducing IMC devices’ size and invasiveness comes at the price of increasing their risk of becoming blocked and malfunctioning.
Now, a multi-disciplinary research collaboration at the Wyss Institute for Biologically Inspired Engineering at Harvard University, Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS), and Massachusetts Eye and Ear (MEE) in Boston provides a complete design overhaul for IMCs by creating a broadly applicable strategy that solves this challenge. Their approach enables IMCs with predictable and effective uni- and bi-directional fluid transport at the millimeter scale that resist various contaminations. With the example of TTs fabricated from a liquid-infused material (iTTs, short for “infused tympanostomy tubes”), they co-optimized difficult-to-reconcile functions, including fast drug delivery into and drainage of fluids out of the middle ear, resistance against water crossing from the outside into the middle ear, as well as the prevention of bacterial and cell adhesion to tubes, by introducing a novel curved lumen geometry of the tube. The findings are published in the recent cover article of Science Translational Medicine.
“As a clinical otologist, I treat pediatric and adult patients with recurrent ear infections on a daily basis and I routinely place tympanostomy tubes, which in children is the most common surgical procedure performed in the United States. Yet, TT medical device technology has remained relatively unchanged for the past 50 years,” said co-senior author Aaron Remenschneider, M.D., M.P.H. “Given our findings, I do see hope on the horizon for patients with chronic ear infections. Not only do our iTTs demonstrate a reduction in cell adhesion and improved selective fluid transport, but we showed how iTTs result in decreased scarring of the eardrum and preserved hearing when compared to standard-of-care control TTs. iTTs could also become an effective tool for delivering a range of drugs to the middle ear.” Remenschneider is a lecturer at Harvard Medical School (HMS), and at MEE collaborates closely with co-author, MEE otologist-colleague, and HMS Assistant Professor Elliott Kozin, M.D., who also investigates therapeutic approaches to ear disorders at MEE.
Material and clinical scientists listen closely — together
Preceding this collaboration, co-senior author Joanna Aizenberg, Ph.D., who is an Associate Faculty member of the Wyss Institute and the Amy Smith Berylson Professor of Material Sciences at SEAS, has pioneered bio-inspired materials with entirely new functionalities. These included SLIPS (short for “Slippery Liquid-Infused Porous Surfaces”), which expose a thin layer of oil-based liquid to prevent biofouling by various organisms while enabling specific interactions with other fluids. Aizenberg’s group had applied SLIPS technology to different industrial and environmental “biofouling” problems and, in search of unmet needs in the medical field that their materials could help address, they consulted with Remenschneider, Kozin and other physicians. A complete design overhaul of TTs and other IMCs became the goal of a long-standing collaboration driven by Aizenberg’s group, and Remenschneider and Kozin, which also included other researchers and clinicians. During its advancement, the cross-institutional project was recognized as a Validation Project at the Wyss Institute, which provided additional financial, technical, and translational support.

First-authors Haritosh Patel, a graduate engineering student in the Aizenberg lab, and Ida Pavlichenko, Ph.D., a former Wyss Technology Development Fellow began to develop the first iTT prototypes, using materials with liquid-infused surfaces and the 3D printing expertise of co-author Jennifer Lewis, Sd.D. at SEAS. “As a mother of a child who had experienced recurrent ear infections and some of their pain and harmful consequences, I could immediately relate to the clinical problem, and felt strongly compelled to spearhead a project with the potential to solve it,” said Pavlichenko. “We soon began to investigate geometry as a possible solution for solving IMCs’ fundamental design challenge. Surprisingly, only cylindrical TTs with straight internal lumen channels existed. We hypothesized that introducing specific curvatures into iTTs’ channels could allow them to discriminate between different fluids at a small scale.”
While focusing on iTTs as a first application, the team developed a much more broadly applicable modeling-enabled design process that can be applied to IMCs with different tasks and locations in the body. Based on the physical parameters of liquids, materials, and size, it starts with the fluid dynamics-based prediction of specific geometries for millimeter-sized IMCs fabricated with liquid-infused surfaces to control the directional transport of different liquids through them. “Besides validating the predicted transport of fluids through rationally designed and fabricated iTT prototypes in in vitro models of the middle ear, we also demonstrated their resistance against adhesion by the five most common bacterial strains causing ear infection in children,” said Patel. The strains were directly isolated from patients with chronic middle ear infections by co-author Paulo Bispo, Ph.D., another MEE collaborator on the project and an Assistant Professor at HMS.
Moving closer to the human ear
To investigate the performance of their iTTs in comparison with conventional TTs in an in vivo model with relevance to the human ear, the collaborators tested their approach on the ears of chinchillas, the gold-standard for studying middle ear diseases and treatment approaches. Chinchillas have a tympanic membrane about the same size of that of humans and a similar frequency range of hearing, and Remenschneider and Kozin had routinely used them in their MEE research lab. “Checking off all essential boxes, iTTs, when implanted into chinchillas’ eardrum, kept out environmental water, prevented infectious buildup, reduced scarring, and remained clear for aeration and pressure equalization,” said Patel. Pavlichenko added, “Importantly, they preserved hearing and enabled more easy and reliable dosing of antibiotic ear drops to the middle ear compared to conventional TTs, which is particularly exciting.” According to Remenschneider, “reliable dosing of medications to the middle ear through iTTs opens the door to rethinking our management of middle and even inner ear conditions, like hearing loss.”
“Based on our excellent safety and efficacy results, iTTs could next be tested in a clinical trial in human patients. But what equally excites us is to extend our patented design approach to other important IMCs, for example, as shunts for the brain, eye, and bile duct. The technology and fabrication process would even enable the creation of personalized devices optimized for specific patients’ characteristics and needs,” said Aizenberg. “We envision that iTTs’ and other IMCs’ material and geometrical properties in the future could be reverse-engineered to adapt them to different drug formulations and make them a part of the drug discovery process for an efficient topical delivery of therapeutics and treatment of various diseases.”
“This is wonderful example of what can happen when you have innovative materials scientists, engineers, and clinicians working together hand in hand to devise a new approach to meet specific patients’ needs,” said Wyss Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at HMS and Boston Children’s Hospital, and the Hansjörg Wyss Professor of Bioinspired Engineering at SEAS.
Other authors on the study are Alison Grinthal, Cathy Zhang, Jack Alvarenga, Michael Kreder, James Weaver, Qin Ji, Christopher Ling, Joseph Choy, Zihan Li, and Nicole Black. The study has been funded by the Wyss Institute for Biologically Inspired Engineering at Harvard University, National Science Foundation (under award# DMR-2011754), and National Institutes of Health (under award# R43DC019318 and K08DC018575).

Published5 hours agoShareclose panelShare pageCopy linkAbout sharingImage source, Poole FamilyBy Sean Seddon & Andre Rhoden-PaulBBC NewsSweden has “placed on hold” the deportation of a British grandmother with Alzheimer’s, her family have told the BBC.Kathleen Poole, 74, was told to leave the country after her application to remain post-Brexit was rejected.Her family have been told that Swedish authorities will continue to plan for the deportation, but have paused any order to carry it out for now.Mrs Poole’s daughter-in-law said: “I just want an end to this situation”.The British embassy in Stockholm informed Mrs Poole’s family on Wednesday that Swedish immigration authorities had received a request to stop the deportation at the end of March.Her removal has been placed on hold until a new decision is made, it said.”I actually don’t believe it for five minutes, even though they’ve paused it,” Angelica Poole told the BBC, calling for a permanent reversal of the decision.She said the situation was taking a toll on the family and they fear the deportation order could be revived.Grandmother-of-four Mrs Poole, who is from Macclesfield, Cheshire, applied for the right to remain in Sweden, where she moved almost two decades ago to be near her only son and his children.But her application was turned down in September 2022, despite the fact she is bedbound, has spent the last 10 years in a care home and has no family she is in contact with in the UK.The case has attracted significant media attention, and campaigners representing EU citizens living in the UK have expressed “grave concern”.MP Hilary Benn, former Brexit Select Committee chair, has urged the UK foreign secretary, James Cleverly, to intervene.Image source, Poole FamilyHer family say Mrs Poole’s application was turned down because she does not have a valid UK passport, which they argue she has not required for some time as she is unable to travel because of her poor health.They have been offered support to make a new application for a passport by the Foreign Office, Mrs Poole’s family told the BBC, but fear power of attorney arrangements in the UK mean they will be unsuccessful. “I don’t know where to go from here,” her daughter-in-law said.”A lot of British people are actually being sent back to the UK, which is not ok but they’re healthy. “She can not do anything. She’s bedridden. That’s what makes me angry. “They’re moving a sick person and her health can deteriorate even more by moving her.” Her family said they have been left confused by the update and renewed their pleas for the situation to be resolved permanently. On Tuesday, Sweden’s Minister of Migration, Maria Malmer Stenergard, said in a statement: “Decisions related to residence applications are applied directly by the Swedish state agencies and courts in line with the EU-UK Withdrawal Agreement.”As laid down in the constitution, the Swedish government is not permitted to interfere in or comment on individual decisions taken by these independent state bodies.”With regard to the case in question, I have been informed that the Swedish Migration Agency is in contact with the family concerning additional information.”More on this storyWoman with Alzheimer’s faces Swedish deportation1 day agoMy labour of love caring for wife with Alzheimer’s29 MarchBBC presenter with Alzheimer’s thanks listeners3 days ago

Scientists at St. Jude Children’s Research Hospital revealed that human ribosomes decode messenger RNA (mRNA) 10 times slower than bacterial ribosomes, but do so more accurately. The study, published today in Nature, used a combination of field-leading structural biology approaches to better understand how ribosomes work. The scientists pinpointed where the process slows down in humans, which will be useful information for developing new therapeutics for cancer and infections.
Ribosomes are molecular machines within cells, responsible for synthesizing proteins by decoding mRNA. By conducting mechanistic studies on bacterial and human ribosomes, researchers can understand their similarities and differences to develop drugs and understand disease. Many antibiotics, the drugs we use to treat bacterial infections, work by targeting bacterial ribosomes. In humans, changes in how accurately ribosomes decode mRNA have been linked to aging and disease, representing a potential point of therapeutic intervention. This gives the work implications for the treatment of infections and cancer.
“Bacteria have been very well studied for many decades, but the kind of studies that we do, careful mechanistic studies, have been missing on human ribosomes,” said corresponding author Scott Blanchard, Ph.D., St. Jude Department of Structural Biology. “We’re very interested in human ribosomes because those are what need to be targeted to find new treatments for cancer and viral infections such as COVID.”
Resolution revolution
Ribosomes decode mRNA using a molecule called aminoacyl-transfer RNA (tRNA) as substrate. The decoding process involves several different steps.
The researchers deployed methods such as single-molecule fluorescence resonance energy transfer (smFRET) and cryo-electron microscopy (cryo-EM) to examine the human ribosome decoding mechanisms. The single-molecule imaging gives the researchers information on how quickly things occur. So, in this case, how quickly human ribosomes go through the different steps during the decoding process. Cryo-EM gives the researchers structural information. So, how the human ribosome looks or what conformations (shapes) it is in at each step. By combining these two methods, the scientists get information on how quickly these processes occur in humans compared to bacteria as well as about the underlying structural causes for any differences they observe.

“We wanted to know how quickly a human ribosome can read the genetic code, how quickly it finds the tRNA that’s complementary to the mRNA,” said co-first author Mikael Holm, Ph.D., St. Jude Department of Structural Biology. “We found that the process is about 10 times slower for human ribosomes than it is in bacteria. But this slow down adds accuracy, because human ribosomes are known to be more accurate at translating the code than bacterial ribosomes.”
Specifically, the researchers found that while humans and bacteria both decode mRNA, the reaction pathway of aminoacyl-tRNA movement during the decoding process is different on human ribosomes and is significantly slower. These differences arise from structural elements in the human ribosome and in the human elongation factor, eEF1A, that together are responsible for faithfully incorporating the right tRNA for each mRNA codon (piece of the sequence). The distinct nature and timing of conformational changes within the ribosome and eEF1A may explain how human ribosomes achieve greater decoding accuracy.
“With our cryo-EM structural studies, we were able to resolve human ribosome structures to atomic resolution, which revealed unprecedented features such as rRNA and protein modifications, ions and solvent molecules present in the human ribosome,” said co-first author Kundhavai Natchiar, Ph.D., St. Jude Department of Structural Biology. “These features finely characterize the molecular basis of interactions of the drug molecules with the human ribosome, which is indispensable for human ribosome-based drug design and discovery.”
Caught in the act
The researchers also pinpointed exactly which step of the decoding process slowed down in human ribosomes. There are two steps in the process of the ribosome selecting the right tRNA: initial selection and proofreading selection. The second step, proofreading selection, is where the ribosome checks for a second time that it chose the right molecule. That is the step that is 10 times slower in humans than in bacteria.
Think of a gymnast, contorting themselves into different shapes on the mat as they work through their routine. This is similar to how ribosomes transition into various conformations to achieve different results. The research showed that a lot of conformational gymnastics that human ribosomes undergo are not present in bacterial ribosomes and are thus likely tied to the slowdown of the proofreading selection process.
The researchers also found that several drugs target the proofreading selection process, not initial selection. So, instead of hitting the step that is similar between humans and bacteria, these drugs focus on the most different, slowest step.
“In structural biology, a single snapshot of a macromolecular machine is not always sufficient to explain how it functions,” said co-first author Emily Rundlet, Ph.D., St. Jude Department of Structural Biology. “Often, the snapshot that’s needed to answer your biological question is not the most stable form of the molecule, but instead it is short-lived and difficult to capture. Using smFRET and cryo-EM together brings the dimension of time to structural biology, which allows us to visualize important transient intermediate steps of human decoding and understand the different mechanisms on a new level.”

Researchers at Simon Fraser University are studying the genes of superbugs to aid the development of new and effective treatments for drug-resistant bacterial infections. Superbugs are characterized as infection-causing bacteria resistant to treatment with antibiotics.
“Antimicrobial resistance occurs when the disease-causing bacteria has ways to overcome the antibiotics that we use in treatment for infections,” says assistant professor Amy Lee, of SFU’s Department of Molecular Biology and Biochemistry. The initiative is a collaboration between the Lee Lab and Brinkman Lab, which are working together as part of the interdisciplinary SFU Omics Data Science Initiative (OSDI). “Our lab tries to understand how bacteria develop resistance because that makes the drug ineffective,” says Lee.
Their review of work to identify pathogen-associated genes in various disease-causing bacteria and develop new antivirulence drug treatments has been published in eBioMedicine, part of The Lancet’s Discovery Science.
Antibiotic or antimicrobial resistance has been named a top global health threat by the World Health Organization (WHO).
“The ultimate goal of our research is to use current sequencing technologies and computational analysis to discover new drug targets, which can be used to develop new drugs to fight bacterial infections,” says SFU alumnus Venus Lau, the study’s lead author.
The team applied bioinformatics, using SFU’s Big Data Hub, to perform a computational analysis of thousands of bacterial genomes from Escherichia coli to Vibrio cholerae.

“The one bacteria species I was most interested in was Pseudomonas aeruginosa,” says Lau. “It is known to be naturally resistant to drugs based on their cell membranes.”
“Drugs don’t get into this bacterium easily and they tend to acquire other resistance mechanisms over time. It’s a difficult bug to treat.”
The bacterial species P. aeruginosa can cause infections in the blood, lungs (pneumonia) or other parts of the body, particularly in those who are ill or recovering from surgery in hospital.
Lau notes that some of the genes the team discovered through analyzing various disease-causing bacteria had not been previously characterized. “Part of our research was to figure out what these genes do and how they’re responsible for causing disease and infection symptoms in humans.”
Antivirulence over antibiotics to treat bacterial infections
An alternative approach to treating bacterial infections with antibiotics to overcome the issue of drug resistance involves antivirulence drugs.

New antivirulence therapies work to ‘disarm’ or inhibit the ability of the bacteria to cause disease without causing resistance to develop. In contrast, antibiotics kill bacteria, which essentially encourages the bacteria to ‘fight back’ by developing drug resistance.
“Antibiotics wipe out bacteria leading to a process of natural selection where those few surviving bacteria in the population will then repopulate,” says SFU molecular biology and biochemistry postdoctoral fellow Patrick Taylor. “The bacteria that are not killed off are really good at sharing their genetics with each other, which is why we have this rising global issue of antibiotic resistance.”
Antibiotics also eliminate non-disease-causing gut microbiota, or the ‘good bacteria’ that exists in the human body, which can have additional negative health impacts.
Taylor says antivirulence therapeutics can mitigate disease and reduce the burden on the healthcare system by reducing the bacteria’s ability to cause damage to the host, which provides time for the person’s immune system to clear the pathogen.
Continued work towards developing antivirulence drugs is needed as the WHO estimates that antimicrobial-related infections currently account for over 700,000 annual deaths and are projected to reach 10 million annual deaths by 2050.

Feeling like we have a degree of control makes us tolerate pain better. In the case of fibromyalgia, however, this simply doesn’t work. A study provides clues as to why.
Fibromyalgia is a mysterious chronic pain disorder that is difficult to treat. Its causes are also still largely in the dark.
A study conducted by the team at the Clinic for Psychosomatic Medicine and Psychotherapy at Ruhr University Bochum, Germany, provides evidence that certain brain areas involved in processing pain don’t function normally in fibromyalgia patients. In healthy people, they ensure that pain that we can control is easier to bear. The study found that these brain areas showed altered activity in patients with fibromyalgia. The research team headed by Professor Martin Diers published their findings in the journal NeuroImage: Clinical of 21 February 2023.
Controlling the off switch for heat pain
The degree to which we experience pain and the restriction caused by it depend largely on how we perceive it. If we have the feeling that we can control the pain and shut it down ourselves, for example, we will tolerate it better than if we feel at its mercy. “For people with chronic pain, the inability to control repeated attacks of pain is one of the most significant causes of impaired quality of life,” explains Benjamin Mosch, lead author of the study. “And yet, the underlying neural mechanisms have so far mainly been studied in healthy controls.”
In the current study, the team compared two female cohorts: 21 healthy participants and 23 fibromyalgia patients. Both groups were exposed to heat pain while their brain activities were monitored by functional magnetic resonance imaging. In one experimental run, the participants were able to stop the pain stimulus themselves. In another run, a computer controlled the start and end of the stimulus. “We kept the duration of the stimuli terminated by the computer the same on average as the stimuli terminated by the test subjects,” says Martin Diers.
Cognitive resources are impaired
When women in the healthy control group were able to terminate the pain stimulus themselves, a number of mainly frontal brain areas were activated that seem to play an important role in modulating pain. This observation is consistent with previous studies involving healthy subjects. “Interestingly, however, we didn’t detect any such activations in our patient group,” points out Martin Diers. “This can serve as evidence for impaired pain processing among patients with fibromyalgia. It indicates that the cognitive resources for dealing with acute pain are impaired in these patients.”
Fibromyalgia
Fibromyalgia was added to the World Health Organisation’s catalogue in 1994. An estimated two per cent of the German population is affected, 90 per cent of them are women. The disorder is characterised by recurring pain as well as various other symptoms, including sleep disturbances, depressive moods, chronic fatigue and digestive problems. On average, it takes 16 years before a diagnosis is made.

Chemotherapy treatments produce strong side effects. A new agent that accumulates in the tumour tissue and is activated there by ultrasound waves does not have this problem.
Platinum complexes are among the most commonly used drugs against cancer. They are successful, but have severe side effects. An international research team led by Dr. Johannes Karges from the Faculty of Chemistry and Biochemistry at Ruhr University Bochum, Germany, has developed a complex that accumulates in tumour tissue and is activated there by ultrasound waves. Its cell-damaging effect thus only unfolds where it is actually wanted. “Where previous studies relied on light activations that can only penetrate a few millimetres deep into the tissue, we have now developed a treatment method with ultrasound activation that penetrates several centimetres deep into the body,” says Karges. This could make treatment with few side effects possible even for large and deep-seated tumours. The researchers published their results in the journal Angewandte Chemie International Edition of 24 March 2023.
Harmless in healthy tissue
The platinum(II) complexes cisplatin, oxaliplatin and carboplatin are among the most commonly used cancer drugs. Their clinical success is offset by severe side effects, such as nausea, vomiting, kidney damage and bone marrow suppression. To overcome these limitations, major research efforts have been invested in the development of so-called platinum(IV) complex prodrugs over the past decades. “These prodrugs are stable and inactive, so they are completely harmless,” explains Johannes Karges. “In healthy tissue, they are supposed to stay that way. In cancer tissue, however, they should be rapidly converted into the therapeutically active platinum(II) complexes.”
Energy is required for the reduction of the metal complex. Previous studies reported activation with ultraviolet, blue or red light. “The problem is that light can only penetrate less than a centimetre deep into the body and thus does not reach many tumours,” explains Johannes Karges. To overcome this limitation, his team has for the first time combined platinum(IV) complex prodrugs with sonosensitizers that can be selectively activated with ultrasound irradiation.
Nanoparticles accumulate in the tumour
To develop a therapeutically effective complex, the researchers encapsulated the platinum(IV) complex prodrugs and the sonosensitizers together in haemoglobin to form nanoparticles. “We were able to observe that the nanoparticles selectively accumulated in a mouse intestinal tumour after injection into the bloodstream, thus supporting targeted treatment,” reports Johannes Karges. “After irradiation with ultrasound, the platinum(IV) prodrug was activated at the tumour site, triggering the release of cisplatin, which is toxic to cells, and almost completely eradicating the tumour.”
Advantages of ultrasound
These results could pave the way for the development of novel techniques and agents for the treatment of very large or deep-seated tumours. Ultrasound can penetrate more than an order of magnitude deeper into tissue than near-infrared light. In addition, ultrasound treatments are generally considered to be less invasive and easy to use. Another advantage is that hospitals are usually already equipped with the necessary equipment. “Our work is still fundamental research,” Johannes Karges emphasises. “Whether and when treatments based on this can be offered in clinical practice is not yet foreseeable.”

A recent study, published in Neuropsychopharmacology, conducted by researchers from the University of Helsinki and the University of Eastern Finland, sheds light on the mechanisms of neural plasticity induced by the antidepressant fluoxetine.
Previous research by the same team showed that chronic treatment with antidepressants increased neural plasticity through direct binding to neurotrophic receptor TrkB, but the mechanism of relevant neural circuits remained unknown.
In the current study, the researchers conducted a classical fear conditioning paradigm with mice and discovered that fluoxetine facilitated the erasure of learned fear responses, as well as decreased the spontaneous reactivation of these responses. Additionally, the mice exhibited faster learning of spatial patterns in pairwise tests when treated with fluoxetine, particularly when the task was reversed. However, the effects were diminished or absent in mice with lower TrkB receptor expression in their PV+ interneurons, an important class of GABAergic inhibitory neurons, responsible for regulating the activity of excitatory neurons and playing a crucial role in various functions, such as cognitive processes and memory.
The researchers also analyzed gene expression specifically in PV+ interneurons following fluoxetine treatment. They found changes related to GABAergic synapses, axon guidance, and enzymes involved in the formation of perineuronal net (PNN), an extracellular matrix surrounding PV+ interneurons, which plays a role in regulating neuronal plasticity. Moreover, they observed a decrease in the number of PV+ interneurons with PNN and a reduction in the intensity of PNN following fluoxetine treatment, indicating enhanced plasticity of PV+ interneurons. However, this effect was attenuated in mice with lower TrkB receptor expression in PV+ interneurons.
The results of the study suggest that the TrkB receptor in PV+ interneurons is primarily responsible for the increased reversal learning observed with fluoxetine treatment. These findings may offer new perspectives for the development for psychiatric diseases and pave the way for new medications targeting brain plasticity via PV+ interneurons.
The study was carried out by Professor Eero Castren’s research group at the University of Helsinki and Docent Juzoh Umemori at the University of Eastern Finland.

In a twist on the question, “Which came first, the chicken or the egg?,” scientists have long faced a similar question about how human adenovirus replicates: “Which comes first, assembly of the viral particle, or packaging of the viral genome?” Now, in a new study published today in Nature, researchers at Children’s Hospital of Philadelphia (CHOP) have answered that question, showing that viral proteins use a process called phase separation to coordinate production of viral progeny.
“This study answers a fundamentally important question: how a viral nucleic acid gets inside a particle so that viral offspring can be delivered to cells,” said Matthew Charman, PhD, a research associate in the Weitzman Lab at Children’s Hospital of Philadelphia. “These findings have broad implications, from potential therapeutic interventions to improved gene therapy delivery, in addition to expanding our understanding of basic cell biology.”
Viruses hijack host cellular processes to replicate and produce infectious offspring that are key for viral spread and transmission. To do so, they must both replicate their viral genomes and package those genomes into viral particles, so that the infectious cycle can continue. However, little is known about how genome replication, particle assembly, and genome packaging are coordinated in the crowded nuclear environment.
“If we think of viral replication as an old-fashioned milk assembly line, we know how the milk bottles are formed and that they come out filled, but prior to this study, the process of filling them was somewhat of a black box,” said senior author Matthew D. Weitzman, PhD, a professor in CHOP’s Department of Pathology and Laboratory Medicine. “Our findings suggest that the viral particle forms around the viral genome. Extending the analogy, many have assumed that the bottle must be made before being filled, but it turns out the bottle is actually formed around the milk. Led by Dr. Charman, we have shown that a biophysical process known as phase separation allows this process to occur in an orderly, coordinated fashion.”
Emerging evidence suggests that membraneless compartments form inside virus-infected cells by phase separation. These membraneless compartments, known as biomolecular condensates (BMCs), can regulate biological processes by concentrating or sequestering biomolecules in an enriched dense phase, while limiting their concentration in the light phase. Although BMCs have been linked to several viral processes, there was insufficient evidence that phase separation contributes functionally to the assembly of infectious viral offspring in infected cells.
To investigate the potential role of BMCs in this process, the researchers studied adenovirus, a nuclear-replicating DNA virus. Because the adenovirus proteins involved in genome replication are distinct from those involved in particle assembly and genome packaging, the researchers reasoned focusing on this virus would allow them to dissect and more easily identify the role of phase separation in specific viral processes.
Through a variety of techniques, including homopropargylglycine (HPG) labeling and fluorophore click chemistry, the researchers demonstrated that the adenovirus 52 kDa protein — a dedicated assembly/packaging protein — makes its own membraneless structures through phase separation and plays a critical role in the coordinated assembly of new infectious particles. They showed that not only does the 52 kDa protein organize viral capsid proteins into nuclear BMCs, but also that this organization is essential for the assembly of complete, packaged particles containing viral genomes.
Additionally, the researchers performed experiments with a mutant adenovirus lacking the 52 kDa protein and showed that incomplete capsids formed in the absence of viral BMCs. Thus, the researchers were able to show that by altering the formation of these membraneless structures within the cell, the “assembly line” producing viral offspring no longer functioned properly.
“Now knowing these steps, the question becomes: could we reengineer viruses based on this biological process to, for example, become better delivery vehicles for innovations like gene therapy?” Dr. Charman said. “Understanding how viruses are made opens up a world where we could not only potentially target those viruses more effectively in the future but also create gene therapy tools that lack the limitations of current delivery approaches.”
This research was supported by NIAID grants R01-AI145266 and R01-AI121321.