Publisher Health

Contrary to the commonly-held view, the brain does not have the ability to rewire itself to compensate for the loss of sight, an amputation or stroke, for example, say scientists from the University of Cambridge and Johns Hopkins University.
Writing in eLife, Professors Tamar Makin (Cambridge) and John Krakauer (Johns Hopkins) argue that the notion that the brain, in response to injury or deficit, can reorganise itself and repurpose particular regions for new functions, is fundamentally flawed — despite being commonly cited in scientific textbooks. Instead, they argue that what is occurring is merely the brain being trained to utilise already existing, but latent, abilities.
One of the most common examples given is where a person loses their sight — or is born blind — and the visual cortex, previously specialised in processing vision, is rewired to process sounds, allowing the individual to use a form of ‘echolocation’ to navigate a cluttered room. Another common example is of people who have had a stroke and are initially unable to move their limbs repurposing other areas of the brain to allow them to regain control.
Krakauer, Director of the Center for the Study of Motor Learning and Brain Repair at Johns Hopkins University, said: “The idea that our brain has an amazing ability to rewire and reorganise itself is an appealing one. It gives us hope and fascination, especially when we hear extraordinary stories of blind individuals developing almost superhuman echolocation abilities, for example, or stroke survivors miraculously regaining motor abilities they thought they’d lost.
“This idea goes beyond simple adaptation, or plasticity — it implies a wholesale repurposing of brain regions. But while these stories may well be true, the explanation of what is happening is, in fact, wrong.”
In their article, Makin and Krakauer look at a ten seminal studies that purport to show the brain’s ability to reorganise. They argue, however, that while the studies do indeed show the brain’s ability to adapt to change, it is not creating new functions in previously unrelated areas — instead it’s utilising latent capacities that have been present since birth.
For example, one of the studies — research carried out in the 1980s by Professor Michael Merzenich at University of California, San Francisco — looked at what happens when a hand loses a finger. The hand has a particular representation in the brain, with each finger appearing to map onto a specific brain region. Remove the forefinger, and the area of the brain previously allocated to this finger is reallocated to processing signals from neighbouring fingers, argued Merzenich — in other words, the brain has rewired itself in response to changes in sensory input.

Not so, says Makin, whose own research provides an alternative explanation.
In a study published in 2022, Makin used a nerve blocker to temporarily mimic the effect of amputation of the forefinger in her subjects. She showed that even before amputation, signals from neighbouring fingers mapped onto the brain region ‘responsible’ for the forefinger — in other words, while this brain region may have been primarily responsible for process signals from the forefinger, it was not exclusively so. All that happens following amputation is that existing signals from the other fingers are ‘dialled up’ in this brain region.
Makin, from the Medical Research Council (MRC) Cognition and Brain Sciences Unit at the University of Cambridge, said: “The brain’s ability to adapt to injury isn’t about commandeering new brain regions for entirely different purposes. These regions don’t start processing entirely new types of information. Information about the other fingers was available in the examined brain area even before the amputation, it’s just that in the original studies, the researchers didn’t pay much notice to it because it was weaker than for the finger about to be amputated.”
Another compelling counterexample to the reorganisation argument is seen in a study of congenitally deaf cats, whose auditory cortex — the area of the brain that processes sound — appears to be repurposed to process vision. But when they are fitted with a cochlear implant, this brain region immediately begins processing sound once again, suggesting that the brain had not, in fact, rewired.
Examining other studies, Makin and Krakauer found no compelling evidence that the visual cortex of individuals that were born blind or the uninjured cortex of stroke survivors ever developed a novel functional ability that did not otherwise exist.
Makin and Krakauer do not dismiss the stories of blind people being able to navigate purely based on hearing, or individuals who have experienced a stroke regain their motor functions, for example. They argue instead that rather than completely repurposing regions for new tasks, the brain is enhancing or modifying its pre-existing architecture — and it is doing this through repetition and learning.
Understanding the true nature and limits of brain plasticity is crucial, both for setting realistic expectations for patients and for guiding clinical practitioners in their rehabilitative approaches, they argue.
Makin added: “This learning process is a testament to the brain’s remarkable — but constrained -capacity for plasticity. There are no shortcuts or fast tracks in this journey. The idea of quickly unlocking hidden brain potentials or tapping into vast unused reserves is more wishful thinking than reality. It’s a slow, incremental journey, demanding persistent effort and practice. Recognising this helps us appreciate the hard work behind every story of recovery and adapt our strategies accordingly.
“So many times, the brain’s ability to rewire has been described as ‘miraculous’ — but we’re scientists, we don’t believe in magic. These amazing behaviours that we see are rooted in hard work, repetition and training, not the magical reassignment of the brain’s resources.”

A collaboration of researchers, led by UCL and Great Ormond Street Hospital, have published successful results from a Phase II clinical trial for the treatment of BRAF mutated low-grade paediatric gliomas.
Gliomas are cancerous brain tumours that start in glial cells — the supporting cells of the brain.
The results from the TADPOLE-G study, published in the New England Journal of Medicine and the Journal of Clinical Oncology, are the first to demonstrate a clear clinical benefit of combining the therapies of Dabrafenib and Trametinib (Novartis) in BRAF mutated low- and high-grade paediatric gliomas respectively.
For children with paediatric low-grade gliomas, the normal course of treatment is a full surgical removal. However, for children where this is not possible, additional treatments like chemotherapy are required. These patients often experience multiple relapses, further disease progression and serious side effects.
In the randomised trial, 73 children with BRAF mutated low-grade gliomas (BM-LGG) were treated with Dabrafenib and Trametinib. Their outcomes were compared to 37 patients who were treated with standard chemotherapy drugs.
Researchers found that the combination therapy lessened chemotherapy side effects, it also improved overall response rate by over four-fold and increased median progression free survival from 7.4 months with chemotherapy to 20.1 months with the new treatment.
The new research follows on from the publication of results from the same study in patients with BRAF mutated high-grade gliomas (BM-HGG).

Children with high-grade gliomas often undergo full surgical resections, followed by radiotherapy and chemotherapy. Unfortunately, overall, less than one in five children respond well to treatment and two-year survival is less than 35%, with many patients’ cancer returning.
41 children who had previously received treatment for their BM-HGG took part in the second study. The treatment led to 56% of patients responding to treatment overall — a significant improvement compared to previous chemotherapy trials — and a median duration of response of 22.2 months.
The study leaders say that these trials demonstrate a clear clinical benefit of the dual treatment, with the recommendation being that it become a first-line treatment for BM-LGG and a clinical option for those with relapsed/refractory BM-HGG.
Evidence from these trials is now being used as part of a NICE scoping review* to appraise the clinical and cost effectiveness of the treatments. The US Food and Drug Administration have already approved the treatment** for children with low-grade glioma.
Professor Darren Hargrave (UCL Great Ormond Street Institute of Child Health and GOSH), said: “The results of these studies highlight how targeted drug therapies can offer patients new treatment avenues that not only improve outcomes but reduce the side effects often associated with cancer therapies.”
Mutations in the BRAF gene were first identified as drivers of cancer in the early 2000s and now targeted therapies such as Dabrafenib and Trametinib are being used to treat melanoma and non-small cell lung cancer in patients with mutations in the BRAF gene.

The BRAF mutation is present in around 15-20% of paediatric low-grade gliomas and around 5-10% of high-grade gliomas in children. These studies are the first to investigate the effectiveness of the combination therapy in paediatric gliomas.
Professor Hargrave chaired the TADPOLE-G Clinical Trial Steering group and led recruitment at GOSH for both this trial and the earlier Phase I arm of the trial.
He said: “It has been incredible to watch research move our ability to treat specific cancers forward at such a rapid pace. I was involved in the original study that identified BRAF gene mutations as drivers of cancer and so it has been fantastic to now be able to see treatments that target the mutation in clinical trials for paediatric gliomas.
“These studies demonstrate the power of collaborative, global research to find new treatments for rare cancers. We’d like to thank all the patients and families who make research like this possible.”
Paediatric gliomas, although the most common type of brain tumour, are still rare, especially when divided into specific molecular subtypes such as BRAF mutated tumours. Global collaboration is therefore essential to achieve timely and scientifically significant results, which led the TADPOLE-G study to enrol patients from 58 sites in 20 countries.
Gerrit Zijlstra, Chief Medical Officer, Novartis UK, said: “New treatments that help improve outcomes and reduce side effects for young patients living with BRAF V600 low- and high-grade gliomas address unmet patient need, where treatment options are very limited.
“We welcome the results of the TADPOLE-G clinical trial and are humbled to be a part of an international scientific community effort in developing targeted therapies based on the unique genetic features of a patient’s tumour.”
* https://www.nice.org.uk/guidance/indevelopment/gid-ta11006
** https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-dabrafenib-trametinib-pediatric-patients-low-grade-glioma-braf-v600e-mutation

To age or not to age! How does aging affect organisms on a cellular level? What mechanisms help cells survive self-inflicted or external harm? It is known that lysosomes — critically important cellular structures — are crucial for digesting damaged cellular components and pathogens, and maintain stability within cells and tissues. But can they also be repaired, and if so, how?
In a study published this month in EMBO Reports, researchers from Osaka University and Nara Medical University have shown that damaged lysosomes are repaired by a mechanism called “microautophagy” and have identified two key regulators of this process.
Microautophagy is one of the three main types of autophagy in most higher organisms. It is a regulated process by which cellular components that have become dysfunctional or are no longer required are broken down. Although it is assumed to be involved in defense mechanisms collectively called lysosomal damage responses, the details remain unknown.
Lysosomes frequently become damaged and lysosomal dysfunction has been linked to accelerated aging and a shortened lifespan. In this study, the researchers tried to understand the repair mechanisms. To identify a novel regulator of lysosomal damage response, they focused a signaling pathway called Hippo pathway which controls multiple processes such as cellular growth. They knocked down individual components of the Hippo pathway in the human cells, and then observed whether the cells could respond to induced lysosomal damage. This screening revealed that a protein called Serine-threonine kinase 38 (STK38) is essential for the lysosomal damage response.
They then found that STK38 works with a protein complex called the “endosomal sorting complex required for transport (ESCRT) machinery,” which was already known to be linked to lysosomal repair. “STK38 recruits the protein ‘vacuolar protein sorting 4’ (VPS4) to damaged lysosomes and is crucial for disassembling the ESCRT machinery at the end of the repair process,” explains lead author of the study Monami Ogura. They further found that lysosomal membrane repair by ESCRT machinery is mediated by microautophagy.
They also identified that non-canonical lipidation of a subfamily of autophagy-related protein 8 (ATG8s) molecules — the key autophagy proteins — known as Gamma-aminobutyric acid receptor-associated proteins (GABARAPs) is required for this process. Lipidation, the process of modifying ATG8s with lipid extensions, is the main process involved in autophagy. In non-canonical lipidation ATG8s are lipidated into single-membrane endolysosomes, instead of double-membrane phagophore seen in canonical lipidation.
The researchers showed that the GABARAPs are essential for the first step of the process of lysosomal repair. “We showed that non-canonical lipidation of ATG8s is crucial for the initial recruitment of the ESCRT machinery to damaged lysosomes and their subsequent repair,” explains senior author Shuhei Nakamura.
The team showed that depletion of the regulators of microautophagy increased the rate of senescent cells and shortened lifespan in C. elegans. Both STK38 and GABARAPs also have evolutionarily conserved roles, indicating the significance of this pathway in maintaining lysosomal integrity, healthy cellular function, and the prevention of cellular senescence and organismal aging. The detailed understanding provided by this study paves the way for increasing healthy aging and has great therapeutic value for the treatment of age-related diseases.

Infections with antibiotic-resistant bacteria are a growing global problem. Part of the solution may lie in copying the bacteria’s own weapons. The research environment in Tromsø has found a new bacteriocin, in a very common skin bacterium. Bacteriocin inhibits the growth of antibiotic-resistant bacteria that are often the cause of disease and can be difficult to treat.
One million deaths each year
The fact that we have medicines against bacterial infections is something many people take for granted. But increasing resistance among bacteria means that more and more antibiotics do not work. When the bacteria become resistant to the antibiotics we have available, we are left without a treatment option for very common diseases. Over one million people die each year as a result of antibiotic resistance.
The first step in developing new antibiotics is to look for substances that inhibit bacterial growth.
Sami name for an exciting discovery
The research group for child and youth health at UiT The Arctic University of Norway has studied substances that the bacteria themselves produce to inhibit the growth of competitors. These substances are called bacteriocins. Through the work, they have discovered a new bacteriocin, in a very common skin bacterium. Bacteriocin inhibits the growth of antibiotic-resistant bacteria that can be difficult to treat with common antibiotics.
The researchers have called the new bacteriocin Romsacin, after the Sami name for Tromsø, Romsa. The hope is that Romsacin can be developed into a new medicine for infections for which there is currently no effective treatment.

Long way to go
At the same time, researcher Runa Wolden at the Department of Clinical Medicine at UiT emphasizes that there is a long way to go before it is known whether Romsacin will be developed and taken into use as a new medicine. Because that’s how it is with basic research; you cannot say in advance when someone will make use of the results you produce.
“This discovery is the result of something we have been researching for several years. Developing Romsacin — or other promising substances — into new antibiotics is very expensive and can take 10-20 years,” says Wolden, who is part of the The research group for child and youth health.
Effective against bacterial types
Before new antibiotics can be used as medicines, one needs to make sure that they are safe to use. Currently, researchers do not know how the bacteriocin works in humans. A further process will involve comprehensive testing, bureaucracy and marketing.
“This naturally means that there is a long way to go before we can say anything for sure. What we already know, however, is that this is a new bacteriocin, and that it works against some types of bacteria that are resistant to antibiotics. It’s exciting,” says Wolden.

The new bacteriocin is produced by a bacterium called Staphylococcus haemolyticus. The bacteriocin is not produced by all S. haemolyticus, but by one of the 174 isolates that the researchers have available in the freezer.
“We couldn’t know that before we started the project, and that’s one of the things that makes research fun,” says Wolden.
She says that ten years ago the researchers collected bacterial samples from healthy people when they wanted to compare S. haemolyticus in healthy people with those found in patients in hospital.
“Subsequently, we have done many experiments with these bacteria, and this is the result from one of our projects,” says Runa Wolden.

Investigators at the University of Kansas have played a key role in deciphering a previously unidentified cluster of genes responsible for producing sartorypyrones, a chemical made by the fungal pathogen Aspergillus fumigatus, whose family causes Aspergillosis in humans.
Their findings recently were published as the cover story of the peer-reviewed journal Chemical Science, the flagship journal of the Royal Society of Chemistry.
Aspergillosis threatens the life of more than 300,000 people each year. A better understanding of the genes responsible for the chemicals — or “secondary metabolites” — produced by A. fumigatus and its fungal cousins could help researchers develop more effective antifungal drugs.
“Fungal infections pose a significant challenge and have garnered increased attention in the media, including scientific reports,” said corresponding author Berl Oakley, Irving S. Johnson Distinguished Professor of Molecular Biology at KU. “Among the problematic organisms is a fungus known as Aspergillus fumigatus. The majority of individuals afflicted with severe pathogenic fungal infections fall into the category of immunocompromised, such as individuals undergoing cancer treatment or those living in sub-Saharan Africa, where a significant number of people that are affected by AIDS aren’t getting medication.”
Oakley and his co-authors were interested in how Aspergillus fumigatus produced secondary metabolites, which often are considered for their medicinal potential — even though they can be tough to study in the lab — because they’re so biologically active.
“Studies have identified numerous gene clusters in fungi responsible for producing these metabolites,” he said. “But these compounds aren’t typically produced under standard laboratory conditions, leaving many of their properties uncharted. These metabolites, while not essential for an organism’s growth, offer selective advantages. They can protect against factors like UV radiation and inhibit competitive species. Some of these secondary metabolites exhibit bioactivities beneficial for various purposes. Others contribute to pathogenic effects, including immune system suppression.”
To isolate and analyze the genes in Aspergillus fumigatus that express secondary metabolites, the team transferred a group of these genes — called a biosynthetic gene cluster (BGC) — to a related strain of Aspergillus, A. nidulans, then activated them. A. nidulans has been modified by researchers to be a model fungal species for this technique, dubbed “heterologous expression.”
“We then can observe the compounds they produce in the lab,” Oakley said. “In one instance, a gene cluster revealed the synthesis of sartorypyrones, a group of compounds with limited prior knowledge of their production.”

The research team named the gene cluster responsible for these compounds the “spy BGC” (spy standing for sartorypyrones). They analyzed the compounds produced by the spy BGC using high-resolution electrospray ionization mass spectrometry, nuclear magnetic resonance and microcrystal electron diffraction (MicroED) to identify 12 chemical products from the spy BGC.
Oakley led the work with longtime collaborator and corresponding author Clay C.C. Wang of the University of Southern California. At KU, Oakley carried out the investigation with C. Elizabeth Oakley and doctoral student Cory Jenkinson. Other co-authors were Shu-Yi Lin and Paul Seidler from USC; Yi-Ming Chiang from Taipei Medical University; Ching-Kuo Lee, Christopher Jones and Hosea Nelson from the California Institute of Technology; and Richard Todd from Kansas State University
They report seven of the compounds had not been isolated previously.
“The spy BGC consists of six contiguous genes involved in the biosynthesis of the sartorypyrones,” they report. “We were able to propose a biosynthetic pathway for this family of compounds. Our approach of refactoring the entire gene cluster in the dereplicated A. nidulans host system provides us with a straightforward way to dissect the biosynthetic pathway.”
Oakley said the same technique could lead to more breakthroughs in understanding A. fumigatus and other fungal pathogens. The results could lead to new therapies for fungal infection as well as eco-friendly industrial uses. For instance, one of Oakley’s other lines of research used genetically modified A. nidulans to convert ocean plastics into raw materials for the pharmaceutical industry.
He said the current paper reflects a proof-of-principle.

“We would like to express the remaining secondary metabolite gene clusters so we know what each one makes,” he said. “We know what 15 or so of them make already. We know that it’s a serious pathogen, and we know some of the secondary metabolites that contribute to pathogenesis. But we don’t know all of the secondary metabolite gene clusters. If we figure them out, then researchers can use that information therapeutically to understand the mechanisms of infection and figure out ways to limit infection.”
However, Oakley cautioned the economic realities of manufacturing antifungal medications could hamper the rapid development of new drugs.
“We need more antibiotics and more antifungals,” he said. “But they’re not profitable. A profitable compound is something that they can give to people for 30 years, not something you give for a week that solves the problem. So there’s not much financial incentive. You can come up with the best antibiotic in the world, they’re going to sit it on the shelf because it’s going to be the last resort, and they’re only going to use it when the other ones don’t work.”

Scientists have identified the genes in the probiotic Bifidobacteria longum responsible for improving gut motility. A research team reporting November 21st in the journal Cell Host & Microbe found that B. longum strains possessing the abfA cluster of genes can ameliorate constipation through enhanced utilization of an indigestible fiber called arabinan in the gut.
“We established the causal link between a genetic variant — the abfA cluster — to the key functional difference of probiotic B. longum in multiple model organisms, including mice and humans, and provided mechanistic and ecological insights into how a single gene cluster can affect the gut motility of hosts through arabinan metabolism,” says Qixiao Zhai of Jiangnan University, one of the paper’s co-senior authors. Constipation is a globally prevalent bowel disorder with a worldwide prevalence of 10% to 15%. Impaired gastrointestinal motility has been implicated in gut microbial dysbiosis, which is characterized by a significant decrease in the abundance of beneficial microorganisms, some of which are conventionally known as probiotics. Orally administrated probiotics have therefore been widely used to alleviate symptoms.
Yet the therapeutic effect of probiotics for constipation often varies substantially across strains within the same species. Due to elusive mechanisms, the rational choice of probiotic remains challenging for medical care professionals and patients. In addition, most evidence on the beneficial effects of probiotics on gut motility mainly emerged from studies using a mouse model.
“Probiotic strains were often effective in animal models yet failed in human clinical trials or were poorly validated in humans,” says Jiachao Zhang of Hainan University, the study’s second co-senior author. “Proof-of-concept studies based on a human cohort in combination with evidence from animal studies are urgently needed for translational research.”
Zhai, Zhang, and Shi Huang of the University of Hong Kong, the paper’s third co-senior author, set out to identify and systematically validate the key genetic factors of exogenous probiotics or resident gut microbiota affecting gastrointestinal motility. They isolated 185 B. longum strains from 354 Chinese subjects who ranged in age from 0 to 108 years.
From a comprehensive library of wild B. longum strains, they discovered that the effective alleviation of constipation in mice is regulated by the abfA cluster. This key genetic factor preferentially enhances the utilization of arabinan — a common constituent of plant polysaccharides, an indigestible fiber for humans, and a poorly accessible source of nutrients for normal gut microbes.
The researchers further validated the abfA cluster’s functional roles using gene-knockout experiments. In mice with constipation, B. longum, but not an abfA mutant, improved gastrointestinal transit time — an effect that was dependent upon dietary arabinan.

To establish its functional roles for ameliorating constipation in humans, the researchers used a clinical trial and a human-to-mouse fecal microbiota transplantation experiment in combination with metagenomics and metabolomics. In the double-blind, randomized, placebo-controlled clinical trial, supplementation with abfA-cluster-carrying B. longum, but not an abfA-deficient strain, enriched arabinan-utilization residents, increased beneficial metabolites, and improved constipation symptoms.
Across human cohorts, abfA-cluster abundance in the fecal microbiomes predicted constipation, and transplantation of abfA cluster-enriched human microbiota to mice with constipation improved gut motility. Notably, other than B. longum, the abfA gene/cluster is prevalent in gut residents, regulating symptoms in both mice and humans.
The authors say that the abfA cluster is a gut-microbiome therapeutic target for constipation in humans. More broadly, the results suggest that genetic factors governing the unique metabolic capability of probiotics should be primarily considered for screening probiotics or inferring their treatment efficacy for gastrointestinal diseases.
“Collectively, this study identified and systematically characterized a key genetic factor responsible for arabinan utilization that addressed one critical challenge in the probiotic field, namely widespread yet unknown strain specificity in probiotic treatment efficacy,” Huang says. “Our proof-of-concept study also established generalizable principles for the rational development of colonizable, functional probiotics with persistent treatment efficacy in multiple model organisms. Moreover, the abfA cluster is so prevalent in the gut microbiota that it can be developed as a simple yet powerful biomarker for gastrointestinal diseases.”
This work was supported by the National Natural Science Foundation of China.

Forensic science has captured the public imagination by storm, as the profusion of “true crime” media in the last decade or so suggests. By now, most of us know that evidence left at a crime scene, such as blood, can often reveal information that is key to investigating and understanding the circumstances around a crime — and that scientific methods can help interpret that information.
In Physics of Fluids, by AIP Publishing, a group of scientists from Boston University and the University of Utah demonstrated how bloodstains can yield even more valuable details than what is typically gathered by detectives, forensic scientists, and crime scene investigators. By examining the protrusions that deviate from the boundaries of otherwise elliptical bloodstains, the researchers studied how these “tails” are formed.
“These protrusions are typically only used to get a sense of the direction that the drop traveled, but are otherwise neglected,” said author James Bird.
In fact, previous studies have primarily focused on larger blood drops falling vertically on flat surfaces or on inclined surfaces where gravity can reshape and obscure the tails. By contrast, the new study involved a series of high-speed experiments with human blood droplets with diameters of less than a millimeter impacting horizontal surfaces at various angles.
“We show that the precise flow that determines the tail length differs from the flow responsible for the size and shape of the elliptical portion of the stain,” said Bird. “In other words, the tail lengths encompass additional independent information that can help analysts reconstruct where the blood drop actually came from.”
Indeed, the tail length can reflect information about the size, impact speed, and impact angle of the blood drop that formed the stain. When measured for several blood stains in a stain pattern, the trajectories of the drops can be backtracked to their presumed origin.
While their analysis employed only horizontal surfaces to examine impact velocity dynamics, Bird and his colleagues hope it triggers more studies that focus on the length of the tail in bloodstain patterns. They believe that incorporating tail length into standard bloodstain analyses will produce more robust evidentiary information.
“Knowing the origin of the blood stains at a crime scene can help detectives determine whether a victim was standing or sitting, or help corroborate or question a witness’s testimony,” said Bird.

Scientists have engineered a living material resembling human phlegm, which will help them to better understand how a certain kind of infection develops on the lungs of patients with cystic fibrosis.
The study, published in Matter, was led by Dr Yuanhao Wu and is a collaboration between Professor Alvaro Mata in the School of Pharmacy and Department of Chemical Engineering and Professor Miguel Cámara from the National Biofilms Innovation Centre in the School of Life Sciences at the University of Nottingham.
Biofilms are strong living 3D materials that play key roles in nature, but also cause major problems in the real world, such as in the contamination of hospital surfaces, or in our tolerance to antibiotic treatment.
One of the biggest challenges in antimicrobial discovery is the lack of biofilm models which reflect the complexity of natural environments, such as those encountered in the lung of cystic fibrosis (CF) patients.
Due to a genetic alteration, these patients are unable to clear infections in their lungs where complex communities of disease-causing microbes accumulate within thick mucus forming 3D biofilms. These natural biofilms are highly resilient to antibiotics and there is a critical need to develop in vitro models which can reliably reproduce them in the lab, so that experts can better understand their biology and develop solutions to the problems they cause.
This will enable a more consistent evaluation of novel therapeutic interventions before being taking into pre-clinical studies. These models will also be key to answering fundamental research questions on the interactions polymicrobial biofilms and their host which lead to chronic infections.
In this study, experts engineered a living material resembling natural sputum, or phlegm, from CF patients that can grow 3D polymicrobial biofilms in a controlled manner, resembling those found in the CF lung. The team were able to achieve this by combining peptides with a culture medium that is known to recreate natural sputum and which can be easily infected.

The living material incorporates multiple microbial communities and key nutritional and chemical factors that promote bacterial growth and exhibit physical properties mimicking those of biofilms from CF sputum. The material has been used to build an infected in vitro lung epithelial model that was used to study the impact of antibiotics.
Professor Mata says: “The capacity to create complex 3D biofilms in the lab in a simple manner, will lead to practical tools to better understand how these living structures form and how to treat them better.”
Professor Cámara says: “The technology developed in this study will revolutionise the way we study biofilm-mediated infections and assess the effectiveness of novel antimicrobials using different in vivo-like infection environments.”
The work has been supported by the National Biofilms Innovation Centre and the European Research Council proof-of-concept grant NOVACHIP.
Scientists have engineered a living material resembling human phlegm, which will help them to better understand how a certain kind of infection develops on the lungs of patients with cystic fibrosis.
The study, published in Matter, was led by Dr Yuanhao Wu and is a collaboration between Professor Alvaro Mata in the School of Pharmacy and Department of Chemical Engineering and Professor Miguel Cámara from the National Biofilms Innovation Centre in the School of Life Sciences at the University of Nottingham.
Biofilms are strong living 3D materials that play key roles in nature, but also cause major problems in the real world, such as in the contamination of hospital surfaces, or in our tolerance to antibiotic treatment.
One of the biggest challenges in antimicrobial discovery is the lack of biofilm models which reflect the complexity of natural environments, such as those encountered in the lung of cystic fibrosis (CF) patients.
Due to a genetic alteration, these patients are unable to clear infections in their lungs where complex communities of disease-causing microbes accumulate within thick mucus forming 3D biofilms. These natural biofilms are highly resilient to antibiotics and there is a critical need to develop in vitro models which can reliably reproduce them in the lab, so that experts can better understand their biology and develop solutions to the problems they cause.
This will enable a more consistent evaluation of novel therapeutic interve

Biofilms are strong living 3D materials that play key roles in nature, but also cause major problems in the real world, such as in the contamination of hospital surfaces, or in our tolerance to antibiotic treatment.
One of the biggest challenges in antimicrobial discovery is the lack of biofilm models which reflect the complexity of natural environments, such as those encountered in the lung of cystic fibrosis (CF) patients.
Due to a genetic alteration, these patients are unable to clear infections in their lungs where complex communities of disease-causing microbes accumulate within thick mucus forming 3D biofilms. These natural biofilms are highly resilient to antibiotics and there is a critical need to develop in vitro models which can reliably reproduce them in the lab, so that experts can better understand their biology and develop solutions to the problems they cause.
This will enable a more consistent evaluation of novel therapeutic interventions before being taking into pre-clinical studies. These models will also be key to answering fundamental research questions on the interactions polymicrobial biofilms and their host which lead to chronic infections.
In this study, experts engineered a living material resembling natural sputum, or phlegm, from CF patients that can grow 3D polymicrobial biofilms in a controlled manner, resembling those found in the CF lung. The team were able to achieve this by combining peptides with a culture medium that is known to recreate natural sputum and which can be easily infected.
The living material incorporates multiple microbial communities and key nutritional and chemical factors that promote bacterial growth and exhibit physical properties mimicking those of biofilms from CF sputum. The material has been used to build an infected in vitro lung epithelial model that was used to study the impact of antibiotics.
Professor Mata says: “The capacity to create complex 3D biofilms in the lab in a simple manner, will lead to practical tools to better understand how these living structures form and how to treat them better.”
Professor Cámara says: “The technology developed in this study will revolutionise the way we study biofilm-mediated infections and assess the effectiveness of novel antimicrobials using different in vivo-like infection environments.”
The work has been supported by the National Biofilms Innovation Centre and the European Research Council proof-of-concept grant NOVACHIP.
Scientists have engineered a living material resembling human phlegm, which will help them to better understand how a certain kind of infection develops on the lungs of patients with cystic fibrosis.
The study, published in Matter, was led by Dr Yuanhao Wu and is a collaboration between Professor Alvaro Mata in the School of Pharmacy and Department of Chemical Engineering and Professor Miguel Cámara from the National Biofilms Innovation Centre in the School of Life Sciences at the University of Nottingham.
Biofilms are strong living 3D materials that play key roles in nature, but also cause major problems in the real world, such as in the contamination of hospital surfaces, or in our tolerance to antibiotic treatment.
One of the biggest challenges in antimicrobial discovery is the lack of biofilm models which reflect the complexity of natural environments, such as those encountered in the lung of cystic fibrosis (CF) patients.
Due to a genetic alteration, these patients are unable to clear infections in their lungs where complex communities of disease-causing microbes accumulate within thick mucus forming 3D biofilms. These natural biofilms are highly resilient to antibiotics and there is a critical need to develop in vitro models which can reliably reproduce them in the lab, so that experts can better understand their biology and develop solutions to the problems they cause.
This will enable a more consistent evaluation of novel therapeutic interventions before being taking into pre-clinical studies. These models will also be key to answering fundamental research questions on the interactions polymicrobial biofilms and their host which lead to chronic infections.
In this study, experts engineered a living material resembling natural sputum, or phlegm, from CF patients that can grow 3D polymicrobial biofilms in a controlled manner, resembling those found in the CF lung. The team were able to achieve this by combining peptides with a culture medium that is known to recreate natural sputum and which can be easily infected.
The living material incorporates multiple microbial communities and key nutritional and chemical factors that promote bacterial growth and exhibit physical properties mimicking those of biofilms from CF sputum. The material has been used to build an infected in vitro lung epithelial model that was used to study the impact of antibiotics.
Professor Mata says: “The capacity to create complex 3D biofilms in the lab in a simple manner, will lead to practical tools to better understand how these living structures form and how to treat them better.”
Professor Cámara says: “The technology developed in this study will revolutionise the way we study biofilm-mediated infections and assess the effectiveness of novel antimicrobials using different in vivo-like infection environments.”
The work has been supported by the National Biofilms Innovation Centre and the European Research Council proof-of-concept grant NOVACHIP.

Hearing loss affects more than 60 percent of adults aged 70 and older in the United States and is known to be related to an increased risk of dementia. The reason for this association is not fully understood.
To better understand the connection, a team of University of California San Diego and Kaiser Permanente Washington Health Research Institute researchers employed hearing tests and magnetic resonance imaging (MRI) to determine whether hearing impairment is associated with differences in specific brain regions.
In the November 21, 2023 issue of the Journal of Alzheimer’s Disease, researchers reported that individuals enrolled in this observational study who had hearing impairment exhibited microstructural differences in the auditory areas of the temporal lobe and in areas of the frontal cortex involved with speech and language processing, as well as areas involved with executive function.
“These results suggest that hearing impairment may lead to changes in brain areas related to processing of sounds, as well as in areas of the brain that are related to attention. The extra effort involved with trying to understand sounds may produce changes in the brain that lead to increased risk of dementia,” said principal investigator Linda K. McEvoy, Ph.D., UC San Diego Herbert Wertheim School of Public Health and Human Longevity Science professor emeritus and senior investigator at the Kaiser Permanente Washington Health Research Institute.
“If so, interventions that help reduce the cognitive effort required to understand speech — such as the use of subtitles on television and movies, live captioning or speech-to-text apps, hearing aids, and visiting with people in quiet environments instead of noisy spaces — could be important for protecting the brain and reduce the risk of dementia.”
McEvoy designed and led the study while at UC San Diego, in collaboration with Reas and UC San Diego School of Medicine investigators who gathered data from the Rancho Bernardo Study of Health Aging, a longitudinal cohort study of residents of the Rancho Bernardo suburb in San Diego that launched in 1972. For this analysis, 130 study participants underwent hearing threshold tests in research clinic visits between 2003 and 2005 and subsequently had MRI scans between 2014 and 2016.
The results of the study show that hearing impairment is associated with regionally specific brain changes that may occur due to sensory deprivation and to the increased effort required to understand auditory processing stimulations.
“The findings emphasize the importance of protecting one’s hearing by avoiding prolonged exposure to loud sounds, wearing hearing protection when using loud tools and reducing the use of ototoxic medications,” said co-author Emilie T. Reas, Ph.D., assistant professor at the UC San Diego School of Medicine.
Disclosures: Donald J. Hagler Jr is listed as an inventor on US Patent 9,568,580, 2017, “Identifying white matter fiber tracts using magnetic resonance imaging (MRI).” Other authors report no conflicts of interest.

Findings from St. Jude Children’s Research Hospital are moving the field of cancer immunotherapy one step closer to treating brain and solid tumors. Scientists at St. Jude validated a cellular immunotherapy target called 78-kDa glucose-regulated protein (GRP78) in proof-of-principle experiments. The group also discovered a resistance mechanism whereby some tumors trick the cancer-killing immune cells into expressing GRP78, thereby turning off the immune cells or causing them to be killed, too. The research, which has implications for developing immunotherapy for the broad range of difficult-to-treat brain and solid tumors expressing GRP78, was published today in Cell Reports Medicine.
Reprogramming a patient’s immune cells to target cancer has been successful against leukemia but not brain or solid tumors. These reprogrammed cells, called chimeric antigen receptor (CAR) T cells, target a specific protein expressed on cancer cells but not healthy ones. This targeting enables CAR T-cell immunotherapy to kill the tumor while leaving healthy tissues unharmed selectively. One difficulty that has stymied the success of CAR T cells in brain and solid tumors is the challenge of identifying a good target for these cancers.
“We found GRP78 is a great CAR T-cell target,” said senior co-corresponding author Giedre Krenciute, Ph.D., St. Jude Department of Bone Marrow Transplantation and Cellular Therapy. “We saw high GRP78 expression in a multitude of brain and solid tumor types, including adult glioblastoma, diffuse intrinsic pontine glioma (DIPG), osteosarcoma, triple-negative breast cancer and Ewing sarcoma, but our therapeutic efficacy was variable.”
The researchers created GRP78-targeted CAR T cells that successfully killed many types of cancers in both cell and mouse models, though with significant variation. The researchers expected that higher levels of GRP78 (more protein to target) would make it easier for the CAR T cells to locate and destroy the cancer; however, that was not the case. The scientists found no relationship between the amount of GRP78 and the ability of the CAR T cells to kill cancer.
“We showed the conventional approach of targeting expression doesn’t mean an equal response,” said co-corresponding author Paulina Velasquez, M.D., St. Jude Department of Bone Marrow Transplantation and Cellular Therapy. “GRP78 seems to be a special target that did not react as we expected, making it a promising but complicated candidate.”
Tumors trick CAR T cells
“We expected two different tumors with the exact same level of antigen [GRP78] expression to be affected by the CAR T-cell therapy in the same way, but they aren’t,” said first author Jorge Ibanez, Ph.D., St. Jude Department of Bone Marrow Transplantation and Cellular Therapy. “Instead, we found certain tumor cell types were altering T-cell activation and T-cell GRP78 expression.”
Ibanez found that resistant tumor cell types were altering the CAR T cells. The tumor cells caused the GRP78-targeted CAR T cells to express GRP78 on the CAR T cells’ surface. The more GRP78 on the T cells, the less active they became, reducing their cancer-killing activity. In addition, CAR T cells that remained active targeted and killed their counterparts expressing GRP78 on their surface.

In effect, the resistant tumors were conning the CAR T cells. These tumors raised the flag of GRP78, saying, “I’m here,” and then convinced the approaching T cells to raise their own GRP78 flag. This tricked the CAR T cells into killing each other or giving up, leaving the tumor relatively unscathed.
Through these experiments, the St. Jude group unveiled the tricky biology of GRP78. The protein remains a tantalizing target, given its presence on many difficult-to-treat tumor types. Findings show scientists will need to expand their understanding of this newfound interaction with T cells to make viable GRP78-targeted immunotherapies. Still, if they can, these CAR T cells may be broadly applicable across a broad range of tumor cell types.
“We always need to find new targets to improve cancer treatment,” Krenciute said. “What we found from a biological perspective is that GRP78 has potential but is different from previous cancer-associated molecules. We showed that as scientists develop the next generation of CAR T-cell therapies, we need to recognize that not all targets are equal.”