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The zebrafish should be known to many aquarium enthusiasts mainly because of its striking pigmentation. However, the characteristic black-blue stripes, to which the animal owes its name, only form over time. Its eyelash-sized larvae, on the other hand, are still more or less transparent. Many developmental processes in their bodies can therefore be observed under the light microscope. For this reason, they now serve as a model organism for research groups around the globe.
“At the University of Bonn, for example, we are investigating how zebrafish repair defective nerve tissue,” explains Prof. Dr. Benjamin Odermatt from the Institute of Anatomy at the University Hospital Bonn. “We are also interested in this because many genes involved in this process also exist in a similar form in humans.” In principle, agents that boost these repair genes in fish could thus also work in humans. However, the differences between the genetic makeup of fish and humans are often significant. The larvae are therefore sometimes of limited use in the search for new drugs.
Fish gene replaced by human gene
“We therefore took a different approach,” explains Prof. Dr. Evi Kostenis from the Institute of Pharmaceutical Biology at the University of Bonn. ” For a human gene known to play a role in the repair of nerve cells we looked for its counterpart in zebrafish. Then we excised this counterpart in the fish and replaced it with the human version.” The new genetic material took over the function of the original zebrafish gene. “If we now find a substance that boosts the repair processes in the fish with the human gene, there is a good chance that this will also be the case in humans,” says the scientist, who is also a member of the Transdisciplinary Research Area “Life and Health” at the University of Bonn.
The researchers demonstrated that this replacement works in their pilot study on the so-called GPR17 receptor. In humans, its overactivation can lead to diseases such as multiple sclerosis (MS). Nerve cells communicate by means of electrical signals. Their extensions are surrounded by a kind of insulating layer, a lipid-like substance called myelin. It prevents short circuits and also significantly speeds up the transmission of stimuli. This protective sheath is produced by specialized cells named oligodendrocytes. These resemble a microscopic octopus: many long arms extend from their cell body, most of which consist of myelin. Like an insulating tape, these wrap themselves around the nerve cell processes during brain development. Normally, the protective layer lasts a lifetime.
Insulating tape dispenser remain in immature state
In multiple sclerosis, however, the body’s own immune system destroys the myelin layer. This results in neurological disorders, for example in speech, vision or walking. But normally there is a supply of immature oligodendrocytes in the brain for repair work. When damage occurs, they mature and patch up the hole. In multiple sclerosis, this mechanism is disrupted — many of the cellular insulating tape donor cells remain in their immature state. The GPR17 receptor seems to bear the main blame for this: if it is activated by a molecular signal, it slows down the maturation of the oligodendrocytes.
“Zebrafish also have a GPR17 receptor,” explains Dr. Jesus Gomeza, who led the study with Kostenis and Odermatt. “And there it also regulates how many oligodendrocytes mature.” The researchers now replaced part of the receptor gene with its human counterpart — namely, the very structure responsible for receiving molecular signals. “We were able to show that this new mosaic gene functions normally in the fish larvae,” says Gomeza. A molecule that inhibits the human GPR17 receptor in the test tube also cranked up the formation of mature oligodendrocytes in the modified fish.
In the search for new active ingredients, substances are first tested in cell cultures. Only individual, very promising candidates are then tested in mice or other animal models. But even if they work there, tests in humans still often end soberingly. “Humanized zebrafish larvae allow many substances to be screened quickly, and with a high chance of success, since the target genes originate from humans,” explains Benjamin Odermatt. “From our point of view, this is a very promising avenue for drug development.”
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One approach to treating cancer is photodynamic therapy using photo-uncaging systems, in which light is used to activate a cancer-fighting agent in situ at the tumor. However, suitable agents must be stable under visible light, have an anti-tumor effect in low-oxygen environments, and have the ability to be activated by low-energy tissue-penetrative red light — a combination of properties that is difficult to achieve. Now, a team from The Institute of Industrial Science at The University of Tokyo has developed a new platform that uses, for the first time, organorhodium(III) phthalocyanine complexes to achieve this combination of traits.
Conventional photodynamic techniques depend on the formation of reactive oxygen species to destroy tumor cells, but many tumors contain environments that lack oxygen. Photo-uncaging systems, where the agent is administered in an inactive form and then activated, or “uncaged,” in the location of the tumor, address this issue. They uncage alkyl radicals, which are known to be capable of inducing cell death both with and without the presence of oxygen. Alkyl radicals are converted into terminal aldehydes in the presence of oxygen, and these terminal aldehydes can also induce cell death. The team used molecules called “organorhodium(III) phthalocyanine (Pc) complexes” to develop, for the first time, a novel platform for photo-uncaging therapy.
“The organorhodium(III) phthalocyanine (Pc) complexes we developed are highly stable under ambient light during the processes of synthesis, purification, and measurement, but can be activated by a laser that gives out nanosecond pulses of red light,” explains lead author Kei Murata. These nanosecond-pulsing lasers (pulsing for a billionth of a second) are relatively easy for medical staff to handle.
They went on to show that the compounds that were released after the organorhodium(III) phthalocyanine (Pc) complexes were activated showed toxicity to HeLa cells, a cell line developed from cancer, indicating that these compounds would have the ability to fight cancer if released inside a tumor.
“Our new technology could allow the photochemical generation of a wide variety of alkyl radicals and aldehydes, making possible the site-selective release of various bioactive molecules,” says senior author Kazuyuki Ishii. As an improvement on other photo-uncaging systems, it opens an exciting new avenue for the treatment of cancer by phototherapy.
The article, “Two-Photon, Red Light Uncaging of Alkyl Radicals from Organorhodium(III) Phthalocyanine Complexes,” was published in Chemical Communications.
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Dozens of species of frogs, salamanders and other amphibians quietly disappeared from parts of Latin America in the 1980s and 2000s, with little notice from humans, outside of a small group of ecologists. Yet the amphibian decline had direct health consequences for people, according to a study from the University of California, Davis.
The study, published in the journal Environmental Research Letters, links an amphibian die-off in Costa Rica and Panama with a spike in malaria cases in the region. At the spike’s peak, up to 1 person per 1,000 annually contracted malaria that normally would not have had the amphibian die-off not occurred, the study found.
“Stable ecosystems underpin all sorts of aspects of human wellbeing, including regulating processes important for disease prevention and health,” said lead author Michael Springborn, a professor in the UC Davis Department of Environmental Sciences and Policy. “If we allow massive ecosystem disruptions to happen, it can substantially impact human health in ways that are difficult to predict ahead of time and hard to control once they’re underway.”
A natural experiment
From the early 1980s to the mid-1990s, a deadly fungal pathogen called Batrachochytrium dendrobatidis, or “Bd,” travelled across Costa Rica, devastating amphibian populations. This amphibian chytrid fungus continued its path eastward across Panama through the 2000s. Globally, the pathogen led to the extinction of at least 90 amphibian species, and to the decline of at least 500 additional species.
Shortly after the mass die-off of amphibians in Costa Rica and Panama, both countries experienced a spike in malaria cases.

The discovery may help scientists better understand what causes a rare condition called posterior urethral valves (PUV), which affects 1 in 4,000 males and leads to blockages in the urethra and a build up of urine in the bladder which can then damage the kidneys. About one-third of individuals with this condition develop kidney failure before age 30. Affected individuals often undergo surgery to remove the blockages, but most continue to have urinary tract problems even after surgery. Therefore, new insights about the condition’s cause are required to better understand how the urinary tract develops in health and disease and potentially inform new treatment approaches in the future.
“PUV does not follow a Mendelian pattern of inheritance, where each parent contributes one of two possible alleles for a trait, and scientists have not identified a single gene cause,” explains lead author Dr Melanie Chan, who conducted the study as a Clinical Research Fellow at the UCL Department of Renal Medicine, London, UK. “This suggests that the genetic basis of this condition is more complex.”
To identify the genetic causes, Chan and colleagues analysed the genomes of 132 unrelated males with PUV and 23,727 individuals without the condition who had been recruited to the UK’s 100,000 Genomes Project. They included individuals with diverse genetic ancestry, including people of South Asian, African and European descent. They found two genetic variants associated with the risk of PUV. One was a common genetic variant located on chromosome 12q24.21 and the other was a rare genetic variant on chromosome 6p21.1. They confirmed the link between these two genetic differences and the disease in a separate group of individuals of European descent that included 395 males with PUV and 4,152 individuals without the condition.
The team then mapped the variation on 12q24.21 to a gene called TBX5, which contributes to turning other genes on or off. They also mapped the 6p21.1 variation to a gene called PTK7, which plays an essential role in cell development. When they looked at cells from developing human embryos, they found that the proteins encoded by the genes are active in the developing urinary tract. This discovery suggests that alterations in these proteins may interfere with normal urethra development.
Finally, they showed that structural changes in chromosomes, including flipped sections of DNA or other changes that alter the regulation of gene expression, were also linked to PUV.
“Our study is the first to identify rare and common genetic variation strongly associated with PUV, as well as structural variations in chromosomes that may contribute to the disease,” says Dr Chan. “It provides new insights on what causes this poorly understood disorder.”
The authors add that the small number of individuals included in this genetic analysis reduces its statistical power to detect very rare genetic variations linked with PUV. Additionally, they say more studies are needed to verify how exactly these genetic changes cause PUV.
But senior author Professor Daniel Gale, the St Peter’s Chair of Nephrology at the UCL Department of Renal Medicine, says the study demonstrates the importance of including people with diverse genetic backgrounds in genome-wide studies of rare conditions. Too often, he noted, genetic studies may consist of only European populations, making them less likely to identify genetic variants that might be important in other groups.
“Increasing diversity in genetic studies is both scientifically and ethically beneficial,” Professor Gale says. “It increases the power of studies to find and verify rare genetic variants and allows detection of genetic variants disproportionately affecting individuals with Asian, African, or other non-European ancestries. It also helps to ensure that people across the world benefit more equally from treatment advances driven by genetic discoveries.”
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Scientists have shown how tumour cells evade immunotherapy by generating unique, temporary cell-in-cell structures, where the inner cells remain in tact and can return to single tumour cells.
These findings, published today in eLife, provide a novel theory as to how tumour cells avoid destruction by the immune system. They could also inform the development of treatments that combine immunotherapy with the timed inhibition of relevant signalling pathways in tumour cells.
“Cancer immunotherapy harnesses the body’s immune system to fight cancer. Despite its remarkable success, the majority of patients who receive immunotherapy will only see their tumours shrink in size temporarily before returning, and these relapsed tumours will likely be resistant to immunotherapy treatment,” says first author Amit Gutwillig, who was a PhD student at the Carmi Lab, Tel Aviv University, Israel, at the time the study was carried out, and is now a Senior Researcher at Nucleai, Tel Aviv.
To identify how tumours relapse after immunotherapy, Carmi and the team began by comparing the genetic sequences of whole genomes in primary and relapsed tumours in the same patient. Their analysis suggested that relapsed tumours do not change dramatically following immunotherapy.
Next, the team studied this process in breast cancer and melanoma, using mouse models in which immunotherapy-resistant tumours had relapsed. They administered the mice with cells from treated tumours and allowed these cells to reach a palpable size. The team found that the cells were equally susceptible to the same immunotherapy approach as the parent tumour, although they relapsed sooner.
To better characterise the tumour cells that survived in mice following immunotherapy, the researchers isolated and studied the live tumour cells. They found that most of the cells responded to the presence of T cells — a type of immune cell that targets foreign particles — by organising into temporary formations. These were made up of clusters of several tumour cell nuclei, which are surrounded by a single, multilayered membrane and a meshwork of cortical actin filaments. The inner cell of the formation was dense and appeared to be compacted within another cell.
To show that this result was not due to the isolation of the melanoma cells, the team also analysed tumours with fluorescently labelled cell nuclei and membranes. They found that the cell-in-cell formation was more prevalent in immunotherapy-treated tumours, particularly in sites associated with tumour cell death. Further analysis indicated that roughly half of the tumour cells that survived immunotherapy were arranged in the cell-in-cell formation. Over time, these cells returned to a single-cell state, with similar structural features to those of the parental cell line.
The team next tested whether this phenomenon occurs in human cancers. To do this, they incubated tumour cell lines with pre-activated T cells from healthy donors. They discovered that the vast majority of breast, colon and melanoma tumour cells that survived T-cell killing organised into the cell-in-cell structure. A three-day observation of T cells interacting with tumour cells showed that these structures were dynamic, with individual tumour cells constantly forming and disseminating from the structure.
Finally, they tested the clinical relevance of this discovery by analysing cancerous tissues from multiple organs of four stage 4 melanoma patients. These patients were undergoing surgical removal of primary and metastatic lymph nodes — that is, lymph nodes that had spread from the primary tumour. The researchers found that in all four patients, the cell-in-cell formation was highly abundant in the T-cell zone of the draining lymph nodes, but not in the primary tumours. Furthermore, in a patient with untreated recurrent melanoma, most of the cells in the primary tumour were single cells, whereas the recurrent tumours had an abundance of the cell-in-cell formations.
“This previously unknown mechanism of tumour resistance highlights a current limitation of immunotherapy,” says senior author Yaron Carmi, Principal Investigator at the Department of Pathology, Sackler School of Medicine, Tel Aviv University. “Over the past decade many clinical studies have used immunotherapy followed by chemotherapy. But our findings suggest that timed inhibition of relevant signalling pathways needs to occur alongside immunotherapy to prevent the tumour becoming resistant to subsequent treatments.”
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A topical gel that blocks the receptor for a metabolic byproduct called succinate treats gum disease by suppressing inflammation and changing the makeup of bacteria in the mouth, according to a new study led by researchers at NYU College of Dentistry and published in Cell Reports.
The research, conducted in mice and using human cells and plaque samples, lays the groundwork for a non-invasive treatment for gum disease that people could apply to the gums at home to prevent or treat gum disease.
Gum disease (also known as periodontitis or periodontal disease) is one of the most prevalent inflammatory diseases, affecting nearly half of adults 30 and older. It is marked by three components: inflammation, an imbalance of unhealthy and healthy bacteria in the mouth, and destruction of the bones and structures that support the teeth. Uncontrolled gum disease can lead to painful and bleeding gums, difficulty chewing, and tooth loss.
“No current treatment for gum disease simultaneously reduces inflammation, limits disruption to the oral microbiome, and prevents bone loss. There is an urgent public health need for more targeted and effective treatments for this common disease,” said Yuqi Guo, an associate research scientist in the Department of Molecular Pathobiology at NYU Dentistry and the study’s co-first author.
Past research has linked increased succinate — a molecule produced during metabolism — to gum disease, with higher succinate levels associated with higher levels of inflammation. Guo and her colleagues at NYU Dentistry also discovered in 2017 that elevated levels of succinate activate the succinate receptor and stimulate bone loss. These findings made the succinate receptor an appealing target for countering inflammation and bone loss — and potentially stopping gum disease in its tracks.
Strengthening the link between succinate and gum disease
The researchers started by examining dental plaque samples from humans and blood samples from mice. Using metabolomic analyses, they found higher succinate levels in people and mice with gum disease compared to those with healthy gums, confirming what previous studies have found.

According to the World Health Organization, 1.6 billion people across the globe are living with hearing loss. Much of that is preventable, stemming from excessive noise, untreated ear infections, and exposure to ototoxic chemicals. About half of youth and young adults are at risk for hearing loss due to recreational noise exposure.
Careful monitoring can create better outcomes for patients with hearing loss. For example, it is estimated that 60% of childhood hearing loss can be mitigated through early detection and intervention. But rural populations often lack the specialists and technology required to diagnose the condition.
In The Journal of the Acoustical Society of America, published on behalf of the Acoustical Society of America by AIP Publishing, Samantha Kleindienst Robler from the University of Arkansas for Medical Sciences (UAMS), with her co-authors, Laura Coco of San Diego State University and Mark Krumm of Kent State University, explored how digital health solutions can expand audiology services in clinical and research settings.
“If undetected and untreated, hearing loss can have significant lifelong consequences for those relying on spoken language,” said Robler. “Preventable hearing loss can negatively impact speech, communication, academic performance, vocational opportunities, and quality of life.”
Audiology assessment via telehealth would allow patients to access care in their home or a local clinic while a specialist is located hundreds of miles away in an urban center. Instead of tabletop equipment in a soundproof room, the hearing tests would use a wireless headset controlled by a mobile phone or laptop.
“Digital health technology is versatile and, in many ways, can meet the patient where they are,” said Robler. “A real strength is that it can help take patient care to the next level by moving from an in-person, visit-centric approach to a person-centric approach that better supports a person’s life and their needs.”
As a research tool, telehealth would allow scientists to gather more representative and decentralized data on hearing, without compromising results.
“Telehealth technology can also be used to facilitate the prevention of permanent hearing loss by monitoring individuals exposed to excessive occupational noise or ototoxic medication,” said Robler.
Robler and the team at UAMS are currently scaling up several audiological studies they conducted in rural areas of Alaska. Their mission is to close the gap on hearing health disparities with large, collaborative research spanning from device development to implementation.
“There is much work to be done to ensure everyone has equal access to hearing health care, regardless of where they live, and that the evidence generated in hearing-related clinical trials is robust and representative,” said Robler.
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Scientists from The Tisch Cancer Institute have uncovered a mechanism by which certain breast cancer cells regulate their own metastases, fuel dissemination from the original tumor site, and determine routes to invade distant organs such as the lungs, according to a study published in Cell Reports in September.
For the first time, scientists have identified a type of cancer cell in triple negative breast tumors, which is highly efficient in invading and colonizing distant organs but slow their growth upon colonization. These cells have a hallmark of slowed production of a protein called srGAP1, which is usually attributed to cancer growth.
Scientists also found in animal models that these unique cells trigger a phenomenon that keeps them in a dormant state in distant organs such as the lungs. This is an important finding because cancer cells have to efficiently survive at distant sites, and staying in this “asleep” existence allows these cells to evade therapies that target cancer cells’ normal rapid growth. Cells that are missed could later become metastatic.
“Our findings emphasize the importance of considering phenotypic changes that could occur when treating cancer cells with therapeutic strategies that target proliferating cells such as chemotherapy,” said Jose Javier Bravo-Cordero, PhD, Associate Professor of Medicine (Hematology and Medical Oncology) at The Tisch Cancer Institute at Mount Sinai. “While these treatment regimens target dividing cells, they may also be selecting for more invasive tumor cells. Our studies suggest that more selective therapeutic strategies combining treatments against both dividing cells and invasive dormant cells may be necessary to prevent metastatic disease.”
To conduct this study, researchers used high-resolution in vivo imaging to visualize extravasation, the process of tumor cells exiting the blood vessels to enter a target tissue. This event was observed in real time, revealing with unprecedented detail the early stages of tumor extravasation. The microscopy studies revealed that after these tumor cells invade the lungs, they enter into a dormant state by secreting the protein TGF-β2. The studies also showed that interfering with that protein can block tumor cell invasion into the lungs.
Partners who contributed to this work include Stony Brook University, University of Illinois at Chicago, Janelia Research Campus at Howard Hughes Medical Institute and University of California at Berkeley.
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Data from the largest mental health survey of the Flint, Michigan community indicate that one in five adults, or roughly 13,600 people, were estimated to have clinical depression, and one in four, or 15,000 people, were estimated to have PTSD five years after the water crisis began.
“The mental health burden of America’s largest public-works environmental disaster clearly continues for many adults in Flint,” said Aaron Reuben, a postdoctoral scholar at Duke University who led the research, which appears Sept. 20 in JAMA Network Open.
On April 25th, 2014, the city of Flint switched its water supply from Lake Huron and the Detroit River to the Flint River and failed to properly treat the water supply to prevent lead and other elements from leaching out of the city’s old water pipes. Virtually all Flint residents were consequently exposed to drinking water with unsafe levels of bacteria, disinfection byproducts, and lead, a neurotoxicant.
Flint drinking water was not declared lead-free until January 24, 2017. During the crisis, tens of thousands of children and adults in Flint developed high blood-lead levels, putting them at greater risk for cognitive deficits, mental health problems, and other health problems later in life.
“We know that large-scale natural or human-caused disasters can trigger or exacerbate depression and PTSD,” said Dean Kilpatrick, PhD, Distinguished University Professor in the Department of Psychiatry and Behavioral Sciences at Medical University of South Carolina and senior author of the study. Kilpatrick noted that there was clear evidence of high rates of mental health problems in the Flint community during the first years of the crisis. “What we did not know until now was the extent to which Flint residents continued to have mental health problems at the clinical diagnosis level five years after the crisis began.”
According to Kilpatrick, past year rates of depression and PTSD identified in Flint today are three to five times greater than national estimates among US adults overall, and likely result from a combination of higher base rates of mental health problems in Flint before the crisis as well as a significant exacerbation of problems resulting from the crisis.