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A new boron agent drastically improves the effectiveness of boron neutron capture therapy for glioblastoma, demonstrate researchers at Tokyo Tech. The agent is selectively absorbed by brain tumor cells, exhibits enhanced blood retention, and can be administered at low doses. Experiments on cell cultures, mice, and rats show promising results, highlighting the potential of the novel agent for radiotherapy.
Glioblastoma (GBM) is a highly aggressive form of brain tumor that originates from supportive cells of the brain called glia. Due to its rapid growth, surgical removal of GBM is often difficult, leaving radiotherapy as the most viable option. Among the many existing radiotherapeutic modalities, boron neutron capture therapy (BNCT) has attracted a lot of attention for the treatment of GBM.
BNCT exploits the high affinity of boron-10 (10B) atoms for low-energy neutrons. When 10B absorbs a neutron, nuclear reactions release high-energy particles that damage the nearby biological tissue. Therefore, an essential requirement in BNCT is to achieve a significantly higher concentration of 10B in tumor cells than that in healthy normal cells. However, this has proven to be challenging, resulting in low survival rates and limited use of BNCT.
Against this backdrop, a research team including Professor Hiroyuki Nakamura from Tokyo Institute of Technology (Tokyo Tech) has developed a novel boron agent that shows great promise for BNCT. This molecule — pteroyl-closo-dodecaborate conjugated with a 4-(p-iodophenyl)butyric acid moiety (PBC-IP) — was thoroughly tested in their recent study published in the Journal of Controlled Release.
PBC-IP consists of three main functional groups: the first is a boron group containing twelve 10B atoms, the second is a ligand designed to bind to folate receptor α (FRα). This receptor, hardly present in normal cells, is greatly overexpressed in various cancers, including GBM. Thus, it acts as the entry point for PBC-IP into tumor cells. Finally, the third group is the 4-(p-iodophenyl)butyric acid moiety, which binds the entire molecule to albumin — an abundant carrier protein in blood that transports substances throughout the body. PBC-IP binds non-covalently to naturally present albumin, which allows it to directly interact with tumor cells, promoting its cellular uptake. Thus, the acid moiety can enhance the blood retention of the boron agent, thereby potentially reducing the required dose.
The researchers conducted several experiments to confirm the viability of PBC-IP for BNCT, finding that it accumulated in GBM cell cultures 10-20 times more than L-4-boronophenylalanine (BPA), a clinically approved boron agent in Japan. In addition, PBC-IP showed no signs of toxicity to cells on its own, demonstrating its safety. “Likewise, PBC-IP administrated intravenously to the human GBM xenograft model showed higher boron accumulation in tumors than BPA, effectively suppressing tumor growth after thermal neutron irradiation,” highlights Prof. Nakamura.
These promising results were also replicated in vivo, both in GBM xenograft models and rat glioma models. PBC-IP administered via convection-enhanced delivery (CED) in the rat model achieved tumor-to-normal brain and tumor-to-blood boron ratios of 37.8 and 94.6, respectively, three hours after completion of CED. “Survival rates at 180 days were 50% and 70% following BNCT with PBC-IP only and PBC-IP in combination with BPA, respectively. There were no residual brain tumors,” says an excited Prof. Nakamura.
Overall, the proposed boron agent may represent a breakthrough in radiotherapy for GBM, with the researchers currently conducting preclinical studies.

Cancer immunotherapy has brought major improvement in patient survival and quality of life, especially with the success of adoptive T cell and immune checkpoint inhibitor therapies. Unfortunately, in contrast to different blood cancers, the effectiveness of adoptive T cell therapies in the treatment of solid tumors, which comprise about 90% of all tumors, has been very limited because of several formidable barriers.
In adoptive T cell therapies, a patient’s T cells with cytotoxic potential are engineered outside the body so that they can bind specific features (antigens) on the surface of tumor cells, which converts them into tumor-killing cells. However, after being reinfused into the donor patient’s blood circulation, they have to travel long distances to reach a solid tumor with only a fraction of them ever arriving there. On-site, they need to infiltrate the often difficult-to-penetrate tumor mass, while their cytotoxic activity is suppressed by tumor cells and their surrounding tissue microenvironment. In addition, the further solid tumors grow, the more heterogenous their cell composition becomes, which also includes tumor cells’ repertoire of surface antigens, and thus allows them to “escape” the attack of adoptively transferred T cells.
Now, a team of immune-engineers at the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) have developed a novel biomaterials-based immunotherapy approach named SIVET (short for “synergistic in situ vaccination enhanced T cell”) that has the potential to break down these barriers. The injectable biomaterial enables both: the local delivery of antigen-specific adoptively transferred T cells directly to tumor sites and their prolonged activation, as well as a broader engagement of the host immune system to provide much longer-lasting anti-tumor effects against tumor cells carrying new antigens. Validated in mice carrying melanomas, a particularly aggressive type of solid tumor, SIVET enabled the fast shrinking of tumors and long-term protection against them. The findings are published in Nature Communications.
“In the SIVET approach, we essentially combined fast-acting adoptive T cell therapy with long-term protective cancer vaccine technology in a locally delivered integrated biomaterial. Advancing this approach towards patient settings could help addresses several limitations of current immunotherapies and offers new inroads into the treatment of solid tumors,” said senior author David Mooney, Ph.D., who is a Founding Core Faculty member at the Wyss Institute and the Robert P. Pinkas Family Professor of Bioengineering at SEAS. Mooney leads the Wyss Institute’s Immunomaterials Platform and co-leads the NIH-funded Immuno-Engineering to Improve Immunotherapy (i3) Centercoordinated at the Wyss Institute and focused on creating biomaterials-driven approaches to enable anti-cancer immunotherapy in solid tumor settings.
Biomaterial convergences
In extensive previous work, Mooney’s team had pioneered biomaterial-based cancer vaccines that are able to program key immune-orchestrating dendritic cells, known as antigen-presenting cells (APCs), into tumor-fighting cells in vivo. Despite the cancer vaccines being able to provide broad therapeutic and prophylactic benefits, their tumor-directed effects take time to manifest in the body. On the other hand, patient-specific adoptively transferred T cells are ready-made to attack tumor cells upon first contact but produce rather short-lived responses.

“Our new platform fully leverages our expertise with adoptive T cell and cancer vaccine technologies. Combining the best of these two worlds in a multi-pronged biomaterial-based approach allows the fast debulking of existing tumor masses while engaging the immune system on a much deeper level through the localized delivery, concentration, and activation of diverse tumor-fighting immune cells,” said co-first author Kwasi Adu-Berchie, Ph.D., who completed his Ph.D. in Mooney’s lab and is currently a Translational Immunotherapy Scientist at the Wyss Institute.
Adu-Berchie, Mooney, and the team developed a cryogel biomaterial that contains collagen and alginate polymers cross-linked into a 3-dimensional porous scaffold. While the alginate provides the biomaterial with structural support, collagen serves to provide ligands needed for T cell trafficking. Following injection of the engineered T cell depot close to a tumor site, the compressed biomaterial recovers its original shape and starts releasing the cytokine interleukin 2 (IL2) to facilitate the expansion of the delivered T cells, which move out of the biomaterial and onto the tumor to carry out an attack.
In addition, the biomaterial releases a second cytokine, abbreviated as GMCSF, which attracts host APCs into the porous scaffold that then also become concentrated and activated with the help of an adjuvant molecule known as CpG close to the tumor. The activated APCs also infiltrate the tumor mass where they take up new antigens created by dying tumor cells that disintegrate as a result of the T cell attack. The APCs then migrate to nearby lymph nodes where they orchestrate a broader vaccine response by presenting processed antigens to other immune cell types, including other cytotoxic T cells that attack the tumor in consecutive waves, as well as memory T cells that stand by for future tumor recurrences.
The researchers investigated SIVET in a mouse model carrying melanoma tumors and found that the multi-functional biomaterial enabled better control over the tumors than the same adoptively transferred T cells injected directly into the tumor site or infused into the blood stream of the animals. SIVETs enabled the delivered T cells to remain active longer and minimized the exhaustion of all T cells in the tumor microenvironment when compared to control conditions.
“Through their vaccine component, SIVETs trained the immune system to reject melanoma tumors for significantly prolonged periods of time, and thus allowed the animals to survive for significantly longer than animals that received any of our control treatments. This likely was facilitated by the biomaterial’s ability to prevent the growth of tumor cells that escape the attack of adoptively transferred T cells due to their loss of the initially targeted antigen,” said Adu-Berchie. “Identifying a tumor-specific antigen against which potent donor-specific T cells can be generated for adoptive transfer could provide SIVETs with enough to go on to initiate a tumor attack on a much broader front and scale.
“This study is a beautiful convergence of two powerful immunotherapy approaches that are programmed in the body to synergize with each other. This work once again demonstrates the power of taking an unconventional trans-disciplinary approach — in this case, combining strategies from materials science and tissue engineering with immunology — to create novel and more powerful therapeutics for the eradication of solid cancers,” said Wyss Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children’s Hospital, and the Hansjörg Wyss Professor of Bioinspired Engineering at SEAS.
The study is also authored by other past and present members of Mooney’s group, including Joshua Brockman, Yutong Liu, Tania To, David Zhang, Alexander Najibi, Yoav Binenbaum, Alexander Stafford, Nikolaus Dimitrakakis, Miguel Sobral, and Maxence Dellacherie. It was supported by grants from the National Institutes of Health (award #U54 CA244726 and #U01 CA214369), National Science Foundation (award #MRSEC DMR-1420570), and Food and Drug Administration (award #R01 FD006589), as well as the National Cancer Institute (award #5K00CA234959).

Transfer RNAs (tRNAs) are among the most common types of RNA in a cell and are indispensable for protein production in all known organisms. They have an important “translation” function: They determine how the sequence of nucleic acids, in which the genetic information is encoded, is transcribed into a sequence of amino acids from which proteins are built.
Transfer RNAs are generated from precursor tRNAs (pre-tRNAs), which are converted in several steps into the mature tRNA with a complex three-dimensional structure. In some tRNAs, this includes a step in which a certain section, known as an intron, is excised. In humans, the tRNA splicing endonuclease (TSEN) performs this task.
The enzyme RNA kinase CLP1, which binds directly to TSEN, also plays a role in ensuring the correct conversion of tRNAs. If TSEN and CLP1 are unable to interact with each other due to a genetic mutation, it seems that tRNAs can no longer form correctly either. The consequences of this are often seen in the development of neurodegenerative disorders. One of these is pontocerebellar hypoplasia, which leads to severe disabilities and premature death in earliest childhood. This very rare progressive disorder manifests itself in an abnormal development of the cerebellum and the pons, a part of the brain stem.
Although TSEN activity is essential for life, it was to date mostly unclear how the enzyme binds pre-tRNAs and how introns are excised. The lack of a three-dimensional structure of the enzyme also made it difficult to assess the changes triggered by specific pathogenic mutations. By means of cryo-electron microscopy (cryo-EM) conducted at facilities of the Julius-Maximilians University of Würzburg and of the Institute of Biochemistry at Goethe University Frankfurt, researchers led by Dr. Simon Trowitzsch from the Institute of Biochemistry at Goethe University have now succeeded in shedding light on the three-dimensional structure of a TSEN/pre-tRNA complex.
With the aid of their cryo-EM reconstructions, the research team was able to show for the first time how TSEN interacts with the L-shaped pre-tRNA. TSEN then excises the intron from the long arm of the L. “First, TSEN settles in the corner of the L. It can then recognize both the short and the long arm as well as the angle between them,” explains Trowitzsch.
The TSEN subunit 54 (TSEN54) plays a key role in pre-tRNA recognition, as the researchers have now been able to corroborate. The subunit serves as a “molecular ruler” and measures the distance between the long and the short arm of the L. In this way, TSEN recognizes at which point the pre-tRNA needs to be cleaved in order to remove the intron.
New findings on the interaction of the RNA kinase CLP1 and the TSEN subunit TSEN54 were a surprise: CLP1 evidently binds to an unstructured and thus very flexible region of TSEN54. It is precisely this region that contains an amino acid most frequently mutated in patients with pontocerebellar hypoplasia. “For us, this is an important indication that drug development in the future should concentrate on maintaining the interaction of TSEN and CLP1,” Samoil Sekulovski, first author of the study, is convinced.
The scientists now hope that the structural data will make it possible to simulate models that can be used to search for potential active substances. Trowitzsch sums up: “Although a promising therapy is still a long way ahead of us, our structure indeed forms a solid foundation for a better understanding of how TSEN works and what the disease patterns of its mutants are.”

Expanding home blood pressure monitoring among US adults with hypertension could substantially reduce the burden of cardiovascular disease and save healthcare costs in the long term, according to a new study in the American Journal of Preventive Medicine, published by Elsevier. The results of the study show that expanding home monitoring has the potential to address pervasive health disparities facing racial and ethnic minorities and rural residents because it would reduce cardiovascular events among US adults.
Co-lead investigator Yan Li, PhD, Professor, School of Public Health, Shanghai Jiao Tong University School of Medicine, explained, “Our study is among the first to assess the potential health and economic impact of adopting home blood pressure monitoring among American adults with hypertension. We found that it facilitates early detection, timely intervention, and prevention of complications, leading to improved control and better health outcomes.”
Analyzing data from the 2019 Behavioral Risk Factor Surveillance System (BRFSS), investigators projected that implementing home blood pressure monitoring, as opposed to traditional clinic-based care, could result in a reduction of myocardial infarction (MI) cases by 4.9% and stroke cases by 3.8% over 20 years.
Non-Hispanic Blacks, women, and rural residents had more averted cardiovascular events and greater cost savings related to adopting home blood pressure monitoring compared to non-Hispanic Whites, men, and urban residents. Adopting home blood pressure monitoring in rural areas would lead to a potential reduction of 21,278 MI cases per one million people compared to 11,012 MI cases per one million people in urban areas. Rural residents tend to have a higher prevalence of hypertension and uncontrolled hypertension than urban residents and often face additional barriers in accessing primary care services.
Estimating healthcare cost parameters based on actual healthcare payment data from the Medical Expenditure Panel Survey (MEPS), researchers projected an average of 4.4% per person annual savings and an average of $7,794 in healthcare costs per person over a span of 20 years in this population due to home blood pressure monitoring adoption and the subsequent reduced cardiovascular disease cases. Previous economic evaluations of home blood pressure monitoring have primarily focused on local health systems or conducted short-term, small-scale randomized controlled trials.
Hypertension — systolic blood pressure (BP) greater than 130 mmHg or a diastolic BP greater than 80 mmHg or being on medication for it — is a pressing public health challenge in the US, with significant implications for the development of heart disease and stroke and leads to substantial healthcare costs. Traditional clinic monitoring, the common method for BP measurement and hypertension diagnosis, has a number of drawbacks: Patients may not visit clinics often enough to pick up the problem, and when they do, accuracy may be compromised by the “white coat” (high office BP but normal BP on home measurements) or “masked” (normal/high normal BP in the office but elevated at home) effects.
Home blood pressure monitoring eliminates these impediments and provides more comprehensive and accurate data compared to sporadic measurements obtained during clinic visits. Yet, the highly effective practice has not been widely adopted in the US because of inadequate health insurance coverage, lack of investment in preventive services, and limited health promotion efforts provided by primary care physicians. However, the landscape has changed between 2020 and 2022 when home blood pressure monitoring attracted increasing attention due to healthcare disruptions caused by the COVID-19 pandemic.
Co-lead investigator Donglan Zhang, PhD, Associate Professor, Center for Population Health and Health Services Research, New York University Long Island School of Medicine, commented, “Given that almost half of all adults in the US (47%) are affected by high blood pressure, and considering the persistent health disparities in cardiovascular health, it is very important to advocate for the widespread adoption of effective and cost-saving strategies. Home blood pressure monitoring empowers patients to take a more active role in managing their chronic conditions. Our findings provide compelling evidence for healthcare systems and payers supporting the broader implementation of this intervention.”

Why do some people take part in genetic studies while others do not? The answer may lie within our genetic makeup. According to a groundbreaking study by Oxford’s Leverhulme Centre for Demographic Science and Big Data Institute, people who participate in genetic studies are genetically more likely to do so, leaving detectable ‘footprints’ in genetics data. This breakthrough equips researchers with the ability to identify and address participation bias, a significant challenge in genetic research.
Stefania Benonisdottir, lead author of the study and a Doctoral candidate from Oxford’s Big Data Institute, explains, ‘Currently, most genetic studies are based on genetic databases which contain large numbers of participants and a wealth of information. However, some people are more likely to be included in these databases than others, which can create a problem called ascertainment bias, where the genetic data collected is not representative of the intended study population.’
To study this link between genetics data and participation bias, the researchers turned to one of the largest biomedical databases in the world, the UK Biobank which contains information from half a million participants.
Using UK Biobank data, it was found there is a genetic component to people’s probability to participate — that is correlated but distinct from other human traits. Published today in Nature Genetics, the study highlights that participation could be an important human trait that has been previously underappreciated and introduces a statistical framework that could lead to more accurate analyses of genetic data.
Professor Augustine Kong, senior author from the Leverhulme Centre for Demographic Science and the Big Data Institute, notes, ‘Ascertainment bias poses a statistical challenge in genetics research, particularly in the era of big data. Adjustments for this bias often rely on known differences between participants and non-participants, introducing imperfections when answering questions involving variables only observed for participants, such as genotypes. Our study identifies detectable footprints of participation bias in the genetic data of participants, which can be exploited statistically to enhance research accuracy for both participants and non-participants alike.’
Genome-wide association studies offer important insights into the role of genetics in human health and diseases. However, such studies can be affected by biases, which arise when genetic databases are not representative of the intended study population. Now, the identified genetic inclination to participate can help scientists assess the representativeness of their study sample.
By analysing the genetic data of over 30,000 related participants with white British descent from the UK Biobank, the researchers found that the genetic component underlying participation in the study is correlated with, but distinct from, the genetic components of traits such as educational attainment and body mass index.
For example, the estimated correlation between the genetic components underlying participation in the UK Biobank and educational attainment is estimated to be 36.6%. This result is consistent with some of the previously reported differences between the participants and the non-participants, but it also shows that the participation bias is not fully captured by these previously known differences. In other words, participation is not simply a consequence of these other traits and characteristics.
The study also found the genetic component of participation can be passed down through families and may affect people’s participation in many different studies over their lifetimes. This highlights the potential for bias in genetic research and underscores the importance of accounting for such biases in study design and analysis.
Professor Melinda Mills, Director of the Leverhulme Centre for Demographic Science concludes, ‘As our GWAS Diversity Monitor shows, the road to improve diversity in genome-wide association studies is long. However, this statistical framework is a huge step in the right direction to mitigate the risk of incomplete or inaccurate data analysis and ensure that genetic research truly benefits everyone.’

Boosting the activity of inhibitory interneurons in Fragile X mice reduced their hypersensitivity to sensory stimuli, according to a new Neuron study led by UCLA Health researchers.
Fragile X Syndrome, which is caused by a mutation in a single gene, is the most common inherited form of intellectual disability and autism. Many people with Fragile X are extremely sensitive to sights, sounds, and touch, among other sensory experiences.
Previous research found Fragile X mice have a lower density of parvalbumin (PV) inhibitory interneurons, the main class of inhibitory neurons in the cerebral cortex — the region of the brain responsible for sensory processing. These neurons act like a brake on excitatory neurons to help them fire only when necessary.
Because autism symptoms first appear during the toddler stage and likely reflect changes in the brain that happened earlier, the researchers sought to establish when the reduced activity of PV interneurons was first apparent during brain development in mice — and whether intervention could help mitigate sensory hypersensitivity.
Researchers recorded neuronal activity in the brains of young mice during the first two weeks of life. They then sought to influence this activity through a novel drug compound that boosts the firing of PV neurons.
Researchers found that the density of PV neurons is indeed lower in Fragile X mice compared to controls — but even in mice as young as six days old. There were also greater numbers of dying PV neurons during early development in Fragile X mice, suggesting that these neurons are dying at a higher rate than what is considered healthy.
They also found that PV neurons in young Fragile X mice were unable to regulate the activity of excitatory neurons during the first two weeks of development, indicating that these neurons are functionally decoupled during this time. That could explain why researchers were able to restore PV neuron density by boosting PV neuron activity during this period of development but could not restore the activity of excitatory neurons.
Researchers then administered a novel drug compound aimed at activating PV neurons in Fragile X mice during the third week of development. The treatment restored the ability of excitatory neurons to respond to touch, resembling how they function in healthy controls. It also reduced hypersensitivity to repeated touch, which is similar to what is known as tactile defensiveness in humans with Fragile X.
While there are no existing treatments for the root cause of Fragile X, there are medications that address symptoms like anxiety, ADHD, or seizures. The new research suggests modulating the activity of PV neurons could be an effective approach to restoring circuit function.
“Our research is an example of how therapies that target circuit differences in neurodevelopmental conditions, like boosting the activity of inhibitory neurons in the brain, could help mitigate bothersome symptoms such as sensory hypersensitivity,” said corresponding author Carlos Portera-Cailliau, MD, PhD, a professor of neurology and neurobiology at the David Geffen School of Medicine at UCLA. Nazim Kourdougli, PhD, a postdoctoral fellow in Portera-Cailliau’s lab, is the first author.
Portera-Cailliau’s lab will continue investigating how inhibitory neurons make synapses with excitatory neurons during development, and how the mutation in Fragile X affects this process. It will also test if the same drug compound can ameliorate other behavioral differences in Fragile X mice.

Use of low-dose atropine eyedrops (concentration 0.01%) was no better than placebo at slowing myopia (nearsightedness) progression and elongation of the eye among children treated for two years, according to a randomized controlled trial conducted by the Pediatric Eye Disease Investigator Group (PEDIG) and funded by the National Eye Institute (NEI). The trial aimed to identify an effective way to manage this leading and increasingly common cause of refractive error, which can cause serious uncorrectable vision loss later in life. Results from the trial were published in JAMA Ophthalmology.
Importantly, the findings contradict results from recent trials, primarily in East Asia, which showed a benefit from 0.01% atropine in slowing myopia.
“The overall mixed results on low-dose atropine show us we need more research. Would a different dose be more effective in a US population? Would combining atropine with other strategies have a synergistic effect? Could we develop other approaches to treatment or prevention based on a better understanding of what causes myopia progression?” said Michael F. Chiang, M.D., director of the NEI, which is part of the National Institutes of Health.
Identifying an optimal approach for preventing high (advanced) myopia is urgently needed given the escalating prevalence of myopia overall and the risk of it progressing to high myopia. By 2030, it’s predicted that 39 million people in the U.S. will have myopia. By 2050, that number is expected to grow to 44 million in the U.S. and to 50% of the global population.
Much stronger concentrations of atropine eyedrops (0.5-1.0%) have long been used by pediatric eye doctors to slow myopia progression. While effective, such doses cause light sensitivity and blurry near vision while on the nightly eyedrops. Thus, there is interest in clinical studies assessing lower concentrations that have been shown to have fewer side effects.
“The absence of a treatment benefit in our U.S.-based study, compared with East Asian studies, may reflect racial differences in atropine response. The study enrolled fewer Asian children, whose myopia progresses more quickly, and included Black children, whose myopia progresses less quickly compared with other races,” noted the study’s lead co-author, Michael X. Repka, M.D., professor of ophthalmology, Johns Hopkins University.
For the study, 187 children ages 5 to 12 years with low-to-moderate bilateral myopia were randomly assigned to use nightly atropine (0.01%) (125 children) or placebo (62 children) eyedrops for two years. Study participants, their parents, and the eye care providers were masked to the group assignments. Patient care was provided at 12 study center sites throughout the U.S.
After the treatment period, and 6 months after treatment stopped, there were no significant differences between the groups in terms of changes in degree of myopia compared with baseline. Nor were there significant differences in axial length within the two groups when compared with baseline measurements.
“It’s possible that a different concentration of atropine is needed for U.S. children to experience a benefit,” noted the study’s other lead co-author, Katherine K. Weise, O.D., professor, University of Alabama at Birmingham. “Clinical researchers could evaluate new pharmaceuticals and special wavelengths of light in combination with optical strategies, like special glasses or contact lenses, to see what works in reducing the progression of myopia.”
Among children, myopia will stabilize in about half of children around age 16 years, and among an increasingly larger percentage as they get older. By their early twenties, about 10% of individuals with myopia will continue to grow more nearsighted, and by age 24 years that percentage is 4%.
“Vision scientists may help us figure out what’s different about the myopic eye, even among different races and ethnicities, to help create new treatment strategies,” she said. It will take a real convergence of eye research to solve the environmental, genetic, and structural mystery of myopia.”
PEDIG is a collaborative network of pediatric ophthalmologists and pediatric optometrists dedicated to conducting multi-center trials on eye disorders that affect children. The trial was funded by the NEI grants EY11751, EY18810 and EY23198. The ClinicalTrials.gov identifier is NCT03334253.

Two pathologies drive the progression of Alzheimer’s disease. Early on, amyloid beta plaques lead the way, but around the time cognitive symptoms arise, tau tangles take over as the driving force and cognition steadily declines. Tracking the course of the disease in individual patients has been challenging because there’s been no easy way to measure tau tangles in the brain.
But now, researchers at Washington University School of Medicine in St. Louis and Lund University in Lund, Sweden, have identified a form of tau that could serve as a marker to track Alzheimer’s progression. The marker also could be used by Alzheimer’s drug developers to assess whether investigational tau-based drugs — the next frontier in Alzheimer’s drug development — are effective against the disease. Such drugs theoretically would benefit people in later stages of the disease, when tau tangles play a crucial role.
By studying 667 people in Sweden and the U.S. at various stages of Alzheimer’s disease, the researchers discovered in the cerebrospinal fluid that levels of a specific form of tau — known as microtubule binding region (MTBR)-tau243 — track with the amount of damaging tau tangles in the brain and with the degree of cognitive decline.
The findings, published July 13 in Nature Medicine, are a major step toward a better approach to diagnosing and staging Alzheimer’s disease. A test based on MTBR-tau243 could speed up drug development by providing a relatively simple and inexpensive way to identify and monitor participants in clinical trials and assess whether the experimental therapies, including tau-based drugs, can change the course of the disease.
“This discovery provides biomarkers to specifically track the progression of tau tangles, the major pathology that predicts dementia and cognition, which is something that hasn’t been within reach until now,” said co-senior author Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology at Washington University. “These findings will help accelerate drug development for patients with symptoms of Alzheimer’s disease. We are also working on developing these biomarkers as a clinical test to stage individual patients and improve patient care.”
The gold standard for measuring tau tangles in the brain is the tau-positron emission tomography (tau-PET) brain scan, which costs thousands of dollars and requires expensive equipment and specialized expertise not available at most hospitals, making such scans impractical for patient care and costly for research studies.

In 2020, Bateman and Kanta Horie, PhD, a research associate professor of neurology and co-first author on the new paper, showed that levels of MTBR-tau243 in the cerebrospinal fluid reflect the amount of tau tangles in the brain. In this new study, Bateman and Horie teamed up with Lund University’s Oskar Hansson, MD, PhD, a professor of neurology and study co-senior author, and Gemma Salvadó, PhD, a postdoctoral researcher and co-first author, to extend the analysis to a larger number of people and to compare MTBR-tau243 to other tau biomarkers.
The researchers analyzed data from people who volunteered for Alzheimer’s research studies through the Biomarkers For Identifying Neurodegenerative Disorders Early and Reliably (BioFINDER)-2 (448 people) study in southern Sweden or the Knight Alzheimer Disease Research Center (219 people) in St. Louis. The average age of participants was 71, and the group included healthy people as well as people at all stages of disease, ranging from those with some amyloid in their brains but no cognitive symptoms, to those with extensive amyloid and tau in their brains and a diagnosis of dementia. The researchers compared cognitive function with levels of various forms of tau in the cerebrospinal fluid and with levels of amyloid and tau in the brain, as measured by amyloid and tau PET scans.
Levels of MTBR-tau243 in the cerebrospinal fluid correlated strongly with brain tau tangle levels and cognitive function. As MTBR-tau243 levels went up, tau levels in the brain also went up, and scores on cognitive tests went down. In contrast, levels of another form of tau in the cerebrospinal fluid, phosphorylated tau, tracked mainly with brain amyloid levels but not with brain tau levels or cognitive function.
“To accurately diagnose Alzheimer’s disease in patients with cognitive symptoms, we need biomarker-based evidence of both amyloid beta plaques and tau tangle pathology,” Hansson said. “With this new biomarker, representing tau pathology, we can do this using a single cerebrospinal fluid sample. This has the potential to clearly improve the diagnostic as well as prognostic work-up of Alzheimer’s worldwide. We hope that we soon can do the same using a simple blood test.”
By combining the two forms of tau in the cerebrospinal fluid — phosphorylated tau and MTBR-tau243 — the researchers were able to predict cognitive function almost as well as by using tau-PET.
“A combination of phosphorylated tau and MTBR-tau243 in the cerebrospinal fluid reveals not only whether an individual has Alzheimer’s disease but identifies the stage of illness — from presymptomatic disease to full-blown dementia,” Horie said.
By taking repeated samples of cerebrospinal fluid, researchers could track the progression of the disease and determine the effect of interventions such as experimental anti-tau therapeutics on the disease trajectory.
“In late stages of Alzheimer’s disease, the effectiveness of anti-amyloid therapies may weaken because amyloid is no longer playing a major role in driving the disease,” Horie said. “But that’s when tau becomes relevant. By stopping the tau pathology, we may be able to stop further cognitive decline including memory loss. By maintaining individuals at the level of mild cognitive impairment and preventing further cognitive decline, we can help people maintain a good quality of life. That’s what we’re working toward.”

A team from the University of Tokyo has combined economic theory with biology to understand how natural systems respond to change. The researchers noticed a similarity between consumers’ shopping behavior and the behavior of metabolic systems, which convert food into energy in our bodies. The team focused on predicting how different metabolic systems might respond to environmental change by using an economic tool called the Slutsky equation. Their calculations indicated that very different metabolic systems actually share previously unknown universal properties, and can be understood using tools from other academic fields. Metabolic processes are used in drug development, bioengineering, food production and other industries, so being able to predict how such systems will respond to change can offer many benefits.
Where do you get your energy from? Perhaps a long night’s sleep, or a good breakfast and some exercise? These activities can all help as they support a healthy metabolism, the chemical processes by which our bodies convert food and drink into energy. Understanding how individual metabolic reactions behave and predicting how they may change under different circumstances is a big challenge. There are thousands of different reactions which enable us to move, think, grow — in short, to live. In recent years, it has become possible to predict some reactions through numerical simulations, but this requires large amounts of data. However, researchers at the University of Tokyo have derived previously unknown universal properties of metabolic systems by applying microeconomic theory to their data.
“Until this research, we thought that metabolic systems varied so much among species and cell types that there were no common properties among them,” explained Assistant Professor Tetsuhiro Hatakeyama from the Graduate School of Arts and Sciences. “However, we were very excited to demonstrate that all metabolic systems have universal properties, and that these properties can be expressed by very simple laws.”According to the researchers, this theory does not require as much detailed background data to be collected as other methods. It can also be effectively applied whether you are trying to understand the behavior of all metabolic processes in a cell or focusing on just one part — say, for example, how much oxygen it is using.
Hatakeyama, a biophysicist, was looking at some metabolic system diagrams when he noticed a striking similarity to diagrams used in economics. This realization inspired him to try an interdisciplinary approach and apply economic theory, which he had briefly studied, to his biology research. Along with co-author Jumpei Yamagishi, a graduate student in the same lab, he decided to explore how both consumers and cells optimize their “spending” to maximize gain: Whereas we as consumers spend money, cells “spend” nutrients. They reasoned if there were similarities in this way, then perhaps the same theories that are used to identify patterns in consumer behavior under changing financial situations could also identify patterns in cellular metabolic behavior under changing environments.
More specifically, the researchers focused on the Slutsky equation, which is used to understand changes in consumer demand. In particular, it is used to understand so-called Giffen goods, which counterintuitively go up in demand when the price increases and go down in demand when the price decreases. According to Hatakeyama, this is similar to cellular metabolic behavior in response to a disturbance. For example, respiration demand (the Giffen goods in this case) in cancer cells goes up, counterintuitively, with increased drug dosage (the “price”), even though this is not beneficial to the growth rate of the cancer. The outcome was that the team uncovered a universal law for how metabolic systems respond to change.
One of the key benefits of this law is that it can be used to understand metabolic systems about which few details are known. “Disturbances in metabolic systems lead to a variety of diseases, and our research could be used to propose new treatment strategies for diseases for which treatments are not fully understood,” said Hatakeyama. “In addition, many foods and medicines are made using the metabolic systems of organisms. By applying the simple equation found in this study, we can know how to increase the output of products made with these systems.” Hatakeyama hopes that through further interdisciplinary research, more universal laws might be discovered that will lead to a variety of useful applications.

Research has shown quality sleep can help bolster resilience to depression and anxiety.
The study, led by researchers at the University of York, highlights that chronic stress is a major risk factor for a number of mental health disorders, including depression and pathological anxiety, but high-quality sleep and coping strategies — such as the ability to reframe a situation to see the positive side — can help to prevent poor mental health when faced with negative or stressful experiences.
The research studied data from over 600 participants during the COVID-19 pandemic in 2020 — an extended stressful period of time. They aimed to test the theory that coping strategies supported positive mental health outcomes, which could be strengthened by high-quality sleep.
Emma Sullivan, PhD student from the Department of Psychology at the University of York, said: “As the COVID-19 pandemic has been a prolonged period of stress for people across the entire world, it offered us with a unique context with which to address our research questions.
“This is the first study to investigate the ways in which positive coping strategies and sleep quality influence depression and anxiety when experiencing a real-world chronic stressor. We found that better sleep quality was associated with fewer symptoms of both depression and anxiety during the initial months of the COVID-19 pandemic.
“These findings highlight the importance of targeting both positive coping strategies and sleep quality when enduring periods of chronic stress.”
The team analysed data from the Boston College Daily Sleep and Well-being Survey where participants regularly self-reported their sleep quality and mental well-being during the pandemic.
They also completed a baseline demographic survey to obtain information such as their age, gender and ethnicity. As well as collecting information on participants’ sleep and mental well-being, the surveys also collected a wealth of additional information such as participants’ alcohol consumption, their quarantine status and physical activity levels.
Dr Scott Cairney, PhD supervisor on the project from the Department of Psychology at the University of York, said: “We have known for a long time that high-quality sleep is associated with better health and wellbeing outcomes, but we wanted to know whether this would change if sleep and coping strategies were put under intense and prolonged periods of stress, as it was for so many during the pandemic.”
“We found that sleep plays a hugely important role in the management of chronic stress and can sustain well-being over a long period of time, reducing symptoms of depression and anxiety.”