For the neurons in the brain to work smoothly and be able to process information, the central nervous system needs a strictly regulated environment. This is maintained by the blood-brain barrier, whereby specialized brain endothelial cells lining the inner walls of blood vessels regulate the exchange of molecules between the circulatory and nervous systems. Earlier studies have shown that various functions that are dependent on these cells, such as the integrity of the blood-brain barrier or the regulation of blood supply to the brain, decline over the course of a person’s life. This dysregulation leads to a dysfunction of the brain vasculature and is therefore a major contributor to medical conditions such as strokes and dementia.
However, the molecular changes that underlie this loss of function have remained largely obscure. To improve our mechanistic understanding, researchers carry out molecular profiling studies to investigate the different components of brain endothelial cells and collect their findings in large databases. “The transcriptome — that is to say, the RNA contained in endothelial cells — has since been quite comprehensively mapped,” says LMU professor Martin Dichgans, Director of the Institute for Stroke and Dementia Research at University of Munich Hospital and Principal Investigator at the SyNergy Cluster of Excellence. “What has been lacking is corresponding data on the complete set of proteins in the cells, the proteome.” A study recently published in the journal Nature Aging, which had major contributions by researchers from LMU and SyNergy, has now closed this knowledge gap.
Dysregulated metabolism
For the study, the team developed a protocol for enriching brain endothelial cells in mice, which makes it possible to resolve age-related changes in protein composition. Using an unsupervised (computer-aided) cluster analysis, the scientists then related these protein dynamics to biological functions. “Our results show a dysregulation of key molecules involved in the uptake of substances into cells, in receptor recycling, and in the degradation of molecules within specific cellular compartments called lysosomes,” says Dichgans.
One of the most striking changes concerned a decrease in proteins involved in vesicle-mediated transport. In addition, the study provides evidence that deficiency of apolipoprotein E, a protein involved in lipid metabolism results in a signature of accelerated endothelial aging. “The results complement and expand findings from studies on the RNA sequencing of brain endothelial cells during aging,” summarizes Dichgans. “Our proteomic approach captures processes that are not detected at the RNA level.” Overall, the study offers a framework for understanding important endothelial signaling pathways during aging and serves as a data basis for future analyses of brain endothelial function. The researchers are making their data on age-related protein abundance of the mouse endothelium available in a publicly accessible database for further use.

Researchers at the Niels Bohr Institute, University of Copenhagen and University of Southern Denmark have recently published FreeDTS — a shared software package designed to model and study biological membranes at the mesoscale — the scale “in between” the larger macro level and smaller micro level.
This software fills an important missing software among the available biomolecular modeling tools and enables modeling and understanding of many different biological processes involving the cellular membranes e.g. cell division.
Membrane shape contains information about the physiological state of the cell and overall health of an organism, so this new tool, with its wide array of applications, will enhance our understanding of cell behavior and open routes for diagnostics of infections and diseases like Parkinsons.
The publication of FreeDTS is now reported in Nature Communications.
Sharing a powerful tool that could have provided NBI with an advantage. Why?
The software package Weria Pezeshkian from the Niels Bohr Institute has been working on for the last 5 years, after an initial idea between him and John Ipsen from the University of Southern Denmark, is shared — laid open for every researcher in this field to use.
Normally the competition for achieving scientific results is high, and science advancements kept secret until publication — so this seems like a very generous attitude indeed. So generous it might seem a bit naive.

It is a strange mix of respect for the “pioneers” of the biomolecular modeling field and the fact that the field offers so many unanswered questions that it would seem almost disrespectful towards the scientific community to keep the tool to ourselves, Weria Pezeshkian explains.
“There are so many questions and bottlenecks to tackle to reach the end goals, that it would be unlikely that we work on exactly the same problems. However, occasional overlap occurs and is a worthwhile cost we pay for advancing the field.
But there is another aspect as well: One of the reasons our community, the biomolecular simulation and modeling community has had this surge in popularity and a fast growth is that we’ve always strived to get more people into the game and share ideas, results and methods and often direct assistance without expecting immediate personal gains.
Acknowledging Herman Berendsen
Herman Berendsen (1934-2019) was a professor of physical chemistry at the University of Groningen (RUG). He was especially known for his contributions to the field of molecular modeling and his dedication to translate models into accessible applications.
Berendsen was especially praised for his non-hierarchical and open approach. This not only locally at his institute, where he was known for enabling the young researchers in his group, but also among the wider scientific community. He contributed to computer simulation applications that are still widely used to study the dynamics of biomolecules. Examples of this are his SPC (simple-point-charge) model, used to model liquid water; and the ‘Berendsen’ thermostat and barostat, that serves to keep the temperature and pressure constant during simulations.

Also, he organized a series of workshops where pioneers in the field met to discuss and share their newest findings.
Berendsen remains one of RUG’s most cited scholars. The applicability of his work ranges far beyond the field of physical chemistry and it is also used by mathematicians, computer scientists, molecular life scientists and in the development of medical applications.
Biological membranes — what are they really?
When you consider a cell, you can imagine a whole lot of small “factories” inside, called organelles, doing their thing — surrounded by a membrane.
The cell also is surrounded by a membrane called Plasma membrane. But membranes are not just a boundary surface. They are actively participating in many processes. They are made from a myriad of different molecules, and they are dynamic, in motion all the time.
Many diseases are associated with irregular membrane shape and abnormal biomolecular organization, so the study of membranes can help us understand the state of a cell and overall health of an organism. For instance, when a neuron has increased spiking activity, indicating a higher energy demand, the structure of mitochondria, an organelle responsible for generating cellular energy parcels from food (often referred to as the powerhouse of the cell), undergoes changes.
Moreover, certain diseases, e.g., Alzheimers for one, have been associated with changes in the mitochondrial membranes shapes.
Computer models will improve our abilities within diagnostics
“For now, we are not able to see exactly what the exact causes of changes in membrane shape are and how are they exactly related to the diagnostics of a certain disease. But at some point, in the future, the try and error works in the lab will become minimal because modelling will guide experiments with unimaginable accuracy, as our modeling becomes more precise and the power of computational options increasing.
We will need a lot of adjustments and there is still long way to go, so it is really nice to work within this sharing community, because we all work on different aspects of it” Weria Pezeshkian explains.
Weria continues with a word of caution: “This is probably stretching it a bit far, but possibly, in the future, by imaging for example our mitochondria and leveraging physics-based computer simulations we may be able to say: This person has this disease with this specific genetic deficiency. So, the perspective for computational modelling is rather great — we are not there yet, but we can see it in the horizon.”

There were multiple unsafe sleep practices at play in more than three-quarters of Sudden Unexpected Infant Deaths reported in 23 jurisdictions between 2011 and 2020, a new study reveals. The researchers say the findings underscore the need for more comprehensive safe-sleep education for new parents, including from healthcare providers.
Of 7,595 infant deaths reviewed, almost 60% of the infants were sharing a sleep surface, such as a bed, when they died. This practice is strongly discouraged by sleep experts, who warn that a parent or other bed partner could unintentionally roll over and suffocate the baby.
Infants who died while sharing a sleep surface were typically younger (less than 3 months old), non-Hispanic Black, publicly insured, and either in the care of a parent at the time of death or being supervised by someone impaired by drugs or alcohol. These infants were typically found in an adult bed, chair or couch instead of the crib or bassinet recommended by sleep experts.
“The large number of hazardous sleep practices for both infants who were sharing a sleep surface and sleeping alone at the time of death is alarming,” said researcher Fern Hauck, MD, MS, a safe-sleep expert at UVA Health and the University of Virginia School of Medicine. “These are known risk factors for SUID [Sudden Unexpected Infant Death], and tells us that we need to do a better job of working with families to increase acceptance of the recommendations to create safer sleep spaces for their infants.”
Sudden Unexpected Infant Deaths
To better understand the factors contributing to SUID and improve safe-sleep messaging, Hauck and her collaborators analyzed data from the federal Centers for Disease Control and Prevention’s SUID Case Registry. That data reflects localities from Alaska to Wyoming, including the Tidewater area of Virginia.
Examining the registry allowed the researchers to obtain important insights on the prevalence of practices such as prenatal smoking, a known risk factor for SUID, and breastfeeding, which is thought to have a protective benefit. More than 36% of mothers of infants who died had smoked while pregnant. This percentage was higher among moms who bed shared than those who didn’t, 41.4% to 30.5%. Both bed sharers and non-bed sharers had breastfed at similar rates.

The researchers note that it was rare for bedsharing to be the only risk factor present during a child’s death. The findings highlight the need for better public education about safe-sleep practices, and for care providers to take a more active role in teaching new parents about the practices, the researchers say.
“Our findings support comprehensive safe sleep counseling for every family at every encounter beyond just asking where an infant is sleeping,” the researchers write in a new paper in the journal Pediatrics.
In addition to helping parents understand safe-sleep practices, care providers should take steps to ensure parents can follow those practices once they leave the hospital. For example, some families may not have the means to purchase a crib or bassinet; a hospital might direct them to resources to help with that.
“SUID deaths in the U.S. are still higher than in most other countries, and this is unacceptable,” Hauck said. “Clinicians and others caring for infants need to have thoughtful conversations with families at risk to understand the barriers to following safe-sleep guidelines and find ways to work together to overcome them.”
About the SUID Research Team
The SUID research team consisted of Alexa B. Erck Lambert, Carrie K. Shapiro-Mendoza, Sharyn E. Parks, Carri Cottengim, Meghan Faulkner and Hauck. The researchers have no financial interest in the work.

Scientists have taken a major step towards developing a blood test that could identify millions of people who spread tuberculosis unknowingly.
A breakthrough study has discovered a group of biological markers that are found in high levels among infectious patients.
The researchers hope the findings will pave the way for a simple test that can diagnose and stop the spread of the estimated 10 million cases annually.
Tuberculosis, or TB, is the world’s deadliest infectious disease and kills more than one million people each year, according to World Health Organisation data.
Scientists from the University of Southampton, working with experts worldwide, carried out the most detailed analysis ever undertaken of blood markers for the bacterial infection.
The study, published in the Journal of Clinical Investigation Insight, used a novel technique that identified a set of six proteins that are highly accurate in pinpointing TB.
Lead author Dr Hannah Schiff, a respiratory expert at Southampton, said as many as three million cases were missed last year, mostly in developing countries.

She added: “TB remains a global catastrophe because our efforts to control the spread are hindered by inadequate testing, which is slow and reliant on specialist equipment and labs.
“A third of people who get infected go undiagnosed and remain infectious.
“In our study, we combined a new measurement technique with deep mathematical analysis to identify these six new markers of TB disease.
“It could lead to a transformative alternative to diagnosing the condition — a simple test that detects proteins in the bloodstream whose levels differ between people with TB, healthy individuals, and those suffering from other respiratory illnesses.”
TB spreads through inhaling tiny droplets from coughs or sneezes of infected people — and, while it mostly affects the lungs, it can devastate any part of the body.
Cases in the UK increased to around 5,000 last year, and are expected to continue rising in 2024, according to the UK Health Security Agency.

The University of Southampton study was undertaken with experts from the University of Cape Town in South Africa and Cayetano Heredia University in Lima, Peru.
It was published for world TB day, on 24 March, which is held to raise awareness and to step up efforts to end the global Tuberculosis pandemic.
The study was funded by the UK Medical Research Council and the National Institute for Health and Care Research (NIHR) Southampton Biomedical Research Centre.
Academics leading the investigation studied proteins found in the blood of people with active TB in Africa and South America.
They compared the biomarkers to those found in healthy people and patients with lung infections, identifying 118 proteins that differed significantly between the groups.
The experts then narrowed these down to the six proteins that, they said, can be used to distinguish contagious patients with TB from people in good health or with lung conditions.
The findings are a roadmap to developing a TB test that is as simple as the lateral flows used during Covid, said study co-director Dr Diana Garay-Baquero, also from Southampton.
She added: “The new markers we discovered are truly exciting, but the important work now is to develop these into tests that can be used for the millions of people who are transmitting TB without knowing it.
“As the Covid-19 pandemic confirmed, we ignore highly infectious airborne diseases at our peril.”

Eating one avocado per day may improve overall diet quality, according to a team led by researchers in Penn State’s Department of Nutritional Sciences. Poor diet quality is a risk factor for many diseases, including heart disease, and many American adults have poor diet quality and do not meet key dietary recommendations provided by the Dietary Guidelines for Americans.
This study was led by Kristina Petersen, associate professor of nutritional sciences, and Penny Kris-Etherton, retired Evan Pugh University Professor of Nutritional Sciences, and recently published in the journal Current Developments in Nutrition. The researchers examined how a food-based intervention — one avocado per day — impacts overall diet quality.
“Avocados are a nutrient-dense food, containing a lot of fiber and other important nutrients. We wanted to see if regular intake of this food would lead to an increase in diet quality,” Petersen said. “Previous observational research suggests avocado consumers have higher diet quality than non-consumers. So, we developed this study to determine if there is a causational link between avocado consumption and overall diet quality.”
Petersen stated that because only 2% of American adults are regular avocado consumers, the researchers wanted to determine if including avocados in an individual’s daily diet could significantly increase their diet quality.
Researchers conducted phone interviews with participants before the study began and at a few points throughout to determine what their dietary intake was like in the previous 24 hours and evaluated their diets using the Healthy Eating Index to determine how well they adhered to the Dietary Guidelines for Americans. Adherence to the guidelines was used as a measure of overall diet quality.
The study consisted of 1,008 participants who were split into two groups. One group continued their usual diet and limited their avocado intake during the 26-week study, while the other group incorporated one avocado per day into their diet.
“We found that the participants who had an avocado per day significantly increased their adherence to dietary guidelines,” Petersen said. “This suggests that strategies, like eating one avocado per day, can help people follow dietary guidelines and improve the quality of their diets.”
Although researchers said they were not surprised to see that eating avocados daily improved diet quality, they had not predicted how participants were able to achieve it.

“We determined that participants were using avocados as a substitute for some foods higher in refined grains and sodium,” Petersen said. “In our study, we classified avocados as a vegetable and did see an increase in vegetable consumption attributed to the avocado intake, but also participants used the avocados to replace some unhealthier options.”
According to Petersen, having poor diet quality substantially increases the risk for conditions like heart disease, type 2 diabetes, kidney disease and many other preventable diseases.
“By improving people’s adherence to dietary guidelines, we can help to reduce their risk of developing these chronic conditions and prolong healthy life expectancy,” Petersen said.
Petersen has also conducted similar studies investigating the impact of food-based interventions, including the relationship between pistachios and diet quality, but said that more research is needed to determine what other food-based strategies can be used to improve people’s adherence to dietary guidelines.
“In studies like this one, we are able to determine food-based ways to improve diet quality, but behavioral strategies are also needed to help people adhere to dietary guidelines and reduce their risk of chronic disease,” Petersen said.
Other contributors to the study include Sydney Smith and David M. Reboussin, Wake Forest University School of Medicine; Alice H. Lichtenstein and Nirupa R. Matthan, Tufts University; Zhaoping Li, David Geffen School of Medicine at the University of California, Los Angeles; and Joan Sabate, Sujatha Rajaram and Gina Segovia-Siapco, Loma Linda University.
The Avocado Nutrition Center supported this study. The funder did not influence the data analysis, data interpretation or writing of the published study.

On the surface, the movement disorder amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, and the cognitive disorder frontotemporal lobar degeneration (FTLD), which underlies frontotemporal dementia, manifest in very different ways. In addition, they are known to primarily affect very different regions of the brain.
However, doctors and scientists have noted several similarities over the years, and a new study in Cell reveals that the diseases have remarkable overlaps at the cellular and molecular levels, revealing potential targets that could yield therapies applicable to both disorders.
The new paper, led by scientists at MIT and the Mayo Clinic, tracked RNA expression patterns in 620,000 cells spanning 44 different cell types across motor cortex and prefrontal cortex from postmortem brain samples of 73 donors diagnosed with ALS, FTLD, or who were neurologically unaffected.
“We focused on two brain regions that we expected would be differentially affected between the two disorders,” said Manolis Kellis, co-senior author of the paper and professor in the Computer Science and Artificial Intelligence Laboratory at MIT. “It turns out that at the molecular and cellular level, the changes we found were nearly identical in the two disorders, and affected nearly identical subsets of cell types between the two regions.”
Indeed, one of the most prominent findings of the study revealed that in both diseases the most vulnerable neurons were almost identical both in the genes that they express, and in how these genes changed in expression in each disease.
“These similarities were quite striking, suggesting that therapeutics for ALS may also apply to FTLD and vice versa,” said lead corresponding author Myriam Heiman, associate professor in The Picower Institute for Learning and Memory and the Department of Brain and Cognitive Sciences at MIT. “Our study can help guide therapeutic programs that would likely be effective for both diseases.”
Heiman and Kellis collaborated with co-senior author Veronique Belzil, then associate professor of neuroscience at the Mayo Clinic Florida, now director of the ALS Research Center at Vanderbilt University.

Another key realization from the study is that brain donors with inherited vs. sporadic forms of the disease showed similarly altered gene expression changes, even though these were previously thought to have different causes. That suggests that similar molecular processes could be going awry downstream of the diseases’ origins.
“The molecular similarity between the familial (monogenic) form and the sporadic (polygenic) forms of these disorders suggests that convergence of diverse etiologies into common pathways,” Kellis said. “This has important implications for both understanding patient heterogeneity and understanding complex and rare disorders more broadly.”
‘Practically indistinguishable’ profiles
This overlap was especially evident, the study found, when looking at the most affected cells. In ALS, known to cause progressive paralysis and ultimately death, the most endangered cells in the brain are upper motor neurons (UMN) in layer 5 of the motor cortex. Meanwhile in behavioral variant frontotemporal dementia (bvFTD), the most common type of FTLD that is characterized instead by changes to personality and behavior, the most vulnerable neurons are spindle neurons, or von Economo cells, found in layer 5 of more frontal brain regions.
The new study shows that while the cells look different under the microscope, and make distinct connections in brain circuits, their gene expression in health and disease is nevertheless strikingly similar.
“UMNs and spindle neurons look nothing alike and live in very different areas of the brain” said Sebastian Pineda, lead author of the study, and a graduate student jointly supervised by Heiman and Kellis. “It was remarkable to see that they appear practically indistinguishable at the molecular level and respond very similarly to disease.”
The researchers found many of the genes involved in the two diseases implicated primary cilia, tiny antenna-like structures on the cell’s surface that sense chemical changes in the cell’s surrounding environment. Cilia are necessary for guiding the growth of axons, or long nerve fibers that neurons extend to connect with other neurons. Cells that are more dependent on this process, typically those with the longest projections, were found to be more vulnerable in each disease.

The analysis also found another type of neuron, which highly expresses the gene SCN4B and which was not previously associated with either disease, also shared many of these same characteristics and showed similar disruptions.
“It may be that changes to this poorly characterized cell population underlie various clinically-relevant disease phenomena,” Heiman said.
The study also found that the most vulnerable cells expressed genes known to be genetically-associated with each disease, providing a potential mechanistic basis for some of these genetic associations. This pattern is not always the case in neurodegenerative conditions, Heiman said. For example, Huntington’s disease is caused by a well-known mutation in the huntingtin gene, but the most highly affected neurons don’t express huntingtin more than other cells, and the same is true for some genes associated with Alzheimer’s disease.
Looking beyond neurons, the study characterized gene expression differences in many other brain cell types. Notably, researchers saw several signs of trouble in the brain’s circulatory system. The blood-brain barrier (BBB), a filtering system that tightly regulates which molecules can go into or come out of the brain through blood vessels, is believed to be compromised in both disorders.
Building on their previous characterization of human brain vasculature and its changes in Huntington’s and Alzheimer’s disease by Heiman, Kellis, and collaborators including Picower Institute Director Li-Huei Tsai, the researchers found that proteins needed to maintain blood vessel integrity are reduced or misplaced in neurodegeneration. They also found a reduction of HLA-E, a molecule thought to inhibit BBB degradation by the immune system.
Given the many molecular and mechanistic similarities in ALS and FTLD, Heiman and Kellis said they are curious why some patients present with ALS and others with FTLD, and others with both but in different orders.
While the present study examined “upper” motor neurons in the brain, Heiman and Kellis are now seeking to also characterize connected “lower” motor neurons in the spinal cord, also in collaboration with Belzil.
“Our single-cell analyses have revealed many shared biological pathways across ALS, FTLD, Huntington’s, Alzheimer’s, vascular dementia, Lewy body dementia, and several other rare neurodegenerative disorders,” says Kellis. “These common hallmarks can pave the path for a new modular approach for precision and personalized therapeutic development, which can bring much-needed new insights and hope.”
In addition to Pineda, Belzil, Kellis and Heiman, the study’s other authors are Hyeseung Lee, Maria Ulloa-Navas, Raleigh Linville, Francisco Garcia, Kyriaktisa Galani, Erica Engelberg-Cook, Monica Castanedes, Brent Fitzwalter, Luc Pregent, Mahammad Gardashli, Michael DeTure, Diana Vera-Garcia, Andre Hucke, Bjorn Oskarsson, Melissa Murray and Dennis Dickson.
Support for the study came from the National Institutes of Health, Mitsubishi Tanabe Pharma Holdings, The JPB Foundation, The Picower Institute for Learning and Memory, the Robert Packard Center for ALS Research at Johns Hopkins, The LiveLikeLou Foundation, the Gerstner Family Foundation, The Mayo Clinic Center for Individualized Medicine, and the Cure Alzheimer’s Fund.

Academics are proposing a new and improved way to help researchers discover when consciousness emerges in human infancy.
When over the course of development do humans become conscious? When the seventeenth-century French philosopher René Descartes was asked about infant consciousness by his critics, he eventually suggested that infants might have thoughts, albeit ones that are simpler than those of adults. Hundreds of years later, the issue of when human beings become conscious is a question which remains a challenge for psychologists and philosophers alike.
But now, in response to a recent article in Trends in Cognitive Sciences, two academics from the University of Birmingham have suggested an improved way to help scientists and researchers identify when babies become conscious.
In a Letter to the Editor, also published in Trends in Cognitive Sciences, Dr Henry Taylor, Associate Professor of Philosophy, and Andrew Bremner, Professor of Developmental Psychology, have explored a new approach which is being proposed, that involves identifying markers of consciousness in adults, and then measuring when babies start to exhibit larger numbers of these in development.
Dr Taylor says: “For example, imagine that in adults, we know that a certain very specific behaviour, or a specific pattern of brain activation always comes along with consciousness. Then, if we can identify when this behaviour or brain activation arises in babies, we have good reason to think that this is when consciousness emerges in babies. Behaviours and brain activations like this are what we call ‘markers’ of consciousness.”
This kind of approach is desperately needed since babies (unlike adults) cannot tell you what they are conscious of. Professor Bremner said: “It is really hard to establish when babies become conscious. This is mostly because infants can’t report their experiences and, as most parents will know, can be rather uncooperative particularly when it comes to experimental tasks. As we can’t just ask babies when they become conscious, the best approach is to try to identify a broad range of markers of consciousness, which appear in early development and late development, and then group them together, this could help us identify when consciousness emerges.”
In the recent article the researchers (Prof. Tim Bayne and colleagues) suggested four specific markers of consciousness, some of which are present in the late stages of gestation, and others which are found in early infancy. Based on this, the study argues that consciousness emerges early (from the last prenatal trimester).

But Professor Bremner and Dr Taylor say that this ignores other markers of consciousness. Previous research has identified a separate cluster of markers. These include:
• Pointing (bringing a social partner’s attention to an object and checking). • Intentional control (intentional means-end coordination of actions — e.g., pulling a support to retrieve a distal object). • Explicit memory (deferred imitation of actions).
Dr Taylor said: “One of the complicated issues is that it does not look like all the markers point to the same age for the emergence of consciousness. The ones mentioned by Bayne and colleagues suggest somewhere between the third trimester of pregnancy and early infancy, but other markers suggest the age might be around one year old. In fact, at the really extreme end, some markers only emerge at around 3-4 years. Because there are so many different markers of consciousness which appear in early and late development it is extremely hard to come to a conclusion.”
Professor Bremner concluded: “We propose that a broad approach to markers, including those that emerge in early and late stage, is needed. We also recommend that a range of developmental models of the onset of consciousness should be considered. For instance, it may be that some markers emerge in one cluster in early development, with others in a later cluster. As well as this there may be a continuous and gradual emergence of certain markers stretching over gestation and throughout early life.
“We think that by clustering this broad selection of markers, we may finally be able to answer the question which has given us pause for thought for thousands of years. But it’s important to bear in mind that the answer may not be a simple one!”Academics are proposing a new and improved way to help researchers discover when consciousness emerges in human infancy.

Researchers at the University of Toronto and Sinai Health have created a new platform to identify proteins that can be co-opted to control the stability of other proteins — a new but largely unrealized approach to the treatment of disease.
The researchers developed a method to interrogate the entire human proteome for ‘effector’ proteins, which can influence the stability of other proteins via induced proximity. The study marks the first time researchers have searched for effector proteins on this scale, and has identified many new effectors that could be used therapeutically.
“We found more than 600 new effector proteins in 14,000 genes,” said Juline Poirson, first author on the study and visiting scientist at U of T’s Donnelly Centre for Cellular and Biomolecular Research. “Over 200 of the new effectors can efficiently degrade their target proteins, while about 400 effectors were capable of stabilizing, and thereby increasing the abundance of, an artificial target protein.”
The study, which involved researchers at Sinai Health’s Lunenfeld-Tanenbaum Research Institute, was published in the journal Nature.
“Targeting proteins through induced proximity is a new and promising area of biomedical research,” said Mikko Taipale, principal investigator on the study and an associate professor of molecular genetics at the Donnelly Centre and the Temerty Faculty of Medicine. “Not only did we find new effectors worth further investigation for drug discovery, we developed a synthetic platform that can be used to conduct unbiased, proteome-wide, induced-proximity screens to continue expanding the library of effector proteins.”
The effectors currently in use for targeted protein degradation and stabilization are E3 ubiquitin-ligases (E3s) and deubiquitinases (DUBs), respectively. E3 is an enzyme that transfers the ubiquitin molecule to the target protein, which essentially flags the protein for a proteosome to digest it. On the other hand, a DUB enzyme removes the ubiquitin tag from a protein, thereby preventing the protein from being recognized and degraded by a proteosome.
The results of the study demonstrate that E3s are quite varied in the degree to which they can degrade target proteins they are brought into contact with. The research team even discovered four of what they call ‘angry E3s,’ which consistently degrade targets regardless of other factors, such as the location of the target within the cell.

A particularly surprising finding was that some of the strongest effectors for targeted protein degradation were E2 conjugating enzymes, instead of E3s. These differ from E3s in that they are involved at an earlier step of protein degradation and do not directly engage the target protein. Because E2s were not considered to be easily druggable, they had not been harnessed for targeted protein degradation until recently. They represent, however, the untapped potential of stronger effectors than ones currently in use.
The study shows that exploring the whole proteome for induced proximity offers enormous opportunities for therapeutic interventions. KLHL40, one of the identified effectors, could potentially be hijacked for targeted protein stabilization to treat skeletal muscle disorders. The research team also found that targeted protein degradation with FBXL12 and FBXL15 effectors could be particularly useful in treating chronic myeloid leukemia.
Targeted protein degradation and stabilization are innovative methods of drug discovery that have thus far been plagued with the “protein pair problem,” where the best effector for a target protein cannot be predicted accurately. Matching a target protein with the right effector is essential to successfully, and safely, facilitate degradation and stabilization processes in tissues.
“The synthetic screening platform developed by our team solves the protein matching issue through rapid, large-scale testing of effector and target protein interactions,” said Poirson. “We’re confident that an unbiased induced-proximity approach can be used to find effectors for almost any target.”

Researchers at McMaster University and Stanford University have invented a new generative artificial intelligence model which can design billions of new antibiotic molecules that are inexpensive and easy to build in the laboratory.
The worldwide spread of drug-resistant bacteria has created an urgent need for new antibiotics, but even modern AI methods are limited at isolating promising chemical compounds, especially when researchers must also find ways to manufacture these new AI-guided drugs and test them in the lab.
In a new study, published today in the journal Nature Machine Intelligence, researchers report they have developed a new generative AI model called SyntheMol, which can design new antibiotics to stop the spread of Acinetobacter baumannii, which the World Health Organization has identified as one of the world’s most dangerous antibiotic-resistant bacteria.
Notoriously difficult to eradicate, A. baumannii can cause pneumonia, meningitis and infect wounds, all of which can lead to death. Researchers say few treatment options remain.
“Antibiotics are a unique medicine. As soon as we begin to employ them in the clinic, we’re starting a timer before the drugs become ineffective, because bacteria evolve quickly to resist them,” says Jonathan Stokes, lead author on the paper and an assistant professor in McMaster’s Department of Biomedicine & Biochemistry, who conducted the work with James Zou, an associate professor of biomedical data science at Stanford University.
“We need a robust pipeline of antibiotics and we need to discover them quickly and inexpensively. That’s where the artificial intelligence plays a crucial role,” he says.
Researchers developed the generative model to access tens of billions of promising molecules quickly and cheaply.

They drew from a library of 132,000 molecular fragments, which fit together like Lego pieces but are all very different in nature. They then cross-referenced these molecular fragments with a set of 13 chemical reactions, enabling them to identify 30 billion two-way combinations of fragments to design new molecules with the most promising antibacterial properties.
Each of the molecules designed by this model was in turn fed through another AI model trained to predict toxicity. The process yielded six molecules which display potent antibacterial activity against A. baumannii and are also non-toxic.
“Synthemol not only designs novel molecules that are promising drug candidates, but it also generates the recipe for how to make each new molecule. Generating such recipes is a new approach and a game changer because chemists do not know how to make AI-designed molecules,” says Zou, who co-authored the paper.
The research is funded in part by the Weston Family Foundation, the Canadian Institutes of Health Research, and Marnix and Mary Heersink.

Only a very small percentage of neurons show changes after an epileptic seizure in mice, but these alterations can be permanent and trigger future seizures that can affect the whole brain and lead to impaired cognition, like memory and learning, according to new research from the Perelman School of Medicine at the University of Pennsylvania. The researchers identified an experimental treatment that, if provided within the first 48 hours after the first seizure, can prevent these long-term changes. The findings, which were published recently in The Journal of Clinical Investigation, suggest a promising target for developing treatments for epilepsy and preventing downstream effects of seizures.
Epilepsy is characterized by excessive activity of brain cells — neurons — which generate seizures. Research is increasingly showing that the development of epilepsy involves changes of synapses, which are structures that connect one neuron to another. While an estimated 3.4 million people in the United States live with some form of epilepsy, it is still unknown what causes it, and there is no cure. Further, half of individuals with epilepsy experience cognitive impairment, such as problems with memory, or with emotional regulation, but it remains unclear why or how epilepsy changes brain cells to cause this. What’s more, epilepsy is common in children with autism and individuals with dementia.
“It is clear that there is some connection between an epileptic brain, impaired memory and trouble controlling emotions and how we act on those feelings, but we don’t understand the underlying mechanisms,” said Frances E. Jensen, MD, chair of the Department of Neurology, and senior author of the study. “Existing treatments for epilepsy only help manage seizures. This research gives us a promising starting point for developing therapies that prevent them from happening.”
In this study, the researchers used a method that “tagged” neurons in the hippocampus — an area commonly affected by epilepsy, and critical for memory — of mice that were activated by epileptic activity. The researchers were able to monitor those activated neurons over time and observe how they responded to subsequent seizures. They found that only about twenty percent of neurons in the hippocampus were activated by seizures. Over time, the overactivity of these neurons diminished their ability to make connections with other neurons, called synapses, which is necessary for learning.
“The overactive neurons lose their ability to build the strong synapses necessary for learning, which may explain why some people with epilepsy have trouble with learning and with memory,” said Jensen. “If we can stop these neurons from undergoing changes after being activated by seizures, our hope is that we can also prevent not only the progression of epilepsy, but also avoid these cognitive deficits individuals experience long-term.”
To see if they could prevent neurons from becoming permanently epileptic, the researchers used an experimental glutamate receptor-blocker, called IEM-1460, which has been shown to reduce neuron hyperexcitability in models of mice with epilepsy. They found when they treated mice with this blocker in the first 48 hours after their very first seizure the neurons did not become permanently activated, and the subjects did not experience future seizures or the associated effects, like impaired cognition and trouble learning.
“Now that we have identified the subgroup of neurons that are impacted by epilepsy, we can investigate what makes these cells vulnerable to becoming epileptic, and whether that is something we can develop a therapy to stop,” said Jensen. “We are also eager to determine whether there is a glutamate receptor-blocker that works similarly to IEM-1460 in humans, which could be given to people after their first seizure, and prevent the lifelong struggles associated with epilepsy.”