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A new gene therapy targeting the small brain region where dopamine neurons reside, the substantia nigra, substantially boosts the benefits of the drug levodopa in Parkinson’s. The therapy restored the ability of these neurons to convert levodopa to dopamine. Scientists also showed how damage to the powerplants inside dopamine-releasing neurons triggers Parkinson’s. The findings may help identify humans in the earliest stages of Parkinson’s disease, develop therapies to slow disease progression and treat late-stage disease.
In late-stage Parkinson’s disease, the drug levodopa becomes less effective in treating symptoms because of the inexorable loss of dopamine-releasing neurons. But a new Northwestern Medicine preclinical study shows a gene therapy targeting the small brain region where these neurons reside, the substantia nigra, substantially boosts the benefits of levodopa.
The gene therapy restored the ability of neurons in the substantia nigra to convert levodopa to dopamine. In essence, this allowed levodopa to recreate the environment found in the healthy brain and eliminated the aberrant brain activity responsible for difficulty in moving.
In the same study, scientists also provide an explanation for why dopamine-releasing neurons are lost in the disease. Using advanced genetic tools, the authors show that damage to the powerplants inside dopamine-releasing neurons (mitochondria) is sufficient to trigger a sequence of events that faithfully recapitulates what happens to brain circuits in Parkinson’s disease.
The findings in mice, which will be published Nov. 3 in Nature, may help identify humans in the earliest stages of Parkinson’s disease, develop therapies to slow disease progression and treat late-stage disease.
The key new findings: Damage to the power plants in dopamine-releasing neurons is enough to cause Parkinson’s disease. When these power plants (mitochondria) begin to shut down, the ability of neurons to do their jobs in the brain is compromised. Without a sufficient source of energy, neurons eventually wither and die. This finding opens a new path to develop therapies to protect the function of mitochondria. Contrary to the past 30 years of thinking, the emergence of the motor symptoms of Parkinson’s disease requires the loss of dopamine release in a small region of the brain called the substantia nigra. This discovery also opens the door to new therapies for late-stage Parkinson’s disease patients. Scientists demonstrated that a gene therapy targeting the substantia nigra effectively boosts the symptomatic benefit of levodopa.”The development of effective therapies to slow or stop Parkinson’s disease progression requires scientists know what causes it,” said lead study author D. James Surmeier, chair of neuroscience at Northwestern University Feinberg School of Medicine. “This is the first time there has been definitive evidence that injury to mitochondria in dopamine-releasing neurons is enough to cause a human-like parkinsonism in a mouse.
“Whether mitochondrial damage was a cause or consequence of the disease has long been debated. Now that this issue is resolved, we can focus our attention on developing therapies to preserve their function and slow the loss of these neurons.”
In addition to providing a clear target for disease-modifying therapies, the study provides a model of Parkinson’s disease before clinical symptoms appear. The slow, progressive loss of dopamine-releasing neurons in the model allowed researchers to see what may be happening in the brain well before movement becomes difficult.
“This new ‘human-like’ model may help us develop tests that would identify people who are on their way to being diagnosed with Parkinson’s disease in five or 10 years,” Surmeier said. “Doing so would allow us to get them started early on therapies that could alter disease progression.”
Other Northwestern authors are Patricia Gonzalez-Rodriguez, Enrico Zampese, Kristen Stout, Jamie Guzman, Ben Yang, Tatiana Tkatch, Ema Ilijic and Paul Schumacker.
The research was supported by the Michael J. Fox Foundation, the JPB Foundation, the IDP Foundation, the Flanagan Foundation and the National Institutes of Health.
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Materials provided by Northwestern University. Original written by Marla Paul. Note: Content may be edited for style and length.

Scientists have identified how a protein in the brain uses information about the body’s energy balance to regulate growth rate and the onset of puberty in children.
The research, scheduled to publish Nov. 3 in the journal Nature, centered on the melanocortin 3 receptor (MC3R), a member of a family of proteins that have long been known to play central roles in metabolism and energy balance.
University of Michian physiologist Roger Cone and colleagues discovered the MC3R gene more than 20 years ago and demonstrated that mice lacking this protein exhibit reduced linear growth, reduced lean mass and increased obesity. Subsequent studies published by Cone’s group also demonstrated a role for the receptor in regulating the interaction between reproduction and energy state, including the increased feeding and weight gain during pregnancy.
Now, an international team of scientists led by Sir Stephen O’Rahilly at the Wellcome-MRC Institute of Metabolic Science, University of Cambridge, has revealed for the first time how defects in the MC3R translate to humans — with results strikingly similar to the findings in mice.
The O’Rahilly team reports identification of the first individual with mutations in both copies of the MC3R gene, leaving the person with no functioning MC3R. Such cases are extremely rare, perhaps occurring in as little as one in a billion people. This individual showed phenotypes, or physical traits, that were nearly identical to mice with no MC3R.
Using data from UK Biobank and the Avon Longitudinal Study of Parents and Children, the team analyzed the phenotypes in volunteers with mutations in one copy of the gene that encodes the MC3R. These individuals displayed shorter body height and reduced lean mass compared with those who had no MC3R mutations.
“In terms of melanocortins, every phenotype that we have observed in the mouse has ultimately been found to be replicated in humans,” said Cone, director of the U-M Life Sciences Institute and an author of the new study. “This direct correlation between animal models and humans is not always the case; but this research shows that mice are a near-perfect model for studying human syndromes related to melanocortin receptors.”
Additionally, O’Rahilly discovered one new phenotype in people with MC3R mutations: a long delay in the onset of puberty in the patient lacking MC3R, and subtle but significant delays in volunteers from the UK Biobank with mutations in only one copy of the gene. Due to the discovery of only a single patient with loss of both copies of the MC3R gene, the researchers also used mouse gene knockout models to confirm and further understand the findings.
New data generated by the Cone lab and collaborator Richard Simerly at the Vanderbilt School of Medicine, and published in this latest study, verify this effect and also argue that MC3R plays a role in communicating nutritional deprivation to the reproductive axis.
When mice are fasted for 24 hours, the MC3R detects the lack of energy stores in the body and relays that information to the part of the brain that regulates reproductive cycles. In normal mice, the reproductive cycles halt until energy stores return to normal, post-fasting. In mice with no MC3R, however, there is no change to the reproductive axis following fasting, indicating that communication about the energy balance has stopped.
“These types of experiments give us important new understanding of the body’s metabolic and reproductive pathways, but they obviously cannot be done in humans,” said Cone, who is also a professor of molecular and integrative physiology at the U-M Medical School. “This research illustrates the critical role of animal models for studying the fundamentals of physiology, which can then be translated to human health and disease.”
The research was supported by the National Institutes of Health (United States), the UK Medical Research Council, Wellcome and the National institute for Health Research (United Kingdom).

George Washington University researchers have identified a key molecule in certain kinds of breast cancers that prevent immune cells from entering tumors and killing the cancer cells inside. The paper and its findings, published today in Nature, could pave the way toward a new treatment for certain kinds of aggressive breast cancer.
“During cancer progression, this molecule, known as DDR1, organizes a high-order extracellular matrix that acts like barbed wire around the boundary of a tumor to prevent immune cells from entering the tumor,” Rong Li, the Ross Professor of Basic Science Research at GW and lead author of the paper, said. “Knowing that the DDR1 molecule creates a protective boundary around tumors, we were able to use pre-clinical models to show that the moment you deactivate DDR1, immune cells can infiltrate the tumor and kill the cells inside.”
Li and his colleagues studied triple-negative breast cancer, an aggressive form of cancer that accounts for about 15% of all breast cancer cases. This type of cancer, according to the Centers for Disease Control and Prevention, lacks the receptors commonly used in targeted cancer therapies, making it difficult to target the tumor cells. Immunotherapy is designed to activate immune cells when they can get to the center of a tumor, but the DDR1 molecule puts up a physical barrier to anti-tumor immune cells. Identifying the underlying mechanism could provide a new way of looking for novel therapeutic agents for this hard-to-treat cancer, Li said.
In the Nature study, the researchers assessed the impact of removing DDR1 in multiple pre-clinical models. They determined that knocking out DDR1 not only halts tumor growth, but it also may protect the body from future tumors.
In conjunction with the new findings, co-corresponding author Zhiqiang An has developed a therapeutic DDR1-targeting antibody that breaks down that line of defense and helps tumor-killing immune cells cross.
“The discovery of the important role of DDR1 in cancer resistance is a significant advance that can potentially transform treatment pathways,” said An, who serves as director of the Texas Therapeutics Institute and a professor of molecular medicine at The University of Texas Health Science Center at Houston (UTHealth Houston). “I’m delighted by the collaboration between researchers and academic labs, excited by synergies of basic and translational research, and encouraged by the rapid translation from discovery to therapeutic candidates for the benefit of people living with cancer.”
With this more comprehensive understanding of DDR1, researchers also hope to identify additional molecules like DDR1 and use the same approach to fight other cancers.
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In a breakthrough for the treatment of aggressive solid cancers, researchers at Children’s Hospital of Philadelphia (CHOP) have developed a novel cancer therapy that targets proteins inside cancer cells that are essential for tumor growth and survival but have been historically impossible to reach. Using the power of large data sets and advanced computational approaches, the researchers were able to identify peptides that are presented on the surface of tumor cells and can be targeted with “peptide-centric” chimeric antigen receptors (PC-CARs), a new class of engineered T cells, stimulating an immune response that eradicates tumors.
The discovery, which was described today in Nature, opens the door to treating a broader array of cancers with immunotherapy as well as applying each therapy across a greater proportion of the population.
“This research is extremely exciting because it raises the possibility of targeting very specific tumor molecules, expanding both the cancers that can be treated with immunotherapy and the patient population who can benefit,” said Mark Yarmarkovich, PhD, an investigator in the Maris Laboratory at Children’s Hospital of Philadelphia and first author of the paper. “By using a multi-omics approach, we were able to identify peptides specific to neuroblastoma tumors, but this method could be used in any cancer, allowing for a more personalized approach to cancer treatment.”
The development of CAR T cell-based cancer immunotherapy marked a breakthrough in the treatment of leukemia, but the approach has not yet made significant strides against solid tumors due, at least in part, to a lack of tumor-specific targets. In these cancers, most of the proteins responsible for tumor growth and survival are in the nuclei of tumor cells, not on the cell surface, where they would generally be accessible to CAR T cells. Instead, fragments of these proteins may be presented on the tumor cell surface through the presentation of peptides on the major histocompatibility complex (MHC), which evolved to present viral and bacterial peptides to the immune system. Cancer cells can also present intracellular proteins on MHC, and if these are mutant peptides, they may be recognized as foreign. However, all pediatric cancers and many adult malignancies have few mutations and are rather driven by other factors like dysregulated developmental pathways.
Neuroblastoma is an explosively aggressive pediatric cancer that is driven by modifications of gene expression that promote uncontrolled tumor growth. Historically, neuroblastoma has been treated with chemotherapy, surgery, and radiation therapy, but patients often relapse with forms of the disease that are chemotherapy resistant. Additionally, the low mutational burden of the cancer, combined with its low MHC expression, have made it difficult to target with immunotherapies.
Despite these obstacles, the researchers hypothesized that some of the peptides presented on the surface of neuroblastoma tumor cells come from proteins that are essential for tumor growth and survival and could be targeted with synthetic CARs. These PC-CARs would allow for direct targeting and killing of tumor cells. The challenge was differentiating tumor-specific peptides from other, similar looking peptides or peptides that exist in normal tissues to avoid cross-reactivity and lethal toxicity.
To do so, the researchers stripped the MHC molecules off neuroblastoma cells and determined which peptides were present and at what abundance. They used a large genomic dataset that the Maris lab has generated to determine which peptides were unique to neuroblastoma and not expressed by normal tissues. They prioritized peptides that were derived from genes essential to the tumor and had characteristics required to engage the immune system. To weed out any potential antigens that might have cross reactivity with normal tissue, the researchers filtered the remaining tumor peptides against a database of MHC peptides on normal tissues, removing any peptide with a parent gene represented in normal tissue.
Using this multi-omics approach, the researchers pinpointed an unmutated neuroblastoma peptide that is derived from PHOX2B, a neuroblastoma dependency gene and transcriptional regulator that was previously identified and characterized at CHOP. The next major hurdle was developing a PC-CAR that specifically recognized just the peptide, which makes up 2-3% of the peptide-MHC complex. In collaboration with antibody-discovery company Myrio Therapeutics, the researchers developed a PC-CAR targeting this peptide and showed that these PC-CARs recognized the tumor-specific peptide on different HLA types, meaning the treatment could be applied to patients of diverse genetic lineages.
Taking the research a step further, the team tested the PC-CARs in mice and found that the treatment led to complete and targeted elimination of neuroblastoma tumors.
“We are excited about this work because it allows us to now go after essential cancer drivers that have been considered ‘undruggable’ in the past. We think that PC-CARS have the potential to vastly expand the pool of immunotherapies and significantly widen the population of eligible patients,” said senior author John M. Maris, MD, pediatric oncologist and Giulio D’Angio Chair in Neuroblastoma Research at CHOP. “Thanks to the Acceleration grant we received through the Cell and Gene Therapy Collaborative at CHOP, we will bring our PHOX2B PC-CAR to a clinical trial at CHOP in late 2022 or early 2023.”

Who Can Make mRNA Vaccines?Stephanie NolenReporting on Covid vaccine accessThe technology is new, but Pfizer-BioNTech and Moderna found ways to start production quickly. BioNTech went to a former cancer drug maker in Germany to make its shot. Moderna shipped its producers a modular kit, kind of like an Ikea kitchen.What’s essential is a company that does high-quality medicine production, plus a regulating body that can enforce top standards.From my years of reporting on global health, I knew of candidates in developing countries.

SharecloseShare pageCopy linkAbout sharingImage source, Getty ImagesThe puzzle of why humans are growing taller and reaching puberty earlier than ever before can be explained by a sensor in the brain, scientists say.Average height in the UK rose by 3.9in (10cm) during the 20th Century, and up to 7.8in in other countries, as nutritional health improved.But exactly how this happens has never been understood.The discovery could lead to drugs to improve muscle mass and treat delayed growth, UK researchers say.Scientists have known for a long time that humans with good diets and reliable access to food tend to grow taller, and mature more quickly. In South Korea, for example, adult height has rocketed as the nation transformed from a poor country to a developed society. Yet in parts of South Asia and Africa, people are only slightly taller than 100 years ago.’Make lots of babies’It’s known that signals from food reach a part of the brain called the hypothalamus, telling it about the body’s nutritional health, and triggering growth.This new study, published in Nature, and led by researchers from the University of Cambridge alongside teams from Queen Mary University of London, University of Bristol, University of Michigan and Vanderbilt University, has discovered the brain receptor behind that process.It’s called MC3R and is the crucial link between food and sex development and growth. “It tells the body we’re great here, we’ve got lots of food, so grow quickly, have puberty soon and make lots of babies,” said Prof Sir Stephen O’Rahilly, study author, from Cambridge.”It’s not just magic – we have the complete wiring diagram for how it happens.” Image source, Getty ImagesWhen the brain receptor doesn’t work normally in humans, the researchers found people tended to be shorter in height, and started puberty later than other people.The team searched through the genetic make-up of half a million volunteers signed up to the UK Biobank – a huge database of genetic and health information – to confirm this was true.Children found to have gene mutations which disrupt the brain receptor, were all shorter and weighed less than other children, which shows the effect starts early in life.The research team found one person who had mutations in both copies of the gene for MC3R, which is extremely rare and damaging. This person was very short, and started puberty after the age of 20.Drugs for the futureBut humans are not alone in this – researchers studied mice to confirm that the same pathway is at work in animals.The discovery could help children with serious delays in growth and puberty, as well as those who become frail with chronic diseases and need to build up muscle.”Future research should investigate if drugs that selectively activate the MC3R might help redirect calories into muscle and other lean tissues, with the prospect of improving the physical functionality of such patients,” Prof O’Rahilly said.Scientists had already identified a brain receptor which controls appetite, called MC4R, and those who lack it are usually obese.Can people keep growing taller?There is a ceiling for height and it’s reached when people achieve their genetic potential.Factors such as health and diet have a huge impact on whether that happens.When children from poorer families get enough food and calories, they can grow to the height they inherit from their parents and grandparents.Taller people generally live longer and are less likely to suffer from heart problems, and may also end up earning more.But humans can’t keep on growing forever.Like many other countries in Europe, average height in the UK shot up during the last century – but there are signs in the last 10 years that it’s flattening.Elsewhere, the largest height rises over the past century have been in South Korean women and Iranian men.The tallest people in the world are men born in the Netherlands (71.8in), while the shortest are women born in Guatemala (55.1in).UKRI – UK Research and InnovationMRC Institute of Metabolic Science at Cambridge UniversityThe BBC is not responsible for the content of external sites.

Gait disorders manifest themselves in various ways: One walks with small tripping steps, another drags a leg while walking. In one case, a foot does not roll over the sole of the foot, and in another, a foot is not lifted sufficiently but is rather dragged across the floor. For those affected, these disorders may simply have a minor negative impact on their daily routine while for others they can represent a major impairment of their quality of life. In many cases, however, pathological gait patterns are actually accompanying effects or can even be symptomatic of an underlying disease. For this reason, biomechanical gait analysis can be a helpful tool when it comes to diagnosing problems and subsequently treating them. “Until now, there has been a worldwide lack of reference data for healthy persons,” emphasized Dr. Fabian Horst of Johannes Gutenberg University Mainz (JGU). An adequate quantity of data on the walking characteristics of healthy individuals is needed to be able to reliably detect and classify pathological gait patterns and any causative ailments. Dr. Fabian Horst, a sports scientist, has now presented a database that will help to close this gap. The Gutenberg Gait Database is the world’s largest publicly accessible database containing relevant information on healthy volunteers.
Providing data from 350 healthy individuals aged 11 to 64 years
The database has been compiled by Dr. Fabian Horst of the Institute of Sports Science at Mainz University and Djordje Slijepcevic of St. Pölten University of Applied Sciences in Austria and comprises data from 350 healthy volunteers who attended the biomechanics lab at JGU over the past seven years. The database contains ground reaction force (GRF) and center of pressure (COP) data measured for two consecutive steps, which were recorded by force plates embedded in the ground over the entire duration of ground contact of the feet. “GRF is the force exerted by the feet on the ground during contact — it is a standard parameter used throughout the world for the biomechanical analysis of gait,” explained Horst. COP provides additional information on force progression while the progression curve combined with the data on contact force represents an important indicator with regard to interpreting gait patterns.
For their new database, the researchers put together the results of 350 participants aged 11 to 64 years. “Our data originated from ten individual studies, so the (pre-)processing of the measured data had to be standardized before we could merge it,” Horst added.
Gutenberg Gait Database now available to all interested users
Currently the world’s largest database of healthy individuals, the Gutenberg Gait Database is now publicly accessible and can be used for different aims. “Orthopedic institutes, for example, can download the data in order to prepare charts of normative values for use in clinical practice, while research organizations can gain new insights into human gait,” said Slijepcevic, outlining some possible applications. The database provides users with both unprocessed raw data and processed ready-to-use data. “These data records offer new possibilities for future studies on human gait, e.g., the application as a reference set for the analysis of pathological gait patterns, or for automatic classification using machine learning,” write the authors in their article in Scientific Data.
Another feature of the database is that it can be used in combination with GaitRec, the largest dataset of pathological gait patterns. “Combining these two data sources enables the development of more complex and robust algorithms for the automatic analysis of gait patterns,” confirmed Slijepcevic.
The plan is to continually update the database in future. “The information we have collated to date is mainly that of younger persons. It would be desirable to have a more extensive and balanced database with regard to age and other factors,” concluded Dr. Fabian Horst from the Training and Movement Science division at the JGU Institute of Sports Science.
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Obesity risk factors of family background are associated with changes in the brain function, finds a study conducted at the Finnish Turku PET Centre. The results show that the function of neural networks regulating satiety and appetite is altered already before a person develops obesity.
Obesity is a globally increasing health problem, and new interventions to prevent and treat obesity are needed. Obesity is linked to changes in brain insulin sensitivity and neurotransmitter function. These changes may explain increased appetite and overeating.
“However, thus far it has not been determined whether these changes are visible in the brain already before a person develops obesity, and if these changes would increase the risk for future obesity,” says Doctoral Candidate Tatu Kantonen from the Department of Clinical Medicine of the University of Turku.
Kantonen’s study investigated changes in the brain in pre-obesity by studying the insulin, opioid, and cannabinoid function through PET imaging. The participants of the study consisted of 41 young men with varying number of obesity risk factors.
The results showed that family-related risk factors such as parents’ obesity or diabetes were associated with altered insulin signalling in the subject’s brain as well as reduced function of the opioid and cannabioid systems.
“Disturbance in the neural networks controlling satiation and appetite can therefore be observed already before a person develops obesity, and these brain changes are connected to family-related risk factors of obesity. The results may have implications for the development of prevention and treatment interventions for obesity. They show that the brain and central nervous system are important targets in the treatment of obesity,” says Kantonen.
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A therapeutic antibody developed by scientists at UCL has been shown to unblock and normalise blood vessels inside cancerous tumours, enabling the more effective delivery of targeted cancer treatments.
The findings in mice, published in the journal MED, are the first to demonstrate that inhibiting the activity of LRG1, a protein produced in many tumorous tissues, liberates disorganised angiogenesis (blood vessel formation) — a leading cause of morbidity in numerous diseases including cancer.
Researchers say the novel drug offers the potential to achieve a far better outcome in patients who respond poorly to current standard of care for cancers, including those of the breast, colon, bladder, prostate, and lung.
Furthermore, researchers also found the antibody significantly enhanced the ability of immunotherapies to reduce solid tumours, including cancers resistant to immune checkpoint inhibitors* and CAR T-cell** therapy, something that clinicians and scientists have struggled to overcome.
Explaining the study, co-lead author, Professor John Greenwood (UCL Institute of Ophthalmology) said: “Cancers need a blood supply to grow, but when new vessels form inside a tumour they are typically abnormal, resulting in compromised oxygen delivery that may render the tumour more aggressive.
“This impaired blood supply also limits the delivery of therapies reducing their effectiveness and contributing to treatment resistance. We asked whether blocking the activity of a novel molecule that damages blood vessels, namely LRG1, would allow vessels to grow more normally thus reducing tumour expansion and, most importantly, enhancing the delivery and efficacy of other drugs.”
For the study, a UCL-developed LRG1-blocking antibody was administered to tumour-bearing mice in the presence and absence of various cancer therapeutics, simulating similar treatment courses as found in humans.

Thorough hand washing and sanitising are now second nature thanks to COVID-19, but a new study has also highlighted the dangers of open toilet lids, uncovered rubbish bins and defective plumbing drains in spreading infections in public washrooms.
A global review of the risks of bacterial and viral transmission in public bathrooms has found that bioaerosols can potentially be transmitted throughout a multi-storey building by defective plumbing and that leaving toilet lids open after flushing can disperse contaminated droplets beyond a metre.
Uncovered rubbish bins in public bathrooms are also flagged as a risk, especially if located under or close to electric hand dryers.
Researchers from the ANU and University of South Australia assessed 38 different studies from 13 countries that investigated the risk of infectious disease transmission in public washrooms. Their findings have been published in Science of the Total Environment.
Aside from considering the risks of COVID-19 transmission in bathrooms, the review also analysed other infectious disease risks from public toilets in restaurants, workplaces, commercial premises and universities.
The results showed widespread evidence of contaminated surfaces as a cause of faecal-oral transmission, but no documented instances of airborne-related infectious disease transmission.