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Johns Hopkins Medicine scientists have used glowing chemicals and other techniques to create a 3D map of the blood vessels and self-renewing “stem” cells that line and penetrate a mouse skull. The map provides precise locations of blood vessels and stem cells that scientists could eventually use to repair wounds and generate new bone and tissue in the skull.
“We need to see what’s happening inside the skull, including the relative locations of blood vessels and cells and how their organization changes during injury and over time,” says Warren Grayson, Ph.D., professor of biomedical engineering and director of the Laboratory for Craniofacial and Orthopaedic Tissue Engineering at the Johns Hopkins University School of Medicine. His lab focuses on developing biomaterials and transplanting stem cells into the skull to re-create missing bone tissue.
Other scientists have provided maps of small portions of blood vessels and stem cells in the mouse skull. “However, a larger picture of the skull gives us a better understanding of the entire vasculature and distribution of different stem cell types,” says Alexandra Rindone, graduate student at The Johns Hopkins University and School of Medicine and first author of the paper.
The new map, published Oct. 28 in Nature Communications, is a 3D view of the top of a mouse skull — its cranial bone, or calvaria — which is made up of four connected skull bones.
To create the map, which includes hundreds of thousands of cells, the Johns Hopkins researchers used four key techniques to pinpoint vessels and cells.
First, they used immunofluorescence to tag molecules on the surface of a variety of blood vessels and stem cells with a fluorescent, or glowing, chemical.

Immune checkpoint inhibitors can boost the immune system’s response to tumor cells, but the medications tend to be ineffective against certain cancers, especially colorectal and pancreatic cancers. A new clinical trial led by investigators at Massachusetts General Hospital (MGH) indicates that combining radiation with immune checkpoint inhibitors may be an effective strategy to combat these resistant cancers.
Preclinical studies have shown that low-dose radiation can create a “tumor vaccine” environment that triggers an immune response when stimulated with the immune checkpoint inhibitors nivolumab and ipilimumab — which have different targets — in resistant cancers. As reported in Nature Cancer, researchers tested this strategy in a single-arm phase II trial of 40 patients with colorectal cancer and 25 patients with pancreatic cancer. In patients who received the planned treatment of radiation + nivolumab + ipilimumab, 37% of patients with colorectal cancer and 29% of patients with pancreatic cancer experienced responses to the therapy (with complete or partial responses or stable disease that did not progress).
“This is an impressive clinical result given that historically, these cancers respond in the low single digit percentage range,” says senior author David T. Ting, MD, associate clinical director for innovation at the MGH Cancer Center and an associate professor of medicine at Harvard Medical School. He added that new information indicates that improved timing of the sequencing of radiation therapy with immunotherapy may enhance efficacy that merits further investigation.
The investigators noted that analyses of cancer biopsies taken before treatment revealed that tumors that responded to the triple therapy tended to have higher expression of certain viral sequences that are found normally in the human genome. These sequences belong to a retrovirus called HERV-K.
“HERV-K may be a potential marker of response to this immunotherapy regimen, which can be used for future studies to tailor treatments to individual patients,” says Ting. Studies that look into the potential role of these viral sequences in cancer biology are also warranted.
This work was supported by SU2C-AACR-DT22-17 Colorectal Dream Team: Targeting Genomic, Metabolic, and Immunological Vulnerabilities of Colorectal Cancer; National Institutes of Health grants P50CA127003, R01CA240924, U01CA228963; Conquer Cancer Foundation ASCO; SU2C and Lustgarten Foundation; The Robert L. Fine Cancer Research Foundation; and generous donations from David and Ingrid Kosowsky, Sandra and Arthur Irving, and Robert and Marian Ettl.
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Materials provided by Massachusetts General Hospital. Note: Content may be edited for style and length.

An international research team at the Research Neutron Source Heinz Maier-Leibnitz (FRM II) of the Technical University of Munich (TUM) have developed a new imaging technology. In the future this technology could not only improve the resolution of neutron measurements by many times but could also reduce radiation exposure during x-ray imaging.
Modern cameras still rely on the same principle they used 200 years ago: Instead of a piece of film, today an image sensor is exposed for a certain period of time in order to record an image. However, the process also records the noise of the sensor. This constitutes a considerable source of interference especially with longer exposure times.
Together with colleagues from Switzerland, France, the Netherlands and the USA, Dr. Adrian Losko and his TUM colleagues at the Heinz Maier-Leibnitz Zentrum (MLZ) have now developed a new imaging method which measures individual photons on a time-resolved and spatially-resolved basis. This makes it possible to separate photons from noise, greatly reducing the interference.
“Our new detector lets us capture every individual photon and thus overcome many of the physical limitations of traditional cameras,” says Dr. Adrian Losko, instrument scientist at the NECTAR neutron radiography facility of the Heinz Maier-Leibnitz Zentrum at the Technical University of Munich.
Measuring individual photons
Neutron radiography researchers typically use scintillators in their measurements to detect neutrons for example in the examination of fossilized dinosaur eggs. When the scintillator material absorbs a neutron, photons are generated which can then be measured.

In a recent phase 2b/3 clinical trial, a third mRNA vaccine against COVID-19 — known as CVnCoV and developed by CureVac — reported approximately 48 percent efficacy against symptomatic disease. In a head-to-head test of a revised version of the vaccine, CV2CoV, researchers at Beth Israel Deaconess Medical Center (BIDMC) assessed the vaccines’ ability to provoke an immune response as well as their protective efficacy against COVID-19 in non-human primates. Their findings, published in Nature, show the modifications made to the second-generation CV2nCoV induced a ten-fold higher antibody response than the original version, CVnCoV.
“We found that CV2CoV elicited substantially higher immune responses and provided significantly improved protective efficacy against SARS-CoV-2, the virus that causes COVID-19, compared with CVnCoV in macaques,” said Dan H. Barouch, MD, PhD, director of the Center for Virology and Vaccine Research at BIDMC and professor of medicine at Harvard Medical School. “These data suggest that optimizing selected elements of the mRNA backbone can substantially improve the immunogenicity and protective efficacy of mRNA vaccines.”
Barouch and colleagues’ data revealed that, while CVnCoV provided only modest reduction in viral loads in immunized animals later challenged with SARS-CoV-2, CV2CoV induced ten-fold higher antibody responses and dramatically lowered viral loads. They also report that CV2CoV induced antigen-specific memory B cell responses and T cell responses. Moreover, CV2CoV raised similar antibody titers in macaques compared with the BNT162b2 vaccine developed by Pfizer.
“The improved characteristics of CV2CoV compared with CVnCoV may translate into increased efficacy in humans, and clinical trials of the second-generation vaccine are planned,” said Barouch, who is also a member of the Ragon Institute of MGH, MIT and Harvard.
Co-authors included Makda S. Gebre, Jingyou Yu, Abishek Chandrashekar, Noe B. Mercado, Xuan He, Jinyan Liu, Katherine McMahan, Tori Giffin, David Hope, Shivani Patel, Daniel Sellers, Owen Sandborn, Julia Barrett, Xiaowen Liu and Andrew C. Cole of BIDMC; Susanne Rauch, Nicole Roth, Stefan O. Mueller and Benjamin Petsch of Harvard Medical School; Amanda Minot of Tufts University Cummings School of Veterinary Medicine; David R. Martinez and Ralph S. Baric of University of North Carolina at Chapel Hill; Laurent Pessaint, Danile Valentin, Zack Flinchbaugh, Jake Yalley-Ogunro, Jeanne Muench, Renita Brown, Anthony Cook, Elyse Teow, Hanne Andersen and Mark G. Lewis of Bioqual; Adrianus C.M. Boon of Washington University School of Medicine.
This work was supported by CureVac AG and the German Federal Ministry of Education and Research (BMBF; 01KI20703), the National Institutes of Health (CA260476), the Massachusetts Consortium on Pathogen Readiness, and Ragon Institute of MGH, MIT, and Harvard. Development of CV2CoV is carried out in a collaboration of CureVacAG and GSK. Please see the paper for a complete list of disclosures.
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Materials provided by Beth Israel Deaconess Medical Center. Original written by Chloe Meck. Note: Content may be edited for style and length.

Both rare and commonly observed differences in the DNA letters strung along a person’s chromosomes can explain about a third of the risk for being diagnosed with obsessive-compulsive disorder (OCD), according to a new study led by scientists at the Icahn School of Medicine at Mount Sinai.
The researchers analyzed the genomic data of more than 2,000 Swedish-born individuals diagnosed with OCD. Their results, published in the American Journal of Psychiatry, may alter not only how scientists view the role that genomics plays in OCD but also how new treatments might be developed.
The study was led by scientists in the laboratory of Dorothy Grice, MD, Professor of Psychiatry at Icahn Mount Sinai.
Affecting about two percent of Americans, OCD describes a set of potentially life-long and debilitating symptoms, most notably intense and distressing recurring thoughts and actions. Although scientists have yet to find the exact causes of OCD, several studies indicate that multiple genomic and environmental factors may play a role in the disease. For instance, it has been estimated that anywhere between 25 to 50 percent of the risk for OCD behaviors may be attributable to genomic differences between individuals in a population.
Led by Behrang Mahjani, PhD, a researcher in Dr. Grice’s lab, the researchers compared the single nucleotide polymorphisms (SNPs) — the minor DNA spelling differences normally found in a person’s chromosomes — of 2,090 Swedish-born OCD patients with that of 4,567 controls, making it the largest study of its kind to date. Initial results supported previous studies. About 29 percent of the risk for OCD was attributed to differences in SNPs between patients and control subjects and about 90 percent of these differences are commonly observed throughout the general population. However, the researchers also found that about 10 percent of the risk could be linked to rare genomic differences, which were not seen in previous studies. Further analysis showed that the OCD-related SNPs were distributed across patients’ chromosomes, suggesting that multiple genomic differences combine to influence risk. Overall the results support the idea that OCD risk may, in part, be driven by randomly occurring changes to the entire genome rather than a few naturally selected “hot spots.” The researchers concluded that this new view of OCD highlights the important role of rare genomic differences in the risk of OCD, and may alter how scientists study the disorder to develop new treatments for patients.
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Materials provided by The Mount Sinai Hospital / Mount Sinai School of Medicine. Note: Content may be edited for style and length.

Scientists recently gained insights into how vitamin D functions to reduce inflammation caused by immune cells that might be relevant to the responses during severe COVID-19. In a study jointly published by Purdue University and the National Institutes of Health, scientists do just that.
Majid Kazemian, assistant professor in the departments of Computer Science and Biochemistry at Purdue University, was co-lead author of the highly collaborative study, along with Dr. Behdad Afzali, chief of the Immunoregulation Section of the National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Diseases.
“Our work demonstrates a mechanism by which vitamin D reduces inflammation caused by T cells. These are important cells of the immune system and implicated as part of the immune response to the infection causing COVID-19. Further research, especially clinical trials, and testing in patients, are necessary before this can be adopted as a treatment option.” Kazemian said. “We do not recommend the use of normal vitamin D off the shelf at the pharmacy. No one should be taking more than the recommended doses of vitamin D in an attempt to prevent or combat COVID infections.”
Previous studies have shown vitamin D’s ability to reduce the inflammation caused by T cells — inflamed cells in the lung characteristic of the most severe and dangerous cases of COVID-19. But as important as understanding that a drug works is understanding the how and the why. This is both to maximize benefit and minimize harm (such as preventing people from eating livestock dewormer or injecting household cleaners into their veins) as well as to pave the way for future treatments.
If scientists understand how vitamin D works to combat inflammation, they understand more about how both the drug and related diseases work, paving the way for new, even more effective drugs.
Kazemian and his team began by studying how viruses affect lung cells in a previous study. Finding that viruses can trigger a biochemical pathway, known as the immune complement system, the researchers started looking for ways to disrupt that pathway and ameliorate the subsequent inflammation.
The team studied and analyzed individual lung cells from eight people with COVID — something only possible because of Kazemian’s experience with gene sequencing and data mining. They found that in the lung cells of people with COVID, part of the immune response was going into overdrive, exacerbating lung inflammation.
“In normal infections, Th1 cells, a subset of T cells, go through a pro-inflammatory phase,” Kazemian said. “The pro-inflammatory phase clears the infection, and then the system shuts down and goes to anti-inflammatory phase. Vitamin D helps to speed up this transition from pro-inflammatory to the anti-inflammatory phase of the T cells. We don’t know definitively, but theorize the vitamin could potentially help patients with severe inflammation caused by Th1 cells.”
In patients with COVID-19, the pro-inflammatory phase of the Th1 cells seems not switched off, possibly because the patients didn’t have enough vitamin D in their system or because something about the cell’s response to vitamin D was abnormal. In that case, the researchers posit, adding vitamin D to existing treatments in the form of a prescribed highly concentrated intravenous metabolite may further help people recovery from COVID infections, though they have not tested this theory.
“We found that vitamin D — a specialized form of it, not the form you can get at the drugstore — has the potential to reduce inflammation in the test tube, and we figured out how and why it does that,” Kazemian said. However, it’s important to understand that we did not carry out a clinical study, and the results of our experiments in the test tube need to be tested in clinical trials in actual patients.”
The work was funded by NIGMS, NIDDK, NIAID and NHLBI of the NIH, with additional funding from the Wellcome Trust, the Crohn’s and Colitis Foundation of America, the British Heart Foundation, the Showalter Trust, the German Research Foundation, the National Agency of Research and Development of Chile, and England’s National Health Service’s National Institute for Health Research Biomedical Research Centre and Research Facility.
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Materials provided by Purdue University. Original written by Brittany Steff. Note: Content may be edited for style and length.

Alexander disease is a progressive and rare neurological disorder with no cure or standard course of treatment. But a new study led by researchers at the University of Wisconsin-Madison involving a rat model of the disease offers a potential treatment for the typically fatal condition.
It’s a significant step in efforts to help people with the disease, says UW-Madison Waisman Center senior scientist Tracy Hagemann, who led the study alongside Albee Messing, professor emeritus of comparative biosciences and founder of the Alexander Disease Lab. With University of Alabama at Birmingham colleague Michael Brenner, Messing discovered the gene responsible for Alexander disease more than 20 years ago.
People born with Alexander disease may develop an enlarged brain and head, experience seizures or delayed development, have stiffness in their arms and legs, and have intellectual disabilities. The disease, which involves destruction of the white matter of the brain, is often not diagnosed until symptoms are pronounced, says Hagemann.
The new study, published Nov. 17 in Science Translational Medicine, provided preliminary data instrumental for a human clinical trial currently being led by Ionis Pharmaceuticals. Hagemann, Messing, and the Alexander Disease Lab are not directly involved.
However, working with Ionis Pharmaceuticals, the researchers developed a treatment that consists of small pieces of DNA called antisense oligonucleotides, which in their rat model was able to target mRNA in cells and tag the mRNA for destruction, effectively halting it from creating proteins.
One feature of Alexander disease is the formation of abnormal protein aggregates called Rosenthal fibers, caused by mutations in the gene that makes a protein called GFAP. The connection between this abnormal GFAP and the white matter destruction seen in Alexander disease is not yet clear, but changes in the protein are an intrinsic part of the disease in almost all cases.

Some ancestral rodents likely had repeated infections with SARS-like coronaviruses, leading them to acquire tolerance or resistance to the pathogens,according to new research publishing Nov. 18 in PLOS Computational Biology by Sean King and Mona Singh of Princeton University. This raises the possibility that modern rodents may be reservoirs of SARS-like viruses, the researchers say.
SARS-CoV-2, the virus that causes COVID-19 infection, is of zoonotic origin — it jumped from a non-human animal to humans. Previous research has shown that Chinese Horseshoe bats are a host of numerous SARS-like viruses and tolerate these viruses without extreme symptoms. Identifying other animals that have adapted tolerance mechanisms to coronaviruses is important for awareness of potential viral reservoirs that can spread new pathogens to humans.
In the new research, King and Singh performed an evolutionary analysis, across mammalian species, of the ACE2 receptors, used by SARS viruses to gain entry into mammalian cells. Primates had highly conserved sequences of amino acids in the sites of the ACE2 receptor known to bind SARS viruses. Rodents, however, had a greater diversity — and an accelerated rate of evolution — in these spots. Overall, the results indicated that SARS-like infections have not been evolutionary drivers in primate history, but that some rodent species have likely been exposed to repeated SARS-like coronavirus infections for a considerable evolutionary period.
“Our study suggests that ancestral rodents may have had repeated infections with SARS-like coronaviruses and have acquired some form of tolerance or resistance to SARS-like coronaviruses as a result of these infections,” the authors add. “This raises the tantalizing possibility that some modern rodent species may be asymptomatic carriers of SARS-like coronaviruses, including those that may not have been discovered yet.”
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Materials provided by PLOS. Note: Content may be edited for style and length.

New research by a team of University of Florida investigators, and others, provides evidence that host immunity drives evolution of the dengue virus. The work, published today in Science, retrospectively analyzes two decades of dengue virus genetic variation from Thailand, alongside population-level measures of infection and immunity.
There are four types of dengue virus, and all four have co-circulated in Thailand since the early 1960s. This provides an opportunity to study how the viruses compete against each other for human hosts.
“We wanted to understand the ecology and evolution of dengue viruses circulating in one place over a long period of time,” says the study’s lead author, Leah Katzelnick, previously a post-doc in biology at the University of Florida and now Chief of Viral Epidemiology and Immunity Unit at the National Institute of Allergy and Infectious Diseases.
Dengue virus types are grouped according to how their surface proteins, or antigens, interact with infection-fighting antibodies in human blood. The four types, also called serotypes, are noted as DENV1 through DENV4. Although there is genetic variation between each dengue virus type, there is also variation within each dengue virus type.
“We want to understand if or how immunity is driving extinction or persistence of particular lineages of dengue virus circulating in this one place. To do that, we characterized the immune signature of dengue viruses isolated in Bangkok over a long period of time,” says Derek Cummings, the study’s senior author and a professor of biology at UF.
The new study used 1,944 archival blood samples from Bangkok. The samples were preserved from people known to be ill with dengue and they represent all four dengue virus strains from every year between 1994 and 2014. The team genetically sequenced more than 2,000 virus samples.

Using the same approach they recently used to create effective vaccine candidates against COVID-19 and respiratory syncytial virus (RSV), scientists are tackling another virus: the tick-borne Crimean-Congo hemorrhagic fever (CCHF). It causes death in up to 40% of cases, and the World Health Organization identified the disease as one of its top priorities for research and development. The results appear today in the journal Science.
Using what scientists refer to as structural virology, a research consortium called Prometheus reconstructed the first 3D atomic-scale maps, or structures, of an infection-causing part of the virus that allows it to infect host cells. The team also determined how two neutralizing antibodies, fished from recovered patients, disrupt the virus’s ability to infect a cell, which together with the structural information, offers insights for developing therapeutics against the virus.
The research echoes a key approach that scientists, including The University of Texas at Austin’s Jason McLellan, have used in recent years to fight COVID-19 and RSV, signaling the emerging prominence of structural virology — the use of exquisitely detailed imaging of viral components to find their weaknesses — in preventing pandemics and curbing infectious disease.
“Crimean-Congo hemorrhagic fever is a terrible disease and is endemic in Africa, Asia and Europe, without any approved vaccines or antibody therapies to date,” said McLellan, a professor of molecular biosciences and a co-corresponding author on the study. “With structural virology, we’re finding out the secrets of these proteins on the surface of viruses and their vulnerabilities — and that helps us to build better therapeutics and vaccines.”
Directed by Kartik Chandran, professor of microbiology and immunology at the Albert Einstein School of Medicine, the Prometheus team is made up of McLellan’s and other academic labs, biotech companies and the U.S. Army Medical Research Institute of Infectious Diseases. The consortium previously identified two antibodies from recovered CCHF patients that potently neutralize the virus. They then combined the virus-binding regions from the two antibodies to produce a “bispecific antibody” that clears infections in sick mice and protects uninfected mice from the CCHF virus. They’re now working to develop a more stable version that could be tested in human clinical trials.
“Let’s say a researcher, health care worker or a military person from the U.S. needs to visit the Middle East or Africa,” said Akaash Mishra, a University of Texas at Austin graduate student in McLellan’s lab and first author of the paper. “Before they go, they could get a prophylactic shot with one of these antibodies to protect against infection. This is called passive immunization and would protect them for several weeks to months.”
The bispecific antibody could also help patients already infected with CCHF to recover from infection and prevent mortality. Insights from the research could also be used for the creation of a future vaccine.