Publisher Health

Researchers remain perplexed as to what causes dementia and how to treat and reverse the cognitive decline seen in patients. In a first-of-its-kind study, researchers at the Medical University of South Carolina (MUSC) and Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School discovered that cis P-tau, a toxic, non-degradable version of a healthy brain protein, is an early marker of vascular dementia (VaD) and Alzheimer’s disease (AD). Their results, published on June 2 in Science Translational Medicine, define the molecular mechanism that causes an accumulation of this toxic protein. Furthermore, they showed that a monoclonal antibody (mAb) that targets this toxic protein was able to prevent disease pathology and memory loss in AD- and VaD-like preclinical models. Additionally, this treatment was even capable of reversing cognitive impairment in an AD-like preclinical model.
“We believe our findings have not only discovered cis P-tau as a previously unrecognized major early driver of VaD and AD but also identified a highly effective and specific immunotherapy to target this common disease driver for treating and preventing AD and VaD at early stages,” said Onder Albayram, Ph.D., co-lead author and assistant professor in the Division of Cardiology in the Department of Medicine at MUSC.
Aging is a normal part of life — we experience weakening of our bones and muscles, stiffening of our blood vessels and some memory lapses. But for around 50 million people worldwide, these memory lapses become progressively more severe, ultimately leading to a diagnosis of dementia.
Dementia is an umbrella term that covers AD, which accounts for 60% to 80% of cases; VaD, the second most common cause; and other less common pathologies. Currently, there are no effective treatments for AD. Interestingly, most AD cases have a vascular component, suggesting a broader relationship between cognitive function and healthy brain vasculature. A better understanding of that relationship could provide a platform to discover novel therapeutic targets.
“Our work provides evidence that cis P-tau may be a pathogenic factor that explains VaD, which is not generally linked to other dementias,” added Chenxi Qiu, Ph.D., co-lead author and a postdoctoral research fellow at BIDMC, Harvard Medical School.
In a preclinical model of VaD, young mice showed signs of brain inflammation and memory loss within one month. However, treating these mice with the cis P-tau mAb prevented neural degradation and cognitive decline out to six months. In a separate preclinical model of AD, old mice showed severe cognitive impairment. Excitingly, this severe impairment was significantly reversed when mice were given the cis P-tau mAb.

Much like a supply truck crossing the countryside, the misfolded proteins that damage neurons in Alzheimer’s disease travel the “roads” of the brain, sometimes stopping and sometimes re-routing to avoid roadblocks, reports a study published in Science Advances by researchers at Van Andel Institute and University of Pennsylvania.
The findings shed light on how tau proteins, which form tangled clumps that damage brain cells in Alzheimer’s, move through the brain. The study also provides new insights into why some areas of the brain are more vulnerable to damage than other areas.
“While the interconnected structure of the brain is essential to its function, these misfolded proteins commandeer that structure to travel through the brain and cause progressive degeneration,” said Michael X. Henderson, Ph.D., an assistant professor at Van Andel Institute and corresponding author of the study. “By understanding how these proteins travel through the brain and what causes certain neurons to be at risk for damage, we can develop new therapies that can be directed to the right place at the right time to have maximal impact on disease progression.”
Using models of Alzheimer’s disease, the team mapped misfolded tau proteins as they progressed through the brain. They found that tau pathology moved from region to region along the brain’s neural networks, which are similar to biological highways, but that it did not travel to every connected region.
To find out why some areas of the brain seemed to resist the proteins’ spread, the team turned to gene expression patterns.
They identified some genes that were expressed more in regions that had more tau pathology than expected from protein spread alone. By understanding the genetic factors that control protein accumulation in the brain, the team hopes to identify ways to interfere with misfolded protein movement and slow or stop the progression of Alzheimer’s and similar neurodegenerative diseases.
“We used these network models to test our hypothesis that tau spreads both forward and backward along connections between brain regions,” said Eli Cornblath, Ph.D., an M.D./Ph.D. student at University of Pennsylvania and the study’s first author. “After using our models to account for this two-way spreading process, we found several genes that could help inform new molecular targets to clear or prevent these protein aggregates from forming.”
Story Source:
Materials provided by Van Andel Research Institute. Note: Content may be edited for style and length.

Pairing sky-mapping algorithms with advanced immunofluorescence imaging of cancer biopsies, researchers at The Mark Foundation Center for Advanced Genomics and Imaging at Johns Hopkins University and the Bloomberg~Kimmel Institute for Cancer Immunotherapy developed a robust platform to guide immunotherapy by predicting which cancers will respond to specific therapies targeting the immune system.
A new platform, called AstroPath, melds astronomic image analysis and mapping with pathology specimens to analyze microscopic images of tumors.
Immunofluorescent imaging, using antibodies with fluorescent tags, enables researchers to visualize multiple cellular proteins simultaneously and determine their pattern and strength of expression. Applying AstroPath, the researchers studied melanoma, an aggressive type of skin cancer. They characterized the immune microenvironment in melanoma biopsies by examing the immune cells in and around the cancer cells within the tumor mass and then identified a composite biomarker that includes six markers and is highly predictive of response to a specific type of an immunotherapy called anti-PD-1 therapy.
PD-1 (programmed cell death 1) is a protein found on immune system T cells which, when bound to another protein called PD-L1 (programmed death ligand), helps cancer cells evade attack by the immune system. Anti-PD-1 drugs block the PD-1 protein and can help the immune system see and kill cancer cells. Only some patients with melanoma respond to anti-PD-1 therapy, and the ability to predict response or resistance is critical to choosing the best treatments for each patient’s cancer, the researchers explain. The AstroPath platform is also being applied to study in lung cancer and potentially can provide therapeutic guidance for many other cancers. The research team was led by Janis Taube, M.D., M.Sc., professor of dermatology and co-director of the Tumor Microenvironment Laboratory at the Bloomberg~Kimmel Institute, and Alexander Szalay, Ph.D., director of the Institute for Data Intensive Engineering and Science (IDIES) at Johns Hopkins University.
“This platform has the potential to transform how oncologists will deliver cancer immunotherapy,” says says Drew Pardoll, M.D., Ph.D., director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy. “For the last 40 years, pathology analysis of cancer has examined one marker at a time, which provides limited information. Leveraging new technology, including instrumentation to image up to 12 markers simultaneously, the AstroPath imaging algorithms provide 1,000 times the information content from a single biopsy than is currently available through routine pathology. This facilates precision cancer immunotherapy — identifying the unique features of each patient’s cancer to predict who will respond to a given immunotherapy, such as anti-PD-1, and who will not. In doing so, it also advances diagnostic pathology from uniparameter to multiparameter assays.”
The research was published June 11 in Science.

Ever since scientists discovered cells under the microscope more than 350 years ago, they have noted that each type of cell has a characteristic size. From tiny bacteria to inches-long neurons, size matters for how cells work. The question of how these building blocks of life regulate their own size, however, has remained a mystery.
Now we have an explanation for this long-standing biological question. In a study focusing on the growing tip of plants, researchers show that cells use their DNA content as an internal gauge to assess and adjust their size.
Professor Robert Sablowski, a group leader at the John Innes Centre and corresponding author of the study said: “It has been suggested for a long time that DNA could be used as a scale for cell size, but it was unclear how cells could read the scale and use the information. The key is to use the DNA as a template to accumulate the right amount of a protein, which then needs to be diluted before the cell divides. It’s exciting to come across such a simple solution to a long-standing problem.”
The average cell size results from a balance between how much cells grow and how often they split in two. It has long been clear that cells grow to a certain size before they divide. But how can a cell know how much it has grown?
A good place to investigate this question is in the shoot meristem, the growing tip of the plant, which supplies new cells to make leaves, flowers and stems. Meristem cells constantly grow and divide. Their divisions are often not equal, producing cells of different sizes. Over time, these differences should build up, but the meristem cells stay within a narrow range of sizes over long periods.
In this study, which appears in Science, John Innes Centre researchers carefully followed the growth and division of meristem cells over time. They found that although cells can start their life with variable sizes, by the time the cells are ready to replicate their DNA (a necessary step before cell division, as each new cell needs its own copy of the DNA), most of the initial variability in cell sizes has been corrected.
They then monitored a protein called KRP4, whose role is to delay the start of DNA replication, and found that, regardless of their initial size, cells were always born with the same amount of KRP4. This means that when a cell is born too small, it receives a higher concentration of KRP4, which delays its progression to DNA replication, allowing time for the cell to catch up to the same size of the other cells. Conversely, if a cell is born too big, KRP4 is diluted so it can move quickly onto the next stage without growing further. Over time this keeps meristem cells within a narrow size range.
But what ensures that cells start off with the same amount of KRP4? It turned out that when cells divide, KRP4 “takes a ride” on the DNA, which is given in identical copies to each newborn cell. In this way, the initial amount of KRP4 becomes proportional to the cell’s DNA content. To make sure that KRP4 accumulates in the mother cell in proportion to the DNA content, any excess KRP4 not bound to the DNA is destroyed before cell division by another protein called FBL17. Mathematical models and using gene-edited mutants with varying quantities of these genetic components confirmed the mechanism.
Professor Robert Sablowski, explains this process, “One riddle we had to solve is how a cell can know how much it has grown when most of the components of a cell increase together in number and size so they cannot be used as a fixed ruler to measure size. One exception is DNA which exists in the cell in a discrete amount — its amount precisely doubles before cell division, but it does not vary with cell growth.”
Future experiments will seek to explain exactly how the regulatory protein KRP4 associates, then dissociates from chromosomes during cell division. The researchers also want to understand whether the mechanism is modulated in different cell types to produce different average sizes.
The findings may explain the relation between genome size and cell size — species with large genomes and, therefore a lot of DNA in their cells, tend to have larger cells. This is particularly important in crop plants, many of which have been selected to contain multiple copies of the genomes present in their wild ancestors, leading to larger cells and often larger fruits and seeds.
Components of the genetic mechanism that includes KRP4 are present in many organisms, and it has been suggested that these components are important to regulate cell size in human cells. Thus the mechanism uncovered in the study may also be relevant across biological Kingdoms, with implications for animal and human cell biology.
Story Source:
Materials provided by John Innes Centre. Note: Content may be edited for style and length.

Imagine being woken up at 3 a.m. to navigate a corn maze, memorize 20 items on a shopping list or pass your driver’s test.
According to a new analysis out of West Virginia University, that’s often what it’s like to be a rodent in a biomedical study. Mice and rats, which make up the vast majority of animal models, are nocturnal. Yet a survey of animal studies across eight behavioral neuroscience domains showed that most behavioral testing is conducted during the day, when the rodents would normally be at rest.
“There are these dramatic daily fluctuations — in metabolism, in immune function, in learning and memory, in perception — and by the large, they get ignored,” said Randy Nelson, who led the study. “You just have to wonder: to what extent is that affecting the outcomes?”
Nelson chairs the School of Medicine’s Department of Neuroscience and directs basic science research for the Rockefeller Neuroscience Institute.
His findings appear in Neuroscience and Behavioral Reviews.
Nelson and his colleagues — RNI researchers Jacob Bumgarner, William Walker and Courtney DeVries — examined the 25 most frequently cited papers in each of eight categories of rodent behaviors: learning and memory, sensation and perception, attention, food intake, mating, maternal behavior, aggression and drug seeking.

The collection of nasopharyngeal swab (NPS) samples for COVID-19 diagnostic testing poses challenges including exposure risk to healthcare workers and supply chain constraints. Saliva samples are easier to collect but can be mixed with mucus or blood, and some studies have found they produce less accurate results. A team of researchers has found that an innovative protocol that processes saliva samples with a bead mill homogenizer before real-time PCR (RT-PCR) testing results in higher sensitivity compared to NPS samples. Their protocol appears in The Journal of Molecular Diagnostics, published by Elsevier.
“Saliva as a sample type for COVID-19 testing was a game changer in our fight against the pandemic. It helped us with increased compliance from the population for testing along with decreased exposure risk to the healthcare workers during the collection process,” said lead investigator Ravindra Kolhe, MD, PhD, Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA, USA.
The study included samples from a hospital and nursing home as well as from a drive-through testing site. In the first phase (protocol U), 240 matched NPS and saliva sample pairs were tested prospectively for SARS-CoV-2 RNA by RT-PCR. In the second phase of the study (SalivaAll), 189 matched pairs, including 85 that had been previously evaluated with protocol U, were processed in an Omni bead mill homogenizer before RT-PCR testing. An additional study was conducted with samples with both protocol U and SalivaAll to determine if bead homogenization would affect the clinical sensitivity in NPS samples. Finally, a five-sample pooling strategy was evaluated. Twenty positive pools containing one positive and four negative samples were processed with the Omni bead homogenizer before pooling for SARS-CoV-2 RT-PCR testing and compared to controls.
In Phase I, 28.3 percent of samples tested positive for SARS-CoV-2 from either NPS, saliva, or both. The detection rate was lower in saliva compared to NPS (50.0 percent vs. 89.7 percent). In Phase II, 50.2 percent of samples tested positive for SARS-CoV-2 from either saliva, NPS, or both. The detection rate was higher in saliva compared to NPS samples (97.8 percent vs. 78.9 percent). Of the 85 saliva samples tested with both protocols, the detection rate was 100 percent for samples tested with SalivaAll and 36.7 percent with protocol U.
Dr. Kolhe observed that the underlying issues associated with lower sensitivity of saliva to RT-PCR testing could be attributed to the gel-like consistency of saliva samples, which made it difficult to accurately pipet samples into extraction plates for nucleic acid extraction. Adding the homogenization step rendered the saliva samples to uniform viscosity and consistency, making it easier to pipet for the downstream assay.
Dr. Kolhe and his colleagues also successfully validated saliva samples in the five-sample pooling strategy. The pooled testing results demonstrated a positive agreement of 95 percent, and the negative agreement was found to be 100 percent. Pooled testing will be critical for SARS-CoV-2 mass surveillance as schools reopen, travel and tourism resume, and people return to offices.
“Monitoring SARS-CoV-2 will remain a public health need,” Dr. Kolhe said. “The use of a non-invasive collection method and easily accessible sample such as saliva will enhance screening and surveillance activities and bypass the need for sterile swabs, expensive transport media, and exposure risk, and even the need for skilled healthcare workers for sample collection.”
Story Source:
Materials provided by Elsevier. Note: Content may be edited for style and length.

It’s often cancer’s spread, not the original tumor, that poses the disease’s most deadly risk.
“And yet metastasis is one of the most poorly understood aspects of cancer biology,” says Kamen Simeonov, an M.D.-Ph.D. student at the University of Pennsylvania Perelman School of Medicine.
In a new study, a team led by Simeonov and School of Veterinary Medicine professor Christopher Lengner has made strides toward deepening that understanding by tracking the development of metastatic cells. Their work used a mouse model of pancreatic cancer and cutting-edge techniques to trace the lineage and gene expression patterns of individual cancer cells. They found a spectrum of aggression in the cells that arose, with cells that were likely to remain in place at the primary tumor at one end and those that were more likely to move to new sites and colonize other tissues at the other end.
Of the cells that eventually became metastatic and grew in tissues and organs beyond the pancreas, the majority shared a common lineage, the researchers discovered.
“By building a precision tool for probing cancer metastasis in vivo, we’re able to observe previously inaccessible types of information,” says Simeonov. “We were able to use this lineage tracing approach to rank cells based on how metastatic they were and then relate these differences in behavior to gene expression changes.”
The group’s findings, published in the journal Cancer Cell, suggest that it’s not only genetic mutations that can drive cancer’s spread; the single-cell RNA profiling results underscore that gene expression patterns — which genes cells are turning on and off — play a key role in disease outcomes.

New data from Israel, which had the fastest Covid-19 vaccine rollout in the world, provides real-world evidence that widespread vaccination against the coronavirus can also protect people who are unvaccinated.The Israeli study, which was published in the journal Nature Medicine on Thursday, took advantage of the fact that until recently Israel was only vaccinating people 16 or older. For every 20 percentage point increase in the share of 16- to 50-year-olds who were vaccinated in a community, the researchers found, the share of unvaccinated under 16s who tested positive for the virus fell by half.“Vaccination provides benefits not only to the individual vaccinee but also to people around them,” said Roy Kishony, a biologist, physicist and data scientist who studies microbial evolution and disease at Technion-Israel Institute of Technology. Dr. Kishony led the research with Dr. Tal Patalon, who heads a major health organization, KSM, the Maccabi Research and Innovation Center. The first authors of the paper are Oren Milman and Idan Yelin, researchers in Dr. Kishony’s lab.Israel began vaccinating adults in December of last year. Within nine weeks, it had vaccinated nearly half of its population. The researchers examined the anonymized electronic health records of members of Maccabi Healthcare Services, an Israeli H.M.O. They analyzed vaccination records and virus test results between December 6, 2020 and March 9, 2021. The records came from 177 different geographic areas, which had varying rates of vaccination and vaccine uptake. For each community, they calculated the share of adults, between the ages of 16 and 50, who were vaccinated at various time points. They also calculated the fraction of P.C.R. tests of children under 16 that came back positive. They found a clear correlation: As more and more adults in a community got vaccinated, the share of children testing positive for the virus subsequently fell.People who are vaccinated are significantly less likely to become infected with the virus. Research also suggests that even when vaccinated people do contract the virus, they may have lower viral loads, reducing their infectiousness. As a result, as more and more people get vaccinated, unvaccinated people become less likely to encounter infected, contagious people. “The results are consistent with vaccinees not only not getting sick themselves, but also not transmitting the virus to others,” Dr. Kishony said. “Such effects can be amplified over multiple cycles of infections.”In another recent paper, which has not yet been published in a scientific journal, researchers in Finland reported that after health care workers got vaccinated, unvaccinated members of their households were also less likely to contract the virus.

In order for cancer to grow and spread, it has to evade detection by our immune cells, particularly specialized “killer” T cells. Salk researchers led by Professor Susan Kaech have found that the environment inside tumors (the tumor microenvironment) contains an abundance of oxidized fat molecules, which, when ingested by the killer T cells, suppresses their ability to kill cancer cells. In a vicious cycle, those T cells, in need of energy, increase the level of a cellular fat transporter, CD36, that unfortunately saturates them with even more oxidized fat and further curtails their anti-tumor functions.
The discovery, published online in Immunity on June 7, 2021, suggests new pathways for safeguarding the immune system’s ability to fight cancer by reducing the oxidative lipid damage in killer T cells. Identifying factors like these that cause immune suppression in the tumor microenvironment can lead to the development of novel immunotherapies for cancer.
“We know that tumors are a metabolically hostile environment for healthy cells, but elucidating which metabolic processes are altered and how this suppresses immune cell function is an important area of cancer research that is gaining a lot of attention,” says Kaech, senior author and director of Salk’s NOMIS Center for Immunobiology and Microbial Pathogenesis. “Our findings uncovered a novel mode of immunosuppression in tumors involving the import of oxidized fats (AKA lipids) in T cells via the cellular fat transporter CD36, which impairs their anti-tumor functions locally.”
The burgeoning field of cancer immunometabolism studies how immune cell metabolism is reprogrammed within tumors and driven by alterations in nutrient availability. While scientists know that tumors accumulate fats — and that such accumulation is associated with immune dysfunction — the details of the relationship haven’t been clear.
Working with Joseph Witztum’s lab at UC San Diego and Antonio Pinto in the Salk Mass Spectrometry Core facility, the team established that tumors contain elevated amounts of several classes of lipid, and oxidized lipids in particular, which are generally found in oxidized low-density lipoproteins (LDLs), commonly considered “bad” fat. They then observed how killer T cells respond to the oxidized LDLs in tumors and found that killer T cells adapted to the tumor microenvironment by increasing CD36 on their surface and ingesting an abundance of oxidized lipids. Working with Brinda Emu’s lab at Yale University, they found this process served as a catalyst to drive even greater amounts of lipid oxidation internally in the killer T cells and ultimately repressed their defenses.
Next, the team employed various methods to investigate how CD36 impaired killer T cell function. They created mouse models lacking CD36 on T cells and used antibodies to block CD36. They confirmed that CD36 promoted T cell dysfunction in tumors by increasing oxidized lipid import, which caused greater lipid oxidation and damage within the T cells and triggered the activation of a stress response protein, p38.
“We found that when the T cells get ‘stressed out’ by oxidized lipids, they shut down their anti-tumor functions,” says Shihao Xu, a Salk postdoctoral fellow and the first author on the paper.
The team also found new therapeutic opportunities to reduce lipid oxidation and restore killer T cells’ function in tumors through immunotherapy by blocking CD36 with an antibody therapy or by overexpressing glutathione peroxidase 4 (GPX4, a key molecule that removes oxidized lipids in cells).
Importantly, lipid oxidation doesn’t just happen in T cells; it also happens in tumor cells, and too much of it can cause cell death. In fact, there is a lot of excitement in cancer research to increase lipid oxidation in tumor cells to a lethal level, but Kaech and her team urge some caution.
“Now that we’ve uncovered this vulnerability of T cells to lipid oxidation stress, we may need to find more selective approaches to inducing lipid oxidation in the tumor cells but not in the T cells,” says Kaech, who holds the NOMIS Chair at Salk. “Otherwise, we may destroy the anti-tumor T cells in the process, and our work shows a few interesting possibilities for how to do this.”
Story Source:
Materials provided by Salk Institute. Note: Content may be edited for style and length.

Even on a good day, DNA is constantly getting damaged.
Nicks, scratches, breaks: the delicate strands that carry life’s genetic code take a beating as they jumble about in the course of their work. If left untreated, errors accumulate, with fatal consequences — such as cancerous tumors — for the cell and the organism.
This is where two key proteins come to the rescue: PARP — or poly ADP ribose polymerase — acts as a marker for a trouble spot, allowing XRCC1 — or X-ray repair cross-complementing protein 1 — to zoom in and begin a repair.
This much has been known for some time and was even recognized in the 2015 Nobel prizes for chemistry, resulting in the development of anti-cancer drugs known as PARP inhibitors that work to disrupt the growth of certain types of tumors.
But while these actors had been identified, their precise roles were not clear. Now a team of scientists at Tokyo Metropolitan University, the University of Sussex, and Kyoto University have revealed exactly how XRCC1 does its work.
“PARP turns out to be something of a villain,” explains Kouji Hirota at Tokyo Metropolitan. “The spots it marks become ‘PARP traps’, which left un-repaired lead to disfunction and cell death.”
XRCC1 therefore isn’t simply repairing DNA, it is disarming PARP traps.
The scientists compared cells lacking the XRCC1 gene with those lacking PARP as well as with still others lacking both proteins. The team discovered that without XRCC1 on patrol, PARP traps accumulate like landmines.
“PARP exerts toxic effects in the cell and XRCC1 suppresses this toxicity,” Hirota elaborates.
The team next seeks to delve even further into these processes, aiming to aid in the development of future cancer treatments.
KyotoU’s Shunichi Takeda says: “These results indicate that XRCC1 is a critical factor in the resolution of PARP traps and may be a determinant of the therapeutic effect of PARP inhibitors used in the treatment of hereditary breast and ovarian cancer syndromes.”
Story Source:
Materials provided by Kyoto University. Note: Content may be edited for style and length.