Cancer cells can dodge chemotherapy by entering a state that bears similarity to certain kinds of senescence, a type of “active hibernation” that enables them to weather the stress induced by aggressive treatments aimed at destroying them, according to a new study by scientists at Weill Cornell Medicine. These findings have implications for developing new drug combinations that could block senescence and make chemotherapy more effective.
In a study published Jan. 26 in Cancer Discovery, a journal of the American Association for Cancer Research, the investigators reported that this biologic process could help explain why cancers so often recur after treatment. The research was done in both organoids and mouse models made from patients’ samples of acute myeloid leukemia (AML) tumors. The findings were also verified by looking at samples from AML patients that were collected throughout the course of treatment and relapse.
“Acute myeloid leukemia can be put into remission with chemotherapy, but it almost always comes back, and when it does it’s incurable,” said senior author Dr. Ari M. Melnick, the Gebroe Family Professor of Hematology and Medical Oncology and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “A longstanding question in the field has been, ‘Why can’t you get rid of all the cancer cells?’ A similar question can be posed for many other types of aggressive cancer in addition to AML.”
For years, cancer researchers have studied how tumors are able to rebound after they appear to be completely wiped out by chemotherapy. One theory has been that because not all cells within a tumor are the same at the genetic level — a condition called tumor heterogeneity — a small subset of cells are able to resist treatment and begin growing again. Another theory involves the idea of tumor stem cells — that some of the cells within a tumor have special properties that allow them to re-form a tumor after chemotherapy has been given.
The idea that senescence is involved does not replace these other theories. In fact, it could provide new insight into explaining these other processes, Dr. Melnick said.
In the study, the researchers found that when AML cells were exposed to chemotherapy, a subset of the cells went into a state of hibernation, or senescence, while at the same time assuming a condition that looked very much like inflammation. They looked similar to cells that have undergone an injury and need to promote wound healing — shutting down the majority of their functions while recruiting immune cells to nurse them back to health.

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“These characteristics are also commonly seen in developing embryos that temporarily shut down their growth due to lack of nutrition, a state called embryonic diapause,” Dr. Melnick explained. “It’s not a special process, but normal biological activity that’s playing out in the context of tumors.”
Further research revealed that this inflammatory senescent state was induced by a protein called ATR, suggesting that blocking ATR could be a way to prevent cancer cells from adopting this condition. The investigators tested this hypothesis in the lab and confirmed that giving leukemia cells an ATR inhibitor before chemotherapy prevented them from entering senescence, thereby allowing chemotherapy to kill all of the cells.
Importantly, studies published at the same time from two other groups reported that the role of senescence is important not just for AML, but for recurrent cases of breast cancer, prostate cancer and gastrointestinal cancers as well. Dr. Melnick was a contributor to one of those other studies.
Dr. Melnick and his colleagues are now working with companies that make ATR inhibitors to find a way to translate these findings to the clinic. However, much more research is needed, because many questions remain about when and how ATR inhibitors would need to be given.
“Timing will be very critical,” he said. “We still have a lot to work out in the laboratory before we can study this in patients.”
Dr. Cihangir Duy, a former postdoctoral fellow in Dr. Melnick’s lab, was the study’s first author. Dr. Duy now leads his own lab at Fox Chase Cancer Center in Philadelphia.
Dr. Ari Melnick has been a paid consultant for KDAC Therapeutics, Epizyme, and Constellation Pharmaceuticals.

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How much did SARS-CoV-2 need to change in order to adapt to its new human host? In a research article published in the open access journal PLOS Biology Oscar MacLean, Spyros Lytras at the University of Glasgow, and colleagues, show that since December 2019 and for the first 11 months of the SARS-CoV-2 pandemic there has been very little ‘important’ genetic change observed in the hundreds of thousands of sequenced virus genomes.
The study is a collaboration between researchers in the UK, US and Belgium. The lead authors Prof David L Robertson (at the MRC-University of Glasgow Centre for Virus Research, Scotland) and Prof Sergei Pond (at the Institute for Genomics and Evolutionary Medicine, Temple University, Philadelphia) were able to turn their experience of analysing data from HIV and other viruses to SARS-CoV-2. Pond’s state-of-the-art analytical framework, HyPhy, was instrumental in teasing out the signatures of evolution embedded in the virus genomes and rests on decades of theoretical knowledge on molecular evolutionary processes.
First author Dr Oscar MacLean explains, “This does not mean no changes have occurred, mutations of no evolutionary significance accumulate and ‘surf’ along the millions of transmission events, like they do in all viruses.” Some changes can have an effect; for example, the Spike replacement D614G which has been found to enhance transmissibility and certain other tweaks of virus biology scattered over its genome. On the whole, though, ‘neutral’ evolutionary processes have dominated. MacLean adds, “This stasis can be attributed to the highly susceptible nature of the human population to this new pathogen, with limited pressure from population immunity, and lack of containment, leading to exponential growth making almost every virus a winner.”
Pond comments, “what’s been so surprising is just how transmissible SARS-CoV-2 has been from the outset. Usually viruses that jump to a new host species take some time to acquire adaptations to be as capable as SARS-CoV-2 at spreading, and most never make it past that stage, resulting in dead-end spillovers or localised outbreaks.”
Studying the mutational processes of SARS-CoV-2 and related sarbecoviruses (the group of viruses SARS-CoV-2 belongs to from bats and pangolins), the authors find evidence of fairly significant change, but all before the emergence of SARS-CoV-2 in humans. This means that the ‘generalist’ nature of many coronaviruses and their apparent facility to jump between hosts, imbued SARS-CoV-2 with ready-made ability to infect humans and other mammals, but those properties most have probably evolved in bats prior to spillover to humans.
Joint first author and PhD student Spyros Lytras adds, “Interestingly, one of the closer bat viruses, RmYN02, has an intriguing genome structure made up of both SARS-CoV-2-like and bat-virus-like segments. Its genetic material carries both distinct composition signatures (associated with the action of host anti-viral immunity), supporting this change of evolutionary pace occurred in bats without the need for an intermediate animal species.”
Robertson comments, “the reason for the ‘shifting of gears’ of SARS-CoV-2 in terms of its increased rate of evolution at the end of 2020, associated with more heavily mutated lineages, is because the immunological profile of the human population has changed.” The virus towards the end of 2020 was increasingly coming into contact with existing host immunity as numbers of previously infected people are now high. This will select for variants that can dodge some of the host response. Coupled with the evasion of immunity in longer-term infections in chronic cases (e.g., in immunocompromised patients), these new selective pressures are increasing the number of important virus mutants.
It’s important to appreciate SARS-CoV-2 still remains an acute virus, cleared by the immune response in the vast majority of infections. However, it’s now moving away faster from the January 2020 variant used in all of the current vaccines to raise protective immunity. The current vaccines will continue to work against most of the circulating variants but the more time that passes, and the bigger the differential between vaccinated and not-vaccinated numbers of people, the more opportunity there will be for vaccine escape. Robertson adds, “The first race was to develop a vaccine. The race now is to get the global population vaccinated as quickly as possible.”

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Sound sleep plays a critical role in healing traumatic brain injury, a new study of military veterans suggests.
The study, published in the Journal of Neurotrauma, used a new technique involving magnetic resonance imaging developed at Oregon Health & Science University. Researchers used MRI to evaluate the enlargement of perivascular spaces that surround blood vessels in the brain. Enlargement of these spaces occurs in aging and is associated with the development of dementia.
Among veterans in the study, those who slept poorly had more evidence of these enlarged spaces and more post-concussive symptoms.
“This has huge implications for the armed forces as well as civilians,” said lead author Juan Piantino, M.D., MCR, assistant professor of pediatrics (neurology) in the OHSU School of Medicine and Doernbecher Children’s Hospital. “This study suggests sleep may play an important role in clearing waste from the brain after traumatic brain injury — and if you don’t sleep very well, you might not clean your brain as efficiently.”
Piantino, a physician-scientist with OHSU’s Papé Family Pediatric Research Institute, studies the effects of poor sleep on recovery after traumatic brain injuries.
The new study benefited from a method of analyzing MRIs developed by study co-author Daniel Schwartz and Erin Boespflug, Ph.D., under the direction of Lisa Silbert, M.D., M.C.R., professor of neurology in the OHSU School of Medicine. The technique measures changes in the brain’s perivascular spaces, which are part of the brain’s waste clearance system known as the glymphatic system.

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“We were able to very precisely measure this structure and count the number, location and diameter of channels,” Piantino said.
Co-author Jeffrey Iliff, Ph.D., professor of psychiatry and behavioral sciences and of neurology at the University of Washington and a researcher at the VA Puget Sound Health Care System, has led scientific research into the glymphatic system and its role in neurodegenerative conditions such as Alzheimer’s disease. During sleep, this brain-wide network clears away metabolic proteins that would otherwise build up in the brain.
The study used data collected from a group of 56 veterans enrolled by co-authors Elaine Peskind, M.D., and Murray Raskind, M.D., at the Mental Illness Research, Education and Clinical Center at the VA Puget Sound between 2011 and 2019.
“Imagine your brain is generating all this waste and everything is working fine,” Piantino said. “Now you get a concussion. The brain generates much more waste that it has to remove, but the system becomes plugged.”
Piantino said the new study suggests the technique developed by Silbert could be useful for older adults.

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“Longer term, we can start thinking about using this method to predict who is going to be at higher risk for cognitive problems including dementia,” he said.
The study is the latest in a growing body of research highlighting the importance of sleep in brain health.
Improving sleep is a modifiable habit that can be improved through a variety of methods, Piantino said, including better sleep hygiene habits such as reducing screen time before bed. Improving sleep is a focus of research of other OHSU scientists, including Piantino’s mentor, Miranda Lim, M.D., Ph.D., associate professor of neurology, medicine and behavioral neuroscience in the OHSU School of Medicine.
“This study puts sleep at the epicenter of recovery in traumatic brain injury,” Piantino said.
The study was supported by the National heart, Lung and Blood Institute of the National Institutes of Health, award K23HL150217-01; the U.S. Department of Veterans Affairs Rehabilitation Research and Development Service Merit Review grant B77421; and NIH award P30AG008017-18.

SARS-CoV-2, the virus that causes COVID-19, has mutated throughout the pandemic. New variants of the virus have arisen throughout the world, including variants that might possess increased ability to spread or evade the immune system. Such variants have been identified in California, Denmark, the U.K., South Africa and Brazil/Japan. Understanding how well the COVID-19 vaccines work against these variants is vital in the efforts to stop the global pandemic, and is the subject of new research from the Ragon Institute of MGH, MIT and Harvard and Massachusetts General Hospital.
In a study recently published in Cell, Ragon Core Member Alejandro Balazs, PhD, found that the neutralizing antibodies induced by the Pfizer and Moderna COVID-19 vaccines were significantly less effective against the variants first described in Brazil/Japan and South Africa. Balazs’s team used their experience measuring HIV neutralizing antibodies to create similar assays for COVID-19, comparing how well the antibodies worked against the original strain versus the new variants.
“We were able to leverage the unique high-throughput capacity that was already in place and apply it to SARS-CoV-2,” says Balazs, who is also an assistant professor of Medicine at Harvard Medical School and assistant investigator in the Department of Medicine at MGH. “When we tested these new strains against vaccine-induced neutralizing antibodies, we found that the three new strains first described in South Africa were 20-40 times more resistant to neutralization, and the two strains first described in Brazil and Japan were five to seven times more resistant, compared to the original SARS-CoV-2 virus.”
Neutralizing antibodies, explains Balazs, work by binding tightly to the virus and blocking it from entering cells, thus preventing infection. Like a key in a lock, this binding only happens when the antibody’s shape and the virus’s shape are perfectly matched to each other. If the shape of the virus changes where the antibody attaches to it — in this case, in SARS-CoV-2’s spike protein — then the antibody may no longer be able to recognize and neutralize the virus as well. The virus would then be described as resistant to neutralization.
“In particular,” says Wilfredo Garcia-Beltran, MD, PhD, a resident physician in the Department of Pathology at MGH and first author of the study, “we found that mutations in a specific part of the spike protein called the receptor binding domain were more likely to help the virus resist the neutralizing antibodies.” The three South African variants, which were the most resistant, all shared three mutations in the receptor binding domain. This may contribute to their high resistance to neutralizing antibodies.
Currently, all approved COVID-19 vaccines work by teaching the body to produce an immune response, including antibodies, against the SARS-CoV-2 spike protein. While the ability of these variants to resist neutralizing antibodies is concerning, it doesn’t mean the vaccines won’t be effective.
“The body has other methods of immune protection besides antibodies,” says Balazs. “Our findings don’t necessarily mean that vaccines won’t prevent COVID, only that the antibody portion of the immune response may have trouble recognizing some of these new variants.”
Like all viruses, SARS-CoV-2 is expected to continue to mutate as it spreads. Understanding which mutations are most likely to allow the virus to evade vaccine-derived immunity can help researchers develop next-generation vaccines that can provide protection against new variants. It can also help researchers develop more effective preventative methods, such as broadly protective vaccines that work against a wide variety of variants, regardless of which mutations develop.

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There is a great need to generate various types of cells for use in new therapies to replace tissues that are lost due to disease or injuries, or for studies outside the human body to improve our understanding of how organs and tissues function in health and disease. Many of these efforts start with human induced pluripotent stem cells (iPSCs) that, in theory, have the capacity to differentiate into virtually any cell type in the right culture conditions. The 2012 Nobel Prize awarded to Shinya Yamanaka recognized his discovery of a strategy that can reprogram adult cells to become iPSCs by providing them with a defined set of gene-regulatory transcription factors (TFs). However, progressing from there to efficiently generating a wide range of cell types with tissue-specific differentiated functions for biomedical applications has remained a challenge.
While the expression of cell type-specific TFs in iPSCs is the most often used cellular conversion technology, the efficiencies of guiding iPSC through different “lineage stages” to the fully functional differentiated state of, for example, a specific heart, brain, or immune cell currently are low, mainly because the most effective TF combinations cannot be easily pinpointed. TFs that instruct cells to pass through a specific cell differentiation process bind to regulatory regions of genes to control their expression in the genome. However, multiple TFs must function in the context of larger gene regulatory networks (GRNs) to drive the progression of cells through their lineages until the final differentiated state is reached.
Now, a collaborative effort led by George Church, Ph.D. at Harvard’s Wyss Institute for Biologically Inspired Engineering and Harvard Medical School (HMS), and Antonio del Sol, Ph.D., who leads Computational Biology groups at CIC bioGUNE, a member of the Basque Research and Technology Alliance, in Spain, and at the Luxembourg Centre for Systems Biomedicine (LCSB, University of Luxembourg), has developed a computer-guided design tool called IRENE, which significantly helps increase the efficiency of cell conversions by predicting highly effective combinations of cell type-specific TFs. By combining IRENE with a genomic integration system that allows robust expression of selected TFs in iPSCs, the team demonstrated their approach to generate higher numbers of natural killer cells used in immune therapies, and melanocytes used in skin grafts, than other methods. In a scientific first, generated breast mammary epithelial cells, whose availability would be highly desirable for the repopulation of surgically removed mammary tissue. The study is published in Nature Communications.
“In our group, the study naturally built on the ‘TFome’ project, which assembled a comprehensive library containing 1,564 human TFs as a powerful resource for the identification of TF combinations with enhanced abilities to reprogram human iPSCs to different target cell types,” said Wyss Core Faculty member Church. “The efficacy of this computational algorithm will boost a number of our tissue engineering efforts at the Wyss Institute and HMS, and as an open resource can do the same for many researchers in this burgeoning field.” Church is the lead of the Wyss Institute’s Synthetic Biology platform, and Professor of Genetics at HMS and of Health Sciences and Technology at Harvard and MIT.
Tooling up
Several computational tools have been developed to predict combinations of TFs for specific cell conversions, but almost exclusively these are based on the analysis of gene expression patterns in many cell types. Missing in these approaches was a view of the epigenetic landscape, the organization of the genome itself around genes and on the scale of entire chromosome sections which goes far beyond the sequence of the naked genomic DNA.

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“The changing epigenetic landscape in differentiating cells predicts areas in the genome undergoing physical changes that are critical for key TFs to gain access to their target genes. Analyzing these changes can inform more accurately about GRNs and their participating TFs that drive specific cell conversions,” said co-first author Evan Appleton, Ph.D. Appleton is a Postdoctoral Fellow in Church’s group who joined forces with Sascha Jung, Ph.D., from del Sol’s group in the new study. “Our collaborators in Spain had developed a computational approach that integrated those epigenetic changes with changes in gene expression to produce critical TF combinations as an output, which we were in an ideal position to test.”
The team used their computational “Integrative gene Regulatory Network model” (IRENE) approach to reconstruct the GRN controlling iPSCs, and then focused on three target cell types with clinical relevance to experimentally validate TF combinations prioritized by IRENE. To deliver TF combinations into iPSCs, they deployed a transposon-based genomic integration system that can integrate multiple copies of a gene encoding a TF into the genome, which allows all factors of a combination to be stably expressed. Transposons are DNA elements that can jump from one position of the genome to another, or in this case from an exogenously provided piece of DNA into the genome.
“Our research team composed of scientists from the LCSB and CIC bioGUNE has a long-standing expertise in developing computational methods to facilitate cell conversion. IRENE is an additional resource in our toolbox and one for which experimental validation has demonstrated it substantially increased efficiency in most tested cases,” corresponding author Del Sol, who is Professor at LCSB and CIC bioGUNE. “Our fundamental research should ultimately benefit patients, and we are thrilled that IRENE could enhance the production of cell sources readily usable in therapeutic applications, such as cell transplantation and gene therapies.”
Validating the computer-guided design tool in cells
The researchers chose human mammary epithelial cells (HMECs) as a first cell type. Thus far HMECs are obtained from one tissue environment, dissociated, and transplanted to one where breast tissue has been resected. HMECs generated from patients’ cells, via an intermediate iPSC stage, could provide a means for less invasive and more effective breast tissue regeneration. One of the combinations that was generated by IRENE enabled the team to convert 14% of iPSCs into differentiated HMECs in iPSC-specific culture media, showing that the provided TFs were sufficient to drive the conversion without help from additional factors.
The team then turned their attention to melanocytes, which can provide a source of cells in cellular grafts to replace damaged skin. This time they performed the cell conversion in melanocyte destination medium to show that the selected TFs work under culture conditions optimized for the desired cell type. Two out of four combinations were able to increase the efficiency of melanocyte conversion by 900% compared to iPSCs grown in destination medium without the TFs. Finally, the researchers compared combinations of TFs prioritized by IRENE to generate natural killer (NK) cells with a state-of-the-art differentiation method based on cell culture conditions alone. Immune NK cells have been found to improve the treatment of leukemia. The researchers’ approach outperformed the standard with five out of eight combinations increasing the differentiation of NK cells with critical markers by up to 250%.
“This novel computational approach could greatly facilitate a range of cell and tissue engineering efforts at the Wyss Institute and many other sites around the world. This advance should greatly expand our toolbox as we strive to develop new approaches in regenerative medicine to improve patients’ lives,” said Wyss Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at HMS and Boston Children’s Hospital, and Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences.

Since the pandemic hit, researchers have been uncovering ways COVID-19 impacts other parts of the body, besides the lungs.
Now, for the first time, a visual correlation has been found between the severity of the disease in the lungs using CT scans and the severity of effects on patient’s brains, using MRI scans. This research is published in the American Journal of Neuroradiology. It will be presented at the 59th annual meeting of the American Society of Neuroradiology (ASNR) and has also been selected as a semifinalist for that organization’s Cornelius Dyke Award.
The results show that by looking at lung CT scans of patients diagnosed with COVID-19, physicians may be able to predict just how badly they’ll experience other neurological problems that could show up on brain MRIs, helping improve patient outcomes and identify symptoms for earlier treatment.
CT imaging can detect illness in the lungs better than an MRI, another medical imaging technique. However, MRI can detect many problems in the brain, particularly in COVID-19 patients, that cannot be detected on CT images.
The study was led by Achala Vagal, MD, professor in the department of radiology, and Abdelkader Mahammedi, MD, assistant professor of radiology. Both are UC Health radiologists and members of the UC Gardner Neuroscience Institute.
“We’ve seen patients with COVID-19 experience stroke, brain bleeds and other disorders affecting the brain,” says Mahammedi. “So, we’re finding, through patient experiences, that neurological symptoms are correlating to those with more severe respiratory disease; however, little information has been available on identifying potential associations between imaging abnormalities in the brain and lungs in COVID-19 patients.
“Imaging serves as proof for physicians, confirming how an illness is forming and with what severity and helps in making final decisions about a patient’s care.”
In this study, which was conducted not only at UC, but also at large institutions in Spain, Italy and Brazil, researchers reviewed electronic medical records and images of hospitalized COVID-19 patients from March 3 to June 25, 2020. Patients who were diagnosed with COVID-19, experienced neurological issues and who had both lung and brain images available were included.
Of 135 COVID-19 patients with abnormal CT lung scans and neurological symptoms, 49, or 36%, were also found to develop abnormal brain scans and were more likely to experience stroke symptoms.
Mahammedi says this study will help physicians classify patients, based on the severity of disease found on their CT scans, into groups more likely to develop brain imaging abnormalities. He adds that this correlation could be important for implementing therapies, particularly in stroke prevention, to improve outcomes in patients with COVID-19.
“These results are important because they further show that severe lung disease from COVID-19 could mean serious brain complications, and we have the imaging to help prove it,” says Mahammedi. “Future larger studies are needed to help us understand the tie better, but for now, we hope these results can be used to help predict care and ensure that patients have the best outcomes.”
This research was supported by the National Institutes of Health (the National Institute of Neurological Disorders and Stroke and National Institute on Aging) (NS103824, NS117643, NS100417, 1U01NS100699, U01NS110772). Researchers cite no conflict of interest.

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As the world continues to grapple with the COVID-19 pandemic, an international team of researchers have published a review of the best techniques to collect airborne aerosols containing viruses.
In the review, which was published by the Science of the Total Environment journal, a team led by the University of Surrey concluded that the most effective way to collect and detect airborne pathogens, particularly viruses, was to use cyclone sampling techniques.
For example, the sampler draws the air through the cyclone separator. It then uses centrifugal forces to collect the particles on a sterile cone containing the liquid collection vessel, such as DMEM (Dulbecco’s minimal essential medium). The collected sample can then be readily used for any analysis for virus detection.
The research team hope that this wide-ranging review can serve as an information hub packed with the best methods and samplers involved in airborne virus collection.
The study is part of the INHALE project — an EPSRC funded project that aims to assess air pollution’s impact on personal health in urban environments. The project involves Imperial College London, the University of Surrey and the University of Edinburgh.
The INHALE team also reviewed effective techniques for capturing fine (PM2.5) and ultrafine (PM0.1) particles to understand their toxicity and their role on reactive oxygen species in cells, their elemental composition and carbon content. The team also set out to find the best solution to prevent samples from being destroyed, a common problem found in toxicological experiments that makes large sample collection challenging. The study concluded that Harvard impactor samplers could be used for both indoor and outdoor environments to effectively collect these fine and ultrafine samples.
Professor Prashant Kumar, lead author of the study and Founding Director of the Global Centre for Clean Air Research at the University of Surrey, said: “The scientific community will have to become more efficient and resourceful if we are to overcome foes such as airborne viruses and air pollution. Knowing the right tools to use — as well as how and where to use them — is crucial in our ongoing fight to make the air we breathe cleaner and safer for all.”
Professor Fan Chung, co-lead of INHALE from Imperial College London, said: “I am pleased that this timely review found support for the techniques that have been adopted in the INHALE research program. The collection of ultrafine particles is of particular importance because of the commonly found difficulties of collecting enough for toxicity studies. Ultimately, the success of INHALE will depend on the ability to capture enough of these fine and ultrafine particles as far as possible in their natural state.”
Professor Chris Pain, co-lead of INHALE from Imperial College London, said: “Understanding the application of these sampling techniques is hugely important for environmental and health research in general and for the INHALE project itself, particularly concerning collecting ultra-fine particles.”
This work was supported by the EPSRC INHALE (Health assessment across biological length scales for personal pollution exposure and its mitigation) project (EP/T003189/1).

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In asthma, the airways become hyperresponsive. Researchers from Uppsala University have found a new mechanism that contributes to, and explains, airway hyperresponsiveness. The results are published in the scientific journal Allergy.
Some 10 per cent of Sweden’s population suffer from asthma. In asthmatics, the airways are hyperresponsive (overreactive) to various types of stimuli, such as cold air, physical exertion and chemicals. The airways become constricted, making breathing difficult.
To diagnose asthma, a “methacholine test” is commonly used to determine whether a person is showing signs of airway hyperresponsiveness. Methacholine binds to what are known as muscarinic receptors in the smooth muscle cells lining the inside of the trachea. These muscle cells then begin to contract, causing constriction of the trachea.
In the new study, the scientists show that the airway hyperresponsiveness induced by methacholine is due partly to the body’s mast cells. The research was conducted using a mouse model of asthma, where the mice were made allergic to house dust mites.
Mast cells, which are immune cells of a specific type belonging to the innate immune system, are found mainly in tissues that are in contact with the external environment, such as the airways and the skin. Because of their location and the fact that they have numerous different receptors capable of recognising parts of foreign or pathogenic substances, they react quickly and become activated. In their cytoplasm, mast cells have storage capsules, known as granules, in which some substances are stored in their active form. When the mast cell is activated, these substances can be rapidly released and provoke a physiological reaction. This plays a major part in the body’s defence against pathogens, but in asthma and other diseases where the body starts reacting against harmless substances in the environment, it becomes a problem.
In their study, the researchers were able to demonstrate that the mast cells contribute to airway hyperresponsiveness by having a receptor that recognises methacholine: muscarinic receptor-3 (M3). When methacholine binds M3, the mast cells release serotonin. This then acts on nerve cells, which in turn control the airways. Thereafter, the airways produce acetylcholine, which also acts on M3 in smooth muscle cells and makes the trachea contract even more. A vicious cycle is under way.
The scientists’ discovery also means that drugs like tiotropium, which were previously thought to work solely by blocking M3 in smooth muscle, are probably also efficacious because they prevent activation through M3 in mast cells. Accordingly, the ability of mast cells to rapidly release serotonin in response to various stimuli, thereby contributing to airway hyperresponsiveness, has been underestimated.

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Materials provided by Uppsala University. Original written by Linda Koffmar. Note: Content may be edited for style and length.

A comprehensive modeling study sheds new light on socioeconomic-based mechanisms that drive disparities in influenza burden across the U.S. Casey Zipfel of Georgetown University in Washington D.C. and colleagues present this analysis in the open-access journal PLOS Computational Biology.
People of lower socioeconomic status experience increased burden of influenza. Past studies have identified various factors that underlie this health inequity, including decreased flu vaccination, lack of access to paid sick leave, lack of healthcare access, increased susceptibility to infection, and different exposure patterns. However, no previous study has considered all of these factors at once.
For the new study, Zipfel and colleagues considered how multiple underlying factors independently and synergistically drive health disparities in influenza burden. They combined large-scale disease datasets and observations from past studies to develop data-driven computational models, enabling them to explore how various factors impact influenza transmission and burden for people of varying socioeconomic status across the U.S.
The analysis showed that people of lower socioeconomic status bear a disproportionate burden of influenza infection in the U.S., and this disparity arises from the synergistic combination of multiple social-economic and healthcare factors. The researchers also identified geographic regions where disparities are most severe and where existing systems to track influenza tend to overlook flu cases among people of low socioeconomic status.
“As the divide in health disparities grows wider across the world, it is imperative that we continue to understand how social determinants impact health, and how this is reflected geographically,” Zipfel says. “Our work spotlights inequities in respiratory disease transmission, currently on display due to the COVID-19 pandemic.”
The new findings could help inform efforts to eliminate public health disparities due to socioeconomic status and systemic racism. Meanwhile, the researchers note the need to collect better data on healthcare access and usage among people of low socioeconomic status in order to validate their model findings and inform future research and public health efforts.

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University of Otago researchers have discovered one of the reasons why more than 50 per cent of people with type 2 diabetes die from heart disease.
And perhaps more significantly, they have found how to treat it.
Associate Professor Rajesh Katare, of the Department of Physiology, says it has been known that stem cells in the heart of diabetic patients are impaired. While stem cell therapy has proved effective in treating heart disease, it is not the case in diabetic hearts.
It has not been known why; until now.
It comes down to tiny molecules called microRNA which control gene expression.
“Based on the results of laboratory testing, we identified the number of microRNAs that are impaired in stem cells of the diabetic heart,” Associate Professor Katare says.

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“Among several microRNAs we identified that one particular microRNA called miR-30c — which is crucial for the stem cells’ survival, growth and new blood vessel formation — is reduced in the diabetic stem cells. All these functions are required for stem cell therapy to be successful in the heart.
“Importantly, we also confirmed that this microRNA is decreased in the stem cells collected from the heart tissue of the patients undergoing heart surgery at Dunedin Hospital.”
Researchers were able to then increase the level of the lacking miR-30c in the heart by a “simple injection.”
“This resulted in significantly improving the survival and growth of stem cells in the diabetic heart,” Associate Professor Katare says.
“This fascinating discovery has newly identified that impairment in the microRNAs is the underlying reason for the stem cells being not functional in the diabetic heart. More importantly, the results have identified a novel therapy for activation of stem cells in the heart using microRNA, without the need to inject stem cells, which is a time and cost consuming process.”
Associate Professor Katare calls the finding “significant” and says it could help diabetes- sufferers — who are ten per cent of New Zealanders — lead a longer, quality life.
“Apart from identifying the reasons for poor stem cells function in a patient with diabetes, the novel therapy of using microRNA could change the treatment method for heart disease in diabetic individuals.”
Researchers will now undertake more laboratory testing before moving on to humans.
“Our initial analysis revealed that there might be another four potential candidate microRNAs. Therefore, it is essential to test the function of those microRNAs as well. It may be possible that combination therapy with more than one microRNA could further increase the beneficial effects.”

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