Culture

Aging is the biggest risk factor for perturbation of the nervous system, even in the absence of distinct disease or trauma. For yet unknown reasons, the impulse conducting, myelinated projections and synaptic connections between nerve cells are especially vulnerable to aging-related degeneration. These pathological alterations often manifest as cognitive, sensory, and motor decline in older adults and represent a serious socio-economic challenge.

Malactivation leads to damage

Scientists have long assumed that inflammation plays an important role in this process. Mal- or overactivation of distinct cells belonging to the innate immune system - the microglia - appears to promote damage of nerve fibers and synapses in the aging central nervous system (CNS). In a recent project, scientists of the University Hospital Würzburg have now discovered an important role of the adaptive immune system.

The study was conducted at the Department of Neurology under corresponding author and lecturer Dr. Janos Groh from the section of "Developmental Neurobiology" (Prof. Dr. Rudolf Martini) in collaboration with Professor Wolfgang Kastenmüller (Institute for Systems Immunology) and Dr. Antoine-Emmanuel Saliba from the Helmholtz Institute for RNA-based Infection Research. The results of the study have now been published in the scientific journal Nature Aging.

T cells as mediators of neurodegeneration

"Cytotoxic CD8+ T cells normally recognize and fight infected or malignant cells. However, in case of autoimmune diseases like multiple sclerosis, they can also do unwanted damage in the nervous system", says Janos Groh. The scientists could previously identify such CD8+ T cells as important disease amplifiers in models of various genetically mediated neurological disorders. Their role in the aging CNS, however, was so far poorly investigated on a functional level. In order to shed light on this question, the researchers investigated the impact of CD8+ T cells in aged mice, where these cells were found in increased numbers in fiber tracts.

"We show that the accumulation of CD8+ T cells leads to degeneration of nerve fibers in the CNS of normal aging mice, which contributes to motor and cognitive decline", Groh summarizes the most important results of the study. Using modern gene expression analyses on the single-cell level, the team could for the first time characterize distinct populations of these CD8+ T cells in the brains of adult and aged mice in detail. This helped the scientists to subsequently clarify how the CD8+ T cells cause harm in the brain using precise immunological animal experiments.

Inflammation as a risk as well as therapeutic opportunity

"In addition, we show that T cell-mediated damage in aged but not adult mice is aggravated by systemic inflammation", Groh adds. According to him, the study therefore confirms that CD8+ T cells are important effectors of inflammation-driven damage to the aging CNS, for example also after infections at more distant sites of the body. In future studies, the researchers want to clarify why and how exactly this inflammatory response is initiated.

Finally, the scientists could find very similar T cell reactions as observed in mice also in autopsies of CNS white matter from older humans. CD8+ T cells might therefore represent a putative target for therapeutic approaches to mitigate aging-related decline of structure and function of the nervous system. The study thus provides basic-scientific and translationally relevant insights into degenerative aging-related processes and another example for the complex interaction between the nervous and the immune system.

Abu Dhabi, UAE, May 3, 2021: Researchers from NYU Abu Dhabi's Center for Genomics and Systems Biology have successfully sequenced the genome of previously extinct date palm varieties that lived more than 2,000 years ago. They did so using date palm seeds that were recovered from archaeological sites in the southern Levant region and radiocarbon-dated from the 4th century BCE to the 2nd century CE. The seeds were germinated to yield viable, new plants. The researchers conducted whole genome sequencing of these germinated ancient samples and used this genome data to examine the genetics of these previously extinct Judean date palms. This study marks the first time researchers have sequenced the genomes of plants from ancient germinated seeds.

By examining the genome of a species (Phoenix dactylifera L.) that thrived centuries ago, Professor of Biology Michael D. Purugganan and his NYUAD colleagues, along with research partners in Israel, and France, were able to see how these plants evolved over a period of time. In this case, they observed that between the 4th century BCE and 2nd century CE, date palms in the eastern Mediterranean started to show increasing levels of genes from another species, Phoenix theophrasti, which today grows in Crete and some other Greek islands, as well as southwestern Turkey, as a result of hybridization between species. They conclude that the increasing level of genes from P. theophrasti over this period shows the increasing influence of the Roman Empire in the eastern Mediterranean.

Their findings are reported in The genomes of ancient date palms germinated from 2,000-year-old seeds published in the journal Proceedings of the National Academy of Science USA.

"We are fortunate that date palm seeds can live a long time - in this case, more than 2,000 years - and germinate with minimal DNA damage, in the dry environment of the region," said Purugganan. "This 'resurrection genomics' approach is a remarkably effective way to study the genetics and evolution of past and possibly extinct species like Judean date palms. By reviving biological material such as germinating ancient seeds from archaeological, paleontological sites, or historical collections, we can not only study the genomes of lost populations but also, in some instances, rediscover genes that may have gone extinct in modern varieties."

What The Study Did: The findings of this study suggest an association between county-level income inequality and COVID-19 cases and deaths.

Authors: Michelle C. Odden, Ph.D., of Stanford University in Stanford, California, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2021.8799)

Editor's Note: The article includes conflict of interest disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

What The Study Did: Inquiries to a child abuse hotline during the COVID-19 pandemic compared with inquiries during the same period the previous year are assessed in this study.

Authors: Robin Ortiz, M.D., of the University of Pennsylvania in Philadelphia, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamapediatrics.2021.0503)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

What The Study Did: Researchers compared the likelihood of delayed childbearing among physicians and nonphysicians.

Authors: Andrea N. Simpson, M.D., of the University of Toronto, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamainternmed.2021.1635)

Editor's Note: The article includes conflicts of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

BURLINGTON, VT -- In the aftermath of George Floyd's 2020 murder by former police officer Derek Chauvin, many families may find themselves actively engaging in--or uncomfortably fumbling around--discussions about race. For white parents looking to clearly communicate antiracist ideologies with their preadolescent children, a new study offers some insight.

"There's a difference between saying race "shouldn't" matter and race "doesn't" matter," explains Jamie Abaied, professor of developmental psychology at the University of Vermont and lead author of the study, co-authored by Sylvia Perry, a professor of psychology at Northwestern University. Though "shouldn't" and "doesn't" may seem similar, the study reveals just how different they can be.

Released online by the journal Cultural Diversity and Ethnic Minority Psychology on Monday, the study analyzes data collected in summer 2015 (in the weeks immediately following the Charleston church shooting) from a sample of white American parents responding to questions about how they talk about race with their children, ages 8-12. It aims to understand whether or not white American parents communicate contradictory messages about race to their children; and if so, how and why?

The short answer: Yes, they do--but probably unintentionally. The study found that more than a third of parents communicated mixed messages about race, whereas the remaining two-thirds either communicated consistent ideas about their racial ideology or simply communicated no ideas about race at all. "Before we really develop specific interventions to help parents talk to their kids about race, we need to know what they're currently saying to their kids and how they're currently thinking about these discussions," she says. Until now, there hasn't been much research on that, particularly among parents of children older than age 7.

"When parents offered mixed messages about race, they were saying really positive things like, 'Racism is real and it's wrong,' but they were also saying that race isn't that important, or that 'It's only skin deep,' which is a type of thinking that researchers call colorblindness," she explains. About half the parents endorsed colorblindness at least once in their responses, and more than twenty-one percent of parents in the study only communicated colorblind thinking to their children.

Though not the focus of the study, these findings add to an existing body of psychological research that recalibrates the scales from simply "racist" or "not racist," to "racist" or "counteractive to racist." It's a concept known as antiracism, and it significantly impacts today's understanding of racial colorblindness.

The study describes colorblindness as "a modern form of racism, which can take the form of either color-evasion (claiming to 'not see' race) or power evasion (denying that racial inequality is a reality)." It can downplay race, imply that it isn't important, or divert awareness. And according to Abaied, it's the most problematic takeaway from the study.

"The problem with colorblindness is that race is real. It has real effects on people's lived experiences. If you don't think race is real, it makes it easier to go a step further and believe that racism isn't real," Abaied says. "I think some of the parents were well-meaning and trying to voice egalitarian beliefs, such as, 'I believe people of different races should be treated equally,' which is different from, 'I don't see color, everybody's equal.' In doing that, they are implying that race doesn't matter. The difference is very nuanced, but also very important."

"Colorblindness is not a pathway to racial equality," she adds. "There's a false belief that if we just stop talking about race, everything will be fine." In fact, Abaied found that most white parents, sixty-three percent, reported that they didn't discuss race-related news with their children at the time, which included the killings of Trayvon Martin, Michael Brown and Freddie Gray in addition to the 2015 Charleston church shooting.

Reasons for that ranged from parents wanting to shield their children from difficult topics--"No, a child should not be told about death and murder. Those are adult topics," one parent said--to perceptions of relevance--"I have not. Why would I bring that up?" stated another.

"The results indicate that white parents have the potential to be agents of change that socialize color conscious beliefs in their children, but many are reinforcing the current system of colorblind indifference to racial inequality," the study explains.

However, the researchers also found that nearly thirty-four percent of participants exclusively communicated in color conscious ideologies, which directly challenge colorblindness. In practice, that looks like white parents "celebrating racial diversity rather than minimizing it, openly acknowledging rather than denying the impact of race on people's lives through discrimination and structural racism, and advocating for equal rights and treatment across different racial groups," the study explains.

Many parents voiced this belief in response to a hypothetical question that asked what they would say to their child if they encountered an incident of race-related prejudice together. Roughly half the parents endorsed the idea that people should receive equal treatment, regardless of race. "I would tell her that what she witnessed was wrong and only hurtful people act like that and we should accept everyone as equals," one parent stated.

However, another parent stated: "I would tell her that everybody is different and the color of your skin is no reason to treat anyone any differently." Both parents endorse equal treatment regardless of race, but differ on how they define the incident itself as "wrong" to their children--only the former explicitly mentioned race in their answer.

Abaied sees the study as a first step toward developmental trainings and programs designed to help guide parents--or possibly even teachers--through these messaging nuances and straight into constructive, intentional conversations about race. "Kids' ideas about race start to solidify in adolescence, so it's not too late to have these conversations during the elementary school years. I think it would be good for parents to talk about this early," she says.

Though family conversations are just one piece of the puzzle to be solved, Abaied points out by engaging multiple generations through one conversation, those conversations have potential to be highly impactful.

Follow-up research to the study is currently underway, with Abaied and her team analyzing a new data set for the study collected in 2020 (after the murder of George Floyd) that will enable them to track and compare progress over time.

Talking about your bad day at work could lead to great solutions. Cold Spring Harbor Laboratory (CSHL) Associate Professor Saket Navlakha and his wife, Dr. Sejal Morjaria, an infectious disease physician at Memorial Sloan Kettering Cancer Center (MSK), found a way to predict COVID-19 severity in cancer patients. The computational tool they developed prevents unnecessary expensive testing and improves patient care.

Morjaria says, "Generally, I have good intuition for how patients will progress." However, that intuition failed her when confronted with COVID-19. She says:

"When the pandemic first hit, we had a hard time understanding and predicting which patients were going to have severe COVID. People were ordering a slew of labs, and a lot of times, there were unnecessary lab tests."

Navlakha joined CSHL in 2019. He uses computer science to understand biological processes. Morjaria wondered if her husband could help:

"So I came home and I would tell him, 'Saket, it would be great if we could come up with a methodology to figure out, using machine-learning, which patients are going to go on to develop severe COVID versus not.'"

The team collected 267 variables from cancer patients diagnosed with COVID-19. The variables ranged from age and sex to cancer type, most recent treatments, and laboratory results. They trained a machine-learning computer program to classify patients into three groups. Those who will require high levels of oxygen through a ventilator:

immediately

after a few days

not at all

The researchers found approximately 50 variables that contributed most to the outcome prediction. Their method had an accuracy rate of 70-85%, and it performed especially well for patients that would require immediate ventilation. More generally, the tool can help tease apart interactions between multiple risk factors that might not be apparent, even to those with trained eyes. The program also prevents over-testing, which Morjaria knows will "spare patients unnecessary massive hospital costs."

Navlakha believes this work would not have been possible without close collaboration with his wife and other MSK clinician-scientists, including Rocio-Perez Johnston and Ying Taur. He says:

"Sejal and I talk about better ways to integrate what she's experiencing on the bedside versus what we can analyze and do computationally. As someone who's never worked with clinical data, if I were to try to have done this without Sejal's guidance, I would have made tons of mistakes, it would have just been a total disaster and totally unusable."

Navlakha and Morjaria hope their work will inspire more physicians and computer scientists to work together and create innovative clinical solutions for complex diseases.

A Wyss Institute-led collaboration spanning four research labs and hundreds of miles has used the Institute's organ-on-a-chip (Organ Chip) technology to identify the antimalarial drug amodiaquine as a potent inhibitor of infection with SARS-CoV-2, the virus that causes COVID-19.

The Organ Chip-based drug testing ecosystem established by the collaboration greatly streamlines the process of evaluating the safety and efficacy of existing drugs for new medical applications, and provides a proof-of-concept for the use of Organ Chips to rapidly repurpose existing drugs for new medical applications, including future pandemics. The research is reported in Nature Biomedical Engineering.

While many groups around the world have been testing existing drugs for efficacy against COVID-19 using cultured cells, it is well known that cells grown in a dish do not behave like the cells in a living human body, and many drugs that appear effective in lab studies do not work in patients. The Wyss team examined eight existing drugs, including hydroxychloroquine and chloroquine, that they and others had found were active against SARS-CoV-2 in conventional cell culture assays.

When tested in their more sophisticated microfluidic Lung Airway Chip, which had been infected with a pseudotyped SARS-CoV-2 virus, they found that most of these drugs, including hydroxychloroquine and chloroquine, were not effective. However, another antimalarial drug, amodiaquine, was highly effective at preventing viral entry. These results were then validated in cultured cells and in a small animal model of COVID-19 using infectious SARS-CoV-2 virus. Amodiaquine is now in clinical trials for COVID-19 at multiple sites in Africa, where this drug is inexpensive and widely available.

"The speed with which this team assembled, pivoted to COVID-19, and produced clinically significant results is astonishing," said senior author and Wyss Institute Founding Director Don Ingber, M.D., Ph.D. "We started testing these compounds in February 2020, had data by March, and published a preprint in April. Thanks to the openness and collaboration that the pandemic has sparked within the scientific community, our lead drug is now being tested in humans. It's a powerful testament to Organ Chips' ability to accelerate preclinical testing."

From mysterious disease to lead compound in months

In the early months of the COVID-19 pandemic when little was known about the novel SARS-CoV-2 virus, efforts were made around the globe to identify existing drugs that could be repurposed to treat patients who were falling ill. While early data performed on cells grown in lab dishes seemed to suggest that the antimalarial drugs chloroquine and hydroxychloroquine could treat the disease, later studies showed that they aren't active against SARS-CoV-2 in animals or patients, and the quest for an effective oral therapeutic that can both treat and prevent COVID-19 continues.

Fortunately, the Wyss Institute had a ready-made solution to that problem. In a move that today seems prescient, over three years ago the Defense Advanced Research Projects Agency (DARPA) and National Institutes of Health (NIH) awarded funding to Ingber's team to explore whether its human Organ Chip microfluidic culture technology, which faithfully mimics the function of human organs in vitro, could be used to confront potential biothreat challenges including pandemic respiratory viruses.

Two years into the project, the team was making steady progress using its lung Airway Chip to study drugs that could be repurposed to treat influenza virus infections. Then, in January 2020, first authors Longlong Si, Ph.D. and Haiqing Bai, Ph.D. heard about cases of what was being called a novel viral pneumonia in China.

"That caught a lot of scientists' attention, because any new virus could become a global threat given how easily infections spread in today's era of widespread international travel. We closely followed the updates because we thought that our Airway Chip model could provide an important tool for studying this virus," said Si, a Wyss Technology Development Fellow and co-lead author. Once it became clear that people were falling ill due to the mysterious COVID-19 and not pneumonia, the team quickly shifted its focus to the novel SARS-CoV-2 virus.

The human Airway Chip that the Wyss team developed for these studies is a microfluidic device about the size of a USB memory stick that contains two parallel channels separated by a porous membrane. Human lung airway cells are grown in one channel that is perfused with air, while human blood vessel cells are grown in the other channel, which is perfused with liquid culture medium to mimic blood flow. Cells grown in this device naturally differentiate into multiple airway-specific cell types in proportions that are similar to those in the human airway, and develop traits observed in living lungs such as cilia and the ability to produce and move mucus. Airway Chip cells also have higher levels of angiotensin-converting enzyme-2 (ACE2) receptor protein, which plays a central role in lung physiology and is used by SARS-CoV-2 to infect cells.

"Our biggest challenge in shifting our focus to SARS-CoV-2 was that we don't have lab facilities with the necessary infrastructure to safely study dangerous pathogens. To get around that problem, we designed a SARS-CoV-2 pseudovirus that expresses the SARS-CoV-2 spike protein, so that we could identify drugs that interfere with the spike protein's ability to bind to human lung cells' ACE2 receptors," said Bai, who is a Postdoctoral Fellow at the Wyss Institute and co-lead author. "A secondary goal was to demonstrate that these types of studies could be carried out by other Organ Chip researchers who similarly have this technology, but lack access to lab facilities required to study highly infectious viruses."

Armed with the pseudovirus that allowed them to study SARS-CoV-2 infection, the team first perfused the Airway Chips' blood vessel channel with several approved drugs, including amodiaquine, toremifene, clomiphene, chloroquine, hydroxychloroquine, arbidol, verapamil, and amiodarone, all of which have exhibited activity against other related viruses in previous studies. However, in contrast to static culture studies, they were able to perfuse the drug through the channels of the chip using a clinically relevant dose to mimic how the drug would be distributed to tissues in our bodies. After 24 hours they introduced SARS-CoV-2 pseudovirus into the Airway Chips' air channel to mimic infection by airborne viruses, like that in a cough or sneeze.

Only three of these drugs ? amodiaquine, toremifene, and clomiphene ? significantly prevented viral entry without producing cell damage in the Airway Chips. The most potent drug, amodiaquine, reduced infection by about 60%. The team also performed spectrometry measurements with the assistance of Steve Gygi, Ph.D.'s group at Harvard Medical School to assess how the drugs impacted the airway cells. These studies revealed that amodiaquine produced distinct and broader protein changes than the other antimalarial drugs.

The researchers had a lead drug candidate.

All hands on deck

Despite the promise of amodiaquine, the team still needed to demonstrate that it worked against the real infectious SARS-CoV-2 virus. With the help of a new COVID-19-focused grant from DARPA, Ingber teamed up with Matthew Frieman, Ph.D. at the University of Maryland School of Medicin and Benjamin tenOever, Ph.D. at the Icahn School of Medicine at Mount Sinai, both of whom already had biosafety labs set up to study infectious pathogens.

This collaboration created a drug discovery ecosystem that combines the human emulation capability of the Wyss Institute's Organ Chips with Frieman's and tenOever's expertise in the interactions between viruses and their host cells. The Frieman lab tested amodiaquine and its active metabolite, desethylamodiaquine, against native SARS-CoV-2 via high-throughput assays in cells in vitro, and confirmed that the drug inhibited viral infection.

In parallel, the tenOever lab tested amodiaquine and hydroxychloroquine against native SARS-CoV-2 in a head-to-head comparison in a small animal COVID-19 model, and saw that prophylactic treatment with amodiaquine resulted in ~70% reduction in viral load upon exposure, while hydroxychloroquine was ineffective. They also saw that amodiaquine prevented the transmission of the virus from sick to healthy animals more than 90% of the time, and that it was also effective in reducing viral load when administered after introduction of the virus. Thus, their results suggest that amodiaquine could work in both treatment and prevention modes.

"Seeing how beautifully amodiaquine inhibited infection in the Airway Chip was extremely exciting," said Frieman. "And, the fact that it seems to work both before and after exposure to SARS-CoV-2 means that it could potentially be effective in a wide variety of settings."

"This collaboration has allowed us to do things that we never would have had the resources to do otherwise, including recently setting up Organ Chips in our own lab so that we can now use them to study the interactions between infectious viruses and their hosts. While we're proud of what we've accomplished so far for COVID-19, we're also looking forward to studying additional virus-host dynamics using the Organ Chips in the hopes that we'll be able to prevent or address future pandemics," said tenOever, who is a Professor of Microbiology.

A preprint of the amodiaquine results was published online on April 15, 2020, which generated buzz in the scientific community. It eventually caught the eye of Medicines for Malaria Venture, a leading product development partnership in antimalarial drug research. These results, along with studies from several other groups, contributed to amodiaquine's inclusion in a clinical trial in collaboration with the University of Witwatersrand in South Africa and Shin Poong Pharmaceutical in South Korea last fall. A few months later, the Drugs for Neglected Diseases Initiative (DNDi) added amodiaquine to the ANTICOV clinical trial for COVID-19, which spans 19 sites in over 13 different countries in Africa. Amodiaquine is oral, extremely inexpensive, and widely available in Africa. If proven effective in these clinical trials, it could provide a badly needed weapon against COVID-19 in low-resource nations where access to vaccines and expensive new therapeutics is limited.

Preparing for the next pandemic

While the identification of amodiaquine is a major boon in fighting COVID-19, the team already has their sights set on future pandemics. In addition to SARS-CoV-2, their recent publication details their success in finding drugs that could protect against or treat several strains of influenza virus.

"Thanks to our experience using this drug development pipeline to validate amodiaquine for COVID-19, we are now applying what we learned to influenza and other pandemic-causing pathogens," said co-author Ken Carlson, Ph.D., a Lead Senior Staff Scientist who helps lead the Coronavirus Therapeutic Project Team at the Wyss Institute. "This process has given us confidence that Organ Chips are predictive of what we see in more complex living models of viral infections, and helped harness the creative cauldron of the Wyss Institute to consolidate and strengthen our therapeutic discovery engine."

In addition to influenza, the team is now exploring drugs that could be used against the new SARS-CoV-2 mutant strains, to suppress the dangerous "cytokine storm" that leads to many hospitalizations, and to relieve the symptoms of COVID-19 "long haulers."

"The pandemic has really gelled the Wyss Institute's Bioinspired Therapeutics development program, and linking up with the Frieman and tenOever labs has created a drug discovery and development pipeline that dramatically speeds up the whole process, quickly shepherding COVID-19 drugs through preclinical development to the point where they can be tested in humans. With Organ Chip technology in hand, we are now in a stronger position to confront future pandemics," said Ingber, who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children's Hospital, and Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences.

A grass commonly used to fight soil erosion has been genetically modified to successfully remove toxic chemicals left in the ground from munitions that are dangerous to human health, new research shows.

The study - led by the University of York- demonstrates that genetically modified switchgrass (Panicum virgatum) can detoxify residues of the military explosive, RDX, left behind on live-fire training ranges, munitions dumps and minefields.

RDX has been a major component of munitions since WW2 which are still used extensively on military training grounds. This use has now resulted in widespread pollution of groundwater.

Researchers generated the plants by inserting two genes from bacteria able to breakdown RDX. The plants were then grown in RDX contaminated soil on a US military site. The genetically modified grass grew well and successfully degraded RDX to non-detectable levels in their plant tissues.

Study authors, Professor Neil Bruce from the Department of Biology and Director of the Centre for Novel Agricultural Products (CNAP) and Dr Liz Rylott, also from CNAP believe it is the first successful example of the use of a GM plant in-the-field to remove organic pollutants, which are resistant to environmental degradation.

Dr Rylott said: "The removal of the toxic RDX from training ranges is logistically challenging and there is currently a lack of cost-effective and sustainable solutions.

"Our research demonstrates how the expression, in switchgrass, of two bacterial genes that have evolved specifically to degrade RDX give the plants the ability to remove and metabolise RDX in the field at concentrations relevant to live fire military ranges.

"We demonstrated that by inserting these genes into switchgrass, the plant then had the ability to degrade RDX to non-detectable levels in the plant tissue."

The study confirmed that the plants were able remove and degrade RDX at a rate of 27 kg RDX per hectare. RDX is designated as a priority pollutant by the US Environmental Protection Agency and is of significant and increasing public concern. In the US, over 10 million hectares of military land are contaminated with munitions components, of which, RDX is a major component.

Professor Bruce added: "The recalcitrance of RDX to degradation in the environment, combined with its high mobility through soil and groundwater, mean that plumes of toxic RDX continue to spread below these military sites, threatening drinking water supplies."

The paper sites an example when in 1997, plumes of RDX pollution were discovered in both groundwater and the aquifer beneath the training range at the Massachusetts Military Reservation in Cape Cod. The aquifer is the sole source of drinking water for half a million people and resulted in the Environment Protection Agency preventing use of all live munitions during training at this site.

The study says that the continuing demand for vast amounts of military explosives means that RDX will continue to be manufactured and used globally on a massive scale for the foreseeable future.

A research team led by City University of Hong Kong (CityU) scientists recently developed a new generation of microneedles technology which allows the intradermal delivery of living cells in a minimally invasive manner. Their experiment showed that vaccination using therapeutic cells through this ground-breaking technology elicited robust immune responses against tumours in mice, paving the way for developing an easy-to-use cell therapy and other therapeutics against cancers and other diseases.

The study was led by Dr Xu Chenjie, Associate Professor at the Department of Biomedical Engineering (BME) at CityU. The latest findings have been published in the scientific journal Nature Biomedical Engineering, titled "Cryomicroneedles for Transdermal Cell Delivery".

The new technology "cryomicroneedles" are the icy microneedles shorter than 1mm and can deliver therapeutic cells into the skin layers. "It is a skin patch-like device that can load, store, and intradermally deliver the living mammalian cells," explained Dr Xu.

Cell therapy, also called cell transplantation, is a therapy in which living cells like immune cells or stem cells are injected, grafted or implanted into a patient to achieve a medicinal effect. Advances in cell therapies have brought promising treating approach for previously intractable diseases like cancers. The global market size of cell therapy was valued at USD 7.8 billion in 2020.
[Note 1]

"But many problems related to the application of cell therapy yet to be solved," said Dr Xu. For example, the therapeutic cells are currently delivered by either surgical grafts or bolus injection. These methods are invasive, painful, complicated, low-efficient, and they bring the risk of infection and require experienced professionals to implement. It is also hard to store and transport the current solution-like formulations of cell therapeutics.

To solve this challenge, Dr Xu and his team at CityU have developed these cryomicroneedles that carry and deliver living cells into the skin. By putting the patch-like device on the skin, the microneedles would penetrate through the skin, detach from the patch base and then melt. The loaded cells were released, and subsequently migrated and proliferated inside the skin. This innovative device can be stored for months in refrigerators. It is also easy for transportation and deployment.

As a proof-of-concept, the researchers explored cell-based cancer immunotherapy through intradermal delivery of ovalbumin-pulsed dendritic cells. In the study, vaccination with this device elicited robust antigen-specific immune responses and provided strong protection against tumour in mice, which were superior to the therapeutic outcomes by conventional standard vaccination methods such as subcutaneous and intravenous injection.

"The application of our device is not limited to the delivery of cells. This device can also package, store, and deliver other types of bioactive therapeutic agents, such as proteins, peptides, mRNA, DNA, and vaccines. I hope this device offers an easy-to-use and effective alternative method for the delivery of therapeutics in clinics," Dr Xu said.

Dr Chang Hao from CityU's BME is the first author, and Dr Xu is the corresponding author. Professor Wang Dongan and Dr Shi Peng from BME are also part of the research team. Other researchers come from Nanyang Technological University and National University of Singapore. The research was partially funded by the CityU and a patent application has been filed through CityU.

https://www.cityu.edu.hk/research/stories/2021/05/03/cityu-scientists-invent-cryomicroneedles-intradermal-therapeutic-cell-delivery

[Note 1: https://www.grandviewresearch.com/industry-analysis/cell-therapy-market]

Black and Latino neighborhoods in the 30 most populous U.S. cities had fewer pharmacies than white or diverse neighborhoods in 2007-2015, USC research shows, suggesting that 'pharmacy deserts'- like so-called food deserts-may be an overlooked contributor to persistent racial and ethnic health disparities.

Pharmacies are increasingly vital points of care for essential health services. In addition to filling prescriptions to treat chronic health conditions, pharmacists dispense emergency doses of naloxone to reverse opioid overdoses, contraceptives to prevent unplanned pregnancy and COVID-19 testing and vaccinations.

But many neighborhoods in major cities such as Los Angeles, Chicago, Houston, and Memphis lack convenient access to a pharmacy, according to research published published today in the May issue of the journal Health Affairs.

"We focused on cities because of racial/ethnic residential segregation and the fact that more than 80% of the Black and Latino population in the U.S. live in cities," said senior author Dima Mazen Qato, Hygeia Centennial Chair and associate professor of pharmacy at the USC School of Pharmacy and senior fellow at the USC Schaeffer Center for Health Policy & Economics.

"Our findings suggest that addressing disparities in geographic access to pharmacies - including pharmacy closures -- is imperative to improving access to essential medications and other health care services in segregated minority neighborhoods," said Qato, who directs the Program on Medicines and Public Health.

"One in three neighborhoods throughout these cities were pharmacy deserts, affecting nearly 15 million people," said Jenny S. Guadamuz, study first author and Postdoctoral Fellow at the USC Schaeffer Center and the USC Program on Medicines and Public Health at the USC School of Pharmacy. "However, limited access to pharmacies disproportionately impacts racial/ethnic minorities--8.3 million Black and Latino residents of these cities live in deserts."

Researchers focused on census tracts/neighborhoods in cities with populations of 500,000 or more. Census tracts, smaller than ZIP code areas, generally have a population size between 1,200 and 8,000 people. Data from the U.S. Census Bureau's American Community Survey established neighborhood characteristics including total population, and percentage of the population by race/ethnicity, low-income status and vehicle ownership. Pharmacy locations and types of pharmacies came from National Council for Prescription Drug Programs.

Researchers overlaid census tract maps with pharmacy locations. Neighborhoods where the average distance to the nearest pharmacy was 1.0 mile or more were classified as pharmacy deserts. In neighborhoods that were low income and had at least 100 households with no vehicle, the qualifying distance dropped to 1/2 mile or more, to account for transportation barriers.

"Traveling a mile to get your prescription medications may be convenient for people that own a car. Traveling a mile, or even ½ a mile, may be difficult for people who live in low-income neighborhoods and don't drive, particularly older adults who rely on walking or public transportation," said Qato.

Prevalence of pharmacy deserts varied widely across cities. In New York and Philadelphia, for example, fewer than 10 percent of neighborhoods met the definition of pharmacy deserts. On the other hand, more than 60 percent of neighborhoods in Indianapolis, San Antonio, and Charlotte were pharmacy deserts.

In all cities, segregated Black or Latino neighborhoods, or both, were more likely to be pharmacy deserts than white or diverse neighborhoods. These disparities were most pronounced in Los Angeles, Chicago, Albuquerque, Dallas, Memphis, Boston, Milwaukee, Baltimore and Philadelphia.

"We observed stark disparities in Los Angeles, where one-third of all Black and Latino neighborhoods were pharmacy deserts, particularly neighborhoods in South Central LA, including Florence, Broadway-Manchester and Watts," said Guadamuz.

Among all the cities examined, the most pronounced disparities were in Chicago, where 1% of white neighborhoods were pharmacy deserts in comparison to 33% of Black neighborhoods in the South Side neighborhoods of Chatham, West Pullman and Greater Grand Crossing, Guadamuz added.

The researchers said policies could help address the situation. For example, federal, state, and local governments could deploy targeted grants and tax benefits to encourage pharmacies to locate in pharmacy deserts. Other incentives could motivate pharmacies to offer services such as home delivery to improve access.

"Increasing Medicaid and Medicare pharmacy reimbursement rates for prescription medications might encourage pharmacies to open in areas of need," Guadamuz said. "To ensure existing pharmacies don't close, policymakers need to make sure that stores serving Black and Latino areas are not excluded from pharmacy networks."

What would it be like to produce fertilizer in your own basement? Leguminous plants, like peas, beans, and various species of clover, obtain the organic nitrogen they need for their growth from symbiotic soil bacteria via specialized structures in their roots. A team led by the cell biologist Prof. Dr. Thomas Ott from the University of Freiburg's Faculty of Biology has now detected a factor in the root cells that the plants need for the initial contact with these so-called root-associated bacteria, which live in the soil. They discovered a protein found only in legumes called symbiotic formin 1 (SYFO1) and demonstrated the essential role it plays in symbiosis. Together with the molecular biologist Prof. Dr. Robert Grosse University of Freiburg's Faculty of Medicine and the evolutionary biologist Dr. Pierre-Marc Delaux from the Laboratoire de Recherche en Sciences Végétales (LRSV) in Toulouse/France, the team published their results in the journal Current Biology.

When a root nodule bacterium encounters the roots of a leguminous plant in the soil, the SYFO1 protein causes the tiny hairs of the root to change the direction of their growth. They thus wrap themselves around the potential symbiotic partner. Thanks to these bacterial helpers, legumes do not need any nitrogenous fertilizer, in contrast to other plants. "If we understood precisely how the symbiosis comes into being, we could give crop plants back this special property they have lost in the course of evolution," says Ott. Both he and Grosse are members of the Cluster of Excellence CIBSS - Centre for Integrative Biological Signalling Studies. Ott's research at CIBSS involves studying the spatial organization of the signaling paths that enable the symbiotic relationship with symbiotic bacteria in the first place. Grosse, on the other hand, focuses in his work in Freiburg on the cytoskeleton of animal cells. "In our collaboration, which was made possible by CIBSS, we were able to contribute our expertise in different areas of specialization in the best possible way," says Ott.

The team demonstrated in the legume Medicago truncatula (barrel medic) that the root hairs of plants in which the gene for SYFO1 has been switched off are practically no longer capable of wrapping themselves around the bacteria. In further studies, the researchers discovered that the protein binds to actin, a component of the cytoskeleton, and at the same time to the cell wall outside the cells, thus changing the direction of its growth: Instead of growing straight, the tiny hairs now change their direction and form a loop around the bacterium.

"SYFO1 constitutes a special innovative step in the evolution of the plants," explains Ott. "While formin proteins are present in many forms in cells and interact with actin, this special type only responds to symbiotic signals from the bacteria."

Impaired bone health is among the most significant long-term consequences of hematopoietic stem cell transplantation (HSCT), a common therapy for patients with malignant and non-malignant haematological diseases.

To address this serious problem, the International Osteoporosis Foundation (IOF) expert Working Group on Cancer and Bone Disease has published a new Executive Summary of its authoritative state-of-the-art review. The review outlined the major factors affecting bone health in HSCT patients, and provided expert guidance for the monitoring, evaluation and treatment of bone loss in these patients. Published in the Journal of Bone Oncology, the Executive Summary now provides a helpful management algorithm and succinct key guidance based on the Working Group's expert opinion.

Professor René Rizzoli, Chair of the IOF Cancer and Bone Working Group and Emeritus Professor of Medicine at the University Hospitals of Geneva, Switzerland, stated:

"This concise summary aims to encourage and assist haematologists and oncologists in addressing osteoporosis and fracture prevention in their hematopoietic stem cell transplantation patients. The 'check list' includes bone mineral density examination, evaluation of clinical risk factors, and general dietary and physical activity measures, with appropriate application of osteoporosis pharmacotherapies in those who are found to be at increased high risk of fracture."

Professor Nicholas Harvey, Chair of the IOF Committee of Scientific Advisors and Professor of Rheumatology and Clinical Epidemiology at the MRC Lifecourse Epidemiology Unit, University of Southampton, UK added:

"Unfortunately, too many hematopoietic stem cell transplantation recipients are not being monitored and treated for bone fragility, despite the fact that poor bone health is a significant comorbidity post-HSCT. We therefore urge all physicians who care for HSCT recipients to take action to protect their patients' long-term bone health. It is important to keep in mind that fragility fractures can be severely debilitating, with resulting loss of physical independence and quality of life."

Individuals living with severe Alzheimer's disease showed remarkable improvements in behaviour and cognition within days of receiving an innovative new treatment that delivered low doses of radiation, a recent Baycrest-Sunnybrook pilot study found.

"The primary goal of a therapy for Alzheimer's disease should be to improve the patient's quality of life. We want to optimize their well-being and restore communication with family and friends to avoid social isolation, loneliness and under-stimulation. Although the study was a small pilot and should be interpreted with caution, our results suggest that low-dose radiation therapy may successfully achieve this," says Dr. Morris Freedman, scientist at Baycrest's Rotman Research Institute, head of the division of neurology at Baycrest and senior author of the study.

The study was a clinical follow-up to a 2015 case report about a patient in hospice with Alzheimer's disease. After being treated several times with radiation to her brain, she showed such significant improvements in cognition, speech, movement and appetite that she was discharged from the hospice to a long-term care home for older adults.

High doses of radiation are known to have harmful effects on our health. However, low doses, such as those used for diagnostic CT scans, can help the body protect and repair itself.

"Numerous neurological disorders, including Alzheimer's disease, are thought to be caused in part by oxidative stress that damages all cells, including those in the brain. We have natural protection systems to combat the damage, but they become less effective as we get older. Each dose of radiation stimulates our natural protection systems to work harder - to produce more antioxidants that prevent oxidative damage, to repair more DNA damage and to destroy more mutated cells," says Dr. Jerry Cuttler, a retired Atomic Energy of Canada scientist. He has been researching the effects of radiation on health for more than 25 years and is the lead author of the study.

In this study, published in the Journal of Alzheimer's Disease, four individuals living with severe Alzheimer's disease were given three treatments of low-dose radiation, each spaced two weeks apart. A CT scanner at Sunnybrook Health Sciences Centre was employed to provide the treatments, with the supervision and support of Dr. Sandra Black, senior scientist and neurologist, and Dr. Sean Symons, radiologist-in-chief, both at Sunnybrook. The researchers used standardized tests and observation to record changes in the patients' communication and behaviour after the treatment. Most importantly, they collected information (descriptions, photos and videos) from the patients' spouse, children and caregivers.

Remarkably, three of the four individuals showed improvements within one day of the first treatment, with their relatives reporting increased alertness and responsiveness, recognition of loved ones, mobility, social engagement, mood and more.

Two days after the first treatment, the son of one of the patients reported, "When I said hello, she looked at me and said, 'Hello dear.' She hadn't said this to me in years!"

The daughter of another patient noted: "I had an amazing visit with my dad this evening. I'm speechless from last night. He was excited to see me - he spoke to me right away and gave me multiple kisses - real kisses like years ago. He was clapping his hands to the music. My mom agreed it's been years since he has done this. Everyone is amazed."

The results of this study offer hope for those with severe Alzheimer's disease and their loved ones. However, it is important to note that this was a small pilot study with some limitations, including missing a placebo group. Future research is needed to examine the effects of this novel therapy in larger clinical trials.

New research shows that patients who have had contact with the hospital due to serious glandular disease have a greater risk of subsequently developing depression. The study from iPSYCH is the largest yet to show a correlation between glandular fever and depression.

The vast majority of Danes have had glandular fever - also called mononucleosis - before adulthood. And for the vast majority of them, the disease can be cured at home with throat lozenges and a little extra care. But for some, the disease is so serious that they need to visit the hospital.

A new research result now shows that precisely those patients who have been in contact with the hospital in connection with their illness, have a greater risk of suffering a depression later.

"Our study shows that it is associated with a forty per cent greater relative risk of developing depression, if the patient has been in contact with a hospital due to glandular fever," says Professor and Research Director Michael Eriksen Benrós from the Mental Health Centre, Copenhagen, the University of Copenhagen and Aarhus University, who is behind the study.

Demonstrates a correlation

The risk was considerable for up to four years after the infection.

"It is well-known that mononucleosis infection can cause long-term fatigue afterwards, and we can now see that there is also an increased risk of developing actual depression, which requires contact with the hospital. Fortunately, this was only the case for 1 out of 35 with mononucleosis infection within the study's follow-up, he says.

The study is a register-based study which has followed 1,440,590 Danes, of whom 12,510 had contact with the hospital due to glandular fever, and of these, 358 - corresponding to three per cent - subsequently developed depression that required hospital contact.

"Previous studies of the correlation between glandular fever and subsequent depression have primarily been small studies and the correlation has therefore been unclear. This study is the first major study able to demonstrate the correlation with a subsequent risk of depression with great statistical strength," says the lead author of the study, Nina Vindegaard from the Mental Health Centre, Copenhagen.

Affects young people

Glandular fever affects young people aged 10-25 years in particular, and symptoms include fatigue, pain in the neck, fever and swollen lymph nodes on the neck, often accompanied by fatigue in the months following. It is also often young people who come into contact with the hospital because their symptoms are serious.

"This knowledge is important - both for the patient and their parents, but also to a great extent for general practitioners - as there is an increased risk of depression after the infection," explains Nina Vindegaard.

According to Michael Eriksen Benrós, part of the explanation for the increased risk may be that the brain is affected by the infection:

"We know that mononucleosis infection can lead to long-term fatigue, but the actual underlying mechanisms for how this happens to a greater extent for this particular infection compared to many other infections haven't been identified. The general hypotheses are that it happens through activation of the immune system, which may also lie behind the increased risk of depression," he says.

Background for the results

The register-based study followed 1.44 million Danes born between 1977-2005, with 12,510 of these having had contact with the hospital contact with mononucleosis. Mononucleosis infection was associated with a forty percent increased relative risk of subsequently developing depression. Relative risk is the risk of an undesired outcome in the treatment group divided by the same risk in the control group.