Culture

Stem cells can generate a variety of specific tissues and are increasingly used for clinical applications such as the replacement of bone or cartilage. However, stem cells are also present in cancerous tissues and are involved in cancer progression and metastasis. Nerves are fundamental for regulating the physiological and regenerative processes involving stem cells. However, little is known about the interactions between stem cells and neurons in regenerating tissues and in cancers.

Comparing stem cell types in tissue regeneration

A team of researchers led by Thimios Mitsiadis, professor at the Institute of Oral Biology of the University of Zurich, has now published two studies that elucidate how stem cells promote neuronal growth in tissue regeneration and in cancer progression. The first study compared the interaction of neurons with two different human stem cell populations, namely dental pulp stem cells and bone marrow stem cells. Both can differentiate into various cell types such as bone, cartilage and fat cells. Human bone marrow stem cells are isolated from skeletal bones and are the gold standard for bone regenerative approaches. Extracted teeth are the source of dental pulp stem cells, which represent a promising alternative.

Dental stem cells are highly innervated

Using the "organ-on-a-chip" technology, which relies on small three-dimensional devices mimicking the basic functions of human organs and tissues, the researchers demonstrated that both types of stem cells promoted neuronal growth. The dental pulp stem cells, however, yielded better results compared to bone marrow stem cells: They induced more elongated neurons, formed dense neuronal networks and established close contacts with nerves.

"Dental stem cells produce specific molecules that are fundamental for the growth and attraction of neurons. Therefore, stem cells are abundantly innervated," says Mitsiadis. The formation of such extended networks and the establishment of numerous contacts suggest that dental stem cells create functional connections with nerves of the face. "Therefore, these cells could represent an attractive choice for the regeneration of functional, properly innervated facial tissues," adds co-author and junior group leader Pierfrancesco Pagella.

Cancer stem cells also recruit neurons

In the second study, the researchers examined the interaction between nerves and cancer stem cells found in ameloblastoma, an aggressive tumour of the mouth. They first demonstrated that ameloblastomas have stem cell properties and are innervated by facial neurons. When ameloblastoma cells were isolated and placed in the "organ-on-a-chip" devices, they retained not only their stem cell properties but also attracted nerves and established contact with them.

"It appears that nerves are fundamental for the survival and function of cancer stem cells," explains Pagella. "These results create new possibilities for cancer treatment using drugs that modify the communication between neurons and cancer stem cells. We hope this opens unforeseen paths towards effective therapies against cancer," adds Mitsiadis. "The combination of advanced molecular and imaging tools and "organ-on-a-chip" technology offers an exciting opportunity to reveal the hidden functions of neurons and their interactions with various stem cell types, in both healthy and pathological conditions."

Engineers have created a tiny device that can rapidly detect harmful bacteria in blood, allowing health care professionals to pinpoint the cause of potentially deadly infections and fight them with drugs.

The Rutgers coauthored study, led by researchers at Rochester Institute of Technology, is published in the journal ACS Applied Materials & Interfaces.

"The rapid identification of drug-resistant bacteria allows health care providers to prescribe the right drugs, boosting the chances of survival," said coauthor Ruo-Qian (Roger) Wang, an assistant professor in the Department of Civil and Environmental Engineering in the School of Engineering at Rutgers University-New Brunswick.

Drug-resistant bacteria, or super-bugs, are a major public health concern. Globally, at least 700,000 people die each year as a result of drug-resistant infections, including 230,000 deaths from multidrug-resistant tuberculosis. That number could soar to 10 million deaths a year by 2050 if no action is taken, according to a 2019 report.

Based on a new approach, the tiny new device rapidly isolates, retrieves and concentrates target bacteria from bodily fluids. It efficiently filters particles and bacteria, capturing about 86 percent of them. The nano-device has magnetic beads of different sizes that are designed to trap, concentrate and retrieve Escherichia coli (E. coli) bacteria. The small spaces between the beads are used to isolate bacteria in the device.

The inexpensive, transparent device is easy to fabricate and operate, making it ideal for detecting disease-causing organisms in laboratory and health care settings, according to the study. The research team is working to perfect the device and plans to add multiple devices onto a small chip and explore scaling up testing in the field.

Immunotherapy that involves treating cancer with the body's own immune cells, or those of a matched donor, shows promise in clinical trials for some patients, but not all.

A new study from Washington University School of Medicine in St. Louis suggests that the age of certain immune cells used in such therapy plays a role in how effective the immunotherapy is. These cells -- natural killer (NK) cells -- appear to be more effective the earlier they are in development, opening the door to the possibility of an immunotherapy that would not utilize cells from the patient or a matched donor. Instead, they could be developed from existing supplies of what are called human pluripotent stem cells.

"We are trying to improve the effectiveness of immunotherapy for more patients," said senior author Christopher M. Sturgeon, PhD, an assistant professor of medicine. "This special source of natural killer cells has the potential to fill some of the gaps remaining with adult NK cell therapy. There is early evidence that they are more consistent in their effectiveness, and we would not need to process cells from a donor or the patient. They could be manufactured from existing cell supplies following the strict federal guidelines for good manufacturing practices. The characteristics of these cells let us envision a supply of them ready to pull off the shelf whenever a patient needs them."

Unlike the adult versions of NK cells used in most investigational therapies, earlier versions of such cells do not originate from bone marrow. Rather, these NK cells are a special type of short-lived immune cell that forms in the yolk sac of the early mammalian embryo. But for therapeutic purposes, such cells do not need to originate from embryos -- they can be developed from human pluripotent stem cells, which have the ability to give rise to many different cell types, including these specialized natural killer cells. Manufacturing such cells -- which many academic medical centers already have the ability to do -- would make them available quickly, eliminating the time needed to process the patient's or donor's cells, which can take weeks.

The study appears March 19 in the journal Developmental Cell.

"Before a certain time point in early development, there is no such thing as bone marrow, but there is still blood being made in the embryo," Sturgeon said. "It's a transient wave of blood that the yolk sac makes to keep the embryo going until bone marrow starts to form. And that's the blood cell generation that's making these unique natural killer cells. This early blood appears to be capable of things that adult blood simply can't do."

Studying mouse and human induced pluripotent stem cells that have been coaxed into forming these unique NK cells, the researchers showed that the NK cells are better at releasing specific anti-tumor chemicals -- a process called degranulation -- than their adult counterparts. Even NK cells derived from umbilical cord blood do not respond as robustly. NK cells of adult origin also release different chemicals that trigger harmful inflammation, but this response is not necessarily effective against cancer.

Past work by other groups suggested NK cells from earlier development might be more effective, but how and why this was the case remained unknown. The specific origin of these cells was also a mystery.

"Now we know where these special natural killer cells come from and that we can never get them from an adult donor, only a pluripotent stem cell," Sturgeon said. "Based on their unique behavior alone, there is one small clinical trial of these cells that is ongoing. Now that we know how to manufacture them and how they work, it opens the door for more trials and for improving upon their function."

According to Sturgeon, such cells could be produced from existing lines of pluripotent stem cells that would not need to come from a matched donor because, in general, NK cells do not heavily attack the body's healthy tissues, as many T cell therapies can. T cells are another type of immune cell often used to treat blood cancer as part of a stem cell transplant, commonly called a bone marrow transplant. Even when NK cells do cause harm, they do not stay in the body for long periods of time.

From a basic science standpoint, Sturgeon also is interested in understanding why these cells are present in the early embryo in the first place and where they go in later development and after birth.

"We can only speculate at this point, but it's possible that during early embryonic development, when there is so much rapid cell division, these cells are there as a surveillance mechanism to protect against pediatric cancers or infection," he said.

New Orleans, LA - James Diaz, MD, MHA, MPH & TM, Dr PH, Professor and Head of Environmental Health Sciences at LSU Health New Orleans School of Public Health, has proposed a possible explanation for the severe lung complications being seen in some people diagnosed with COVID-19. The manuscript was published by Oxford University Press online in the Journal of Travel Medicine, available here.

The SARS beta coronaviruses, SARS-CoV, which caused the SARS (Severe Acute Respiratory Syndrome) outbreak in 2003 and the new SARS-CoV-2, which causes COVID-19, bind to angiotensin converting enzyme 2 (ACE2) receptors in the lower respiratory tracts of infected patients to gain entry into the lungs. Viral pneumonia and potentially fatal respiratory failure may result in susceptible persons after 10-14 days.

"Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are highly recommended medications for patients with cardiovascular diseases including heart attacks, high blood pressure, diabetes and chronic kidney disease to name a few," notes Dr. Diaz. "Many of those who develop these diseases are older adults. They are prescribed these medications and take them every day."

Research in experimental models has shown an increase in the number of ACE2 receptors in the cardiopulmonary circulation after intravenous infusions of ACE inhibitors.

"Since patients treated with ACEIs and ARBS will have increased numbers of ACE2 receptors in their lungs for coronavirus S proteins to bind to, they may be at increased risk of severe disease outcomes due to SARS-CoV-2infections," explains Diaz.

Diaz writes, this hypothesis is supported by a recent descriptive analysis of 1,099 patients with laboratory-confirmed COVID-19 infections treated in China during the reporting period, December 11, 2019, to January 29, 2020. This study reported more severe disease outcomes in patients with hypertension, coronary artery disease, diabetes and chronic renal disease. All patients with the diagnoses noted met the recommended indications for treatment with ACEIs or ARBs.
Diaz says that two mechanisms may protect children from COVID-19 infections -- cross-protective antibodies from multiple upper respiratory tract infections caused by the common cold-causing alpha coronaviruses, and fewer ACE2 receptors in their lower respiratory tracts to attract the binding S proteins of the beta coronaviruses.

He recommends future case-control studies in patients with COVID-19 infections to further confirm chronic therapy with ACEIs or ARBs may raise the risk for severe outcomes.

In the meantime he cautions, "Patients treated with ACEIs and ARBs for cardiovascular diseases should not stop taking their medicine, but should avoid crowds, mass events, ocean cruises, prolonged air travel, and all persons with respiratory illnesses during the current COVID-19 outbreak in order to reduce their risks of infection."

Kidney stone disease has a high prevalence worldwide, ranging up to 13% in North America, 9% in Europe, and 5% in Asia. They are painful for patients, often lead to surgery, and impart a significant economic impact. Many have reported nephrolithiasis (NL) to be associated with metabolic syndrome, but the mechanism by which they are linked is not understood. This poorly characterized association affords an opportunity to identify new targets that may lead to medical prevention of kidney stone recurrence.

In this study, Dr. Kazumi Taguchi (Assistant Professor, Nagoya City University), Dr. Takahiro Yasui (Professor, Nagoya City University), Dr. Thomas Chi (Associate Professor, University of California San Francisco), and their collaborators investigated gene expression profiling of nephrolithiasis patients by two RNA-sequencing approaches: comparison between renal papilla tissue with and without the presence of calcified Randall's plaques, and comparison between the papilla, medulla, and cortex regions from within a single recurrent stone forming kidney. Results were overlaid between differentially expressed genes found in the patient cohort and in the severely lithogenic kidney to identify common genes.

Overlay of these two RNA-sequencing datasets demonstrated there is impairment of lipid metabolism in renal papilla tissue containing RP linked to downregulation of fatty acid-binding protein (FABP) 4. Immunohistochemistry of human kidney specimens and microarray analysis of renal tissue from a nephrolithiasis mouse model confirmed that FABP4 downregulation is associated with renal stone formation. Furthermore, they discovered that FABP4 deficiency resulted in the development of both renal and urinary crystals in a FABP4 knockout mouse model.

Their study revealed that FABP4 plays an important, previously unrecognized role in kidney stone formation, providing a feasible mechanism to explain the link between nephrolithiasis and metabolic syndrome. They concluded that FABP4 appears to be a key molecule for kidney stone formation and may prove to be a therapeutic target for their prevention.

Cumulative doses of oral steroids in patients with chronic inflammatory diseases are associated with increased hypertension (blood pressure) for those who take them regularly, found new research in CMAJ (Canadian Medical Association Journal).

"The cumulative effect of oral steroid doses on hypertension is substantial, and given that these are commonly prescribed medications, the related health burden could be high," says Dr. Mar Pujades-Rodriguez, Leeds Institute of Health Sciences, University of Leeds, Leeds, United Kingdom.

Hypertension, or high blood pressure, affects one in five adults around the world and can have significant negative health effects. Previous studies have reported a dose-related response between oral steroids and hypertension, although evidence has been inconclusive.

This study of more than 71 000 patients from 389 general practices in England looked at the relationship between oral glucocorticoid doses and hypertension in patients with chronic inflammatory diseases between 1998 and 2017. The most common underlying diseases included inflammatory bowel disease (35%) and rheumatoid arthritis (28%). Researchers found that in the cohort studied, there were 24 896 (35%) new cases of hypertension. When patients reached cumulative doses, rates of hypertension increased accordingly in a dose-response pattern.

The authors recommend that health care providers closely monitor blood pressure in patients who routinely take oral steroids.

X-ray Imaging Reveals Insights into a Natural Mosquito-Killing Compound

Study of a mosquito-targeting toxin produced by bacteria could lead to safer and more effective anti-mosquito products

Many of the chemicals used to deter or eliminate disease-carrying mosquitoes can pollute ecosystems and drive the evolution of even more problematic, insecticide-resistant species - but thankfully, we may have better options soon.

Scientists previously discovered that a strain of naturally occurring bacteria called Bacillus thuringiensis israelensis (Bti) produces several compounds that kill mosquito larvae, yet are harmless to most other organisms. These compounds exist in crystal form inside the bacteria, and when the microbes are eaten by a larva, the high pH and digestive enzymes in their gut cause the crystals to dissolve and rearrange into molecules that perforate the larva's gut cell membranes, quickly killing the insect.

Now, new research led by Grenoble Alpes University and published in Nature Communications has revealed the atomic structure of the most potent Bti crystal and helped explain the mechanism by which the transformed toxin slices through mosquito cell membranes.

"These results help to explain differences in toxicity even by changing a single atom. This opens the door to the rational design of toxins that are safe and effective, for controlling specific mosquito species or disease targets," said Nicholas Sauter, a senior scientist in Berkeley Lab's Molecular Biophysics and Integrated Bioimaging (MBIB) Division and one of the paper's authors.

Sauter and two other MBIB co-authors used their computing expertise to process the structural data collected by the method of X-ray crystallography, which was performed at SLAC National Accelerator Laboratory's Linear Coherent Light Source (LCLS). "X-ray laser light sources like the LCLS are the only technology capable of generating beams focused enough to probe the tiny Bti crystals," added Sauter. "Gathering and then interpreting this complex data involved researchers from 10 institutions - it is a great example of a 'big science' collaboration."

One Step Closer to a Fast-Charging Battery

In collaboration with Brookhaven National Lab, Berkeley Lab researchers were able to visualize a key feature of lithium titanate

Berkeley Lab researchers, working with a team at Brookhaven National Laboratory, have made a key discovery about the dynamic structural changes in a material called lithium titanate, putting scientists one step closer to achieving a fast-charging lithium battery.

The scientists used both experimental and computational techniques to examine lithium titanate, or LTO, while it was undergoing fast charge and were able to see why lithium ions are able to move so fast. Their findings were published recently in the journal Science.

"We were able to visualize a key feature of the structure of LTO," said Tina Chen, a UC Berkeley graduate student and Berkeley Lab researcher who worked with Berkeley Lab scientist Gerbrand Ceder on the study. "We believe that if we can find materials that can accommodate this feature when they're cycling, then they may also be good candidates to have high rate capability. LTO would serve as the anode in a battery, but we also want to find better materials for the cathode, and potentially we could apply this to solid electrolytes with higher lithium mobility."

Lithium-ion batteries, such as those used in cell phones and electric vehicles, can take hours to charge. "There are a lot of materials that if you try to charge your battery too quickly then the capacity will drastically decrease," Chen said. "The goal is to be able to charge your battery very quickly and still maintain a high capacity."

Click here for a news release from Brookhaven National Laboratory on this study.

New Library of Artificial Antibodies Could Target Pathogens With Molecular Precision
Berkeley Lab technique could accelerate the design of affordable antibodies for biomedical applications

A research team led by Berkeley Lab has developed a technique that could accelerate the design of artificial antibodies for biomedical applications - from sensing technologies that detect and neutralize infectious viruses and bacteria, to the early detection of Alzheimer's.

Unfortunately, antibodies are expensive to manufacture and challenging to store. Now, as reported in the journal ACS Nano, scientists at Berkeley Lab have designed artificial antibodies that rival the chemical diversity of their natural counterparts, but without their fragility, nor the expense.

Ron Zuckermann of Berkeley Lab's Molecular Foundry his co-authors engineered a family of protein-like molecules called peptoids to fold into a nanosheet coated with peptoid loops - what the researchers call "loopoids." While the peptoids direct the formation of the nanosheet, the loopoids create libraries of chemically diverse 2D surfaces that can be tested for biological activity, Zuckermann explained.

The density of loops on the nanosheet offers multiple sites that can simultaneously attach to pathogens, boosting their binding strength. Because of their high surface area, a single nanosheet can bind thousands upon thousands of target proteins, and can even grab onto much larger biological targets like bacterial cells.

While testing the technique, the researchers identified a peptoid nanosheet that selectively binds to a key protein involved in the interaction between the anthrax pathogen and its host cell.

"We can now readily build populations of rugged synthetic materials that can be engineered to recognize a potential pathogen," said Zuckermann. "It is a shining example of biomimetic nanoscience."

Researchers from UC San Francisco, New York University, and Pacific Northwest National Laboratory also participated in the work.

Read more at the Molecular Foundry website.

A multi-university team of researchers found that expressive language sampling (ELS) can be useful in measuring outcomes in clinical trials targeting fragile X syndrome (FXS). According to their study, ELS, a set of procedures for collecting and analyzing spoken language in natural verbal interactions, yielded five language-related outcome measures that may be useful for treatment studies in intellectual disabilities, especially FXS.

According to the Centers for Disease Control and Prevention, 1 in every 77 children in the U.S. has an intellectual disability. Fragile X syndrome, a single-gene disorder, is the leading inherited cause of intellectual disability. Individuals with FXS frequently have speech and language delays, behavior challenges and anxiety.

"There have been many clinical trials of medications to help with symptoms of fragile X syndrome," said Leonard Abbeduto, director of UC Davis MIND Institute, professor of psychiatry and behavioral sciences and senior author of the study. "Unfortunately, these trials have generally failed to show benefits of medication, partly due to lack of adequate outcome measures."

The study, led by Abbeduto and Angela John Thurman from UC Davis MIND Institute and the Department of Psychiatry and Behavioral Sciences, focused on language as an outcome measure. Outcome measures are indicators used to detect meaningful change in the symptoms of a disease or disorder such as fragile X syndrome. To assess treatment efficacy, statistically adequate measurable indicators are needed. Yet, the development of outcome measures is a complicated process.

The ELS procedure

This is the first study to validate ELS procedures for studies of treatment efficacy in FXS or any intellectual disability condition. The study included 106 participants between the ages of 6 and 23, with IQ levels within the range of intellectual disability (IQ In conversation, the examiner engaged the participant in conversation on a variety of topics in a sequenced manner, beginning with a topic that the participant enjoys. Preferred topics included favorite activities (such as playing video games), fictional characters and famous people (such as Iron Man), familiar people (such as friends), specific events and activities (such as a visit to the beach) and specific themes (such as trains, weather and country music).

After talking about the participant's preferred subject, the examiner introduced a topic from predetermined ordered lists, created to suit either children and adolescents or adults. The script that the examiner followed during these interactions minimized his/her participation and maximized the participant's contribution. The conversation spanned around 12 minutes.

During narration, the participant told the story in a wordless picture book. The examiner guided the process but provided minimal probes or help, thereby ensuring that the participant constructed the story independently. The narration usually took 10 to 15 minutes.

The researchers then analyzed the collected conversation and narration samples. Based on this analysis, the researchers derived five language outcome measures: talkativeness, lexical diversity (vocabulary), syntax, dysfluency (utterance planning) and unintelligibility (speech articulation).

Strength of the outcome measures from ELS

The ELS measures were generally valid and reliable across the range of ages, IQs and autism symptom severity. The study suggests that the ELS procedures are feasible and provide measures with adequate statistical properties for a majority of 6- to 23-year-olds with FXS and intellectual disability. They, however, are more challenging and have less adequate statistical properties for individuals with FXS and who are younger than 12 years.

The ELS interactive contexts are closely aligned with real-world interactions. The conversation and narration were meaningfully completed by most individuals with FXS. This suggests low rates of noncompliance and an ability to successfully complete the task. However, noncompliance was higher for participants who were younger, with lower IQ and more severe autism.

"Most importantly, the measures are functional for the individual," Abbeduto said. "If a treatment can improve language, it can have far reaching benefits for the individual at school, in the workplace, with peers and beyond."

The researchers are sharing manuals with the research community for conversation and narration including procedures for administration, training and assessment of fidelity. The study was published March 24 in Journal of Neurodevelopmental Disorders.

What The Study Did: This survey study of almost 1,300 health care workers in China at 34 hospitals equipped with fever clinics or wards for patients with COVID-19 reports on their mental health outcomes, including symptoms of depression, anxiety, insomnia and distress.

Authors: Zhongchun Liu, M.D., of the Renmin Hospital of Wuhan University, in Wuhan, and Shaohua Hu, M.D., of the First Affiliated Hospital, Zhejiang University School of Medicine in Hangzhou, China, are the corresponding authors.

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

(10.1001/jamanetworkopen.2020.3976)

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

Drug therapies that help older adults maintain their skeletal muscle mass and physical function for longer could be a step closer after researchers at the University of Birmingham identify a key mechanism that drives the clearance of damaged mitochondria.

A team in the University's School of Sport, Exercise and Rehabilitation Sciences are well-versed at investigating dynamic machinery within cells called mitochondria. Mitochondria act as the power plant in every cell and help to supply energy for all living things.

Because mitochondria are so important to energy supply, they constantly undergo synthesis and break down to match energy demands. However, in older people, the way that mitochondria are naturally broken down in cells starts to change, leading to a build-up of damaged mitochondria or old mitochondria that are not functioning as well. It is thought these changes might contribute to the decline in the function of older people's muscles, which in turn reduces their physical capabilities. The team wanted to find out more about mitochondrial break down in muscle and the factors controlling it. Their results are published today in FASEB.

The lead researcher Alex Seabright (PhD candidate in the Lai lab) developed a new tool that uses fluorescent tags to study the mitochondria in muscle cells. In healthy cells, networks of mitochondria appear gold in colour, but turn red when undergoing break down. Using this experimental set up, they discovered that activating a master energy sensor molecule, called AMP-activated protein kinase (AMPK), helps to stimulate mitochondrial break down. These exciting findings suggest that other well-known AMPK activators, such as exercise, may stimulate the clearance of damaged mitochondria, thus keeping mitochondria in muscle healthy and prolonging older people's physical capabilities.

Project Leader Dr Yu-Chiang Lai says: "The idea of targeting AMPK with drugs is not new. Many studies, including some of our previous work, demonstrate that AMPK activation in muscle elicits many beneficial effects for treating type 2 diabetes. As a consequence, many pharmaceutical companies are currently working to develop pre-clinical compounds that activate AMPK. We hope that our new discovery will accelerate targeted drug development to help identify new and safe compounds to activate this key molecule in muscle.

Alex Seabright adds: "We know that exercise and diet regimes can be used to help people maintain their muscle mass and physical capabilities in later life. But, improving our understanding as to why muscle loss occurs with ageing, will aid the development of targeted pharmacological interventions to help people to stay physically capable for longer."

(New York City. March 20, 2020.) A study by investigators at Hospital for Special Surgery (HSS) has discovered a molecule in the lymphatic system that has the potential to play a role in autoimmune disease. The study, “Lymph node stromal CCL2 limits antibody responses,” was published online today in the journal Science Immunology.

Lead investigator Theresa Lu, MD, PhD, senior scientist in the Autoimmunity and Inflammation Program at the HSS Research Institute, and colleagues launched the study to gain a better understanding of how the immune system works.

A healthy immune system defends the body against diseases and infection. When someone has an autoimmune disease, the immune system malfunctions and the body mistakenly attacks healthy cells, tissues and organs. Rheumatoid arthritis, lupus and scleroderma are examples of autoimmune diseases. If scientists can elucidate the underlying mechanism that causes autoimmune and inflammatory conditions, they can develop ways to correct the immune system flaws that lead to disease.

Dr. Lu’s study focused on the lymphoid tissues, which house immune cells and are sites of immune cell activation. Lymphoid tissues, which include the tonsils, spleen and lymph nodes, contain structural elements, such as fibroblasts and blood vessels. These structural elements were thought to mainly provide an infrastructure for the immune cells, but recent advances in the field have shown that they actively shape immune cell responses, and multiple populations of fibroblasts have different functions, according to Dr. Lu.

“We found that one fibroblast population expressed a molecule called CCL2 in the area of antibody-secreting immune cells, called plasma cells. We focused on the CCL2-expressing fibroblasts to see if they regulate plasma cell function,” she explained. “We found that CCL2 limits the magnitude of plasma cell responses by acting on an intermediary cell to reduce plasma cell survival. This was surprising in some ways, as CCL2 can also promote inflammation, and yet we are finding a role in limiting immune responses. This underscores the multiple functions that any molecule can have in different contexts.”

The findings have implications for better understanding autoimmune diseases, according to Dr Lu. Plasma cells in autoimmune diseases generate autoantibodies that then deposit and cause inflammation in organs such as the kidneys and skin. “By understanding that plasma cells can be controlled by this subset of fibroblasts, we can study these fibroblasts to see if they are perhaps not working properly in autoimmune and inflammatory diseases. We can then search for a way correct the malfunction, so they are less likely to cause disease,” she notes.

“As the immune system is so central to how well our bodies function and often acts in similar ways in a number of different settings, what we are learning about manipulating fibroblasts can also help the biomedical community better understand how to treat related processes, such as healing after a musculoskeletal injury, fighting cancer and fighting infections,” she adds. “For example, medications used in adults and children with different forms of autoimmune inflammatory arthritis or lupus are being examined in the setting of coronavirus infections. We all learn from each other.”

Dr. Lu’s lab and colleagues have been studying the vasculature and fibroblasts of lymph nodes for 16 years. Dragos Dasoveanu, PhD, was the first author of the current study. He conducted the research at HSS with Will Shipman, PhD; Susan Chyou, BA; and Varsha Kumar, PhD. In addition, scientists at research centers in New York, Switzerland and Australia collaborated on the study.

About HSS | Hospital for Special Surgery

HSS is the world’s leading academic medical center focused on musculoskeletal health. At its core is Hospital for Special Surgery, nationally ranked No. 1 in orthopedics (for the tenth consecutive year), No. 3 in rheumatology by U.S. News & World Report (2019-2020), and named a leader in pediatric orthopedics by U.S. News & World Report “Best Children’s Hospitals” list (2019-2020). Founded in 1863, the Hospital has one of the lowest infection rates in the country and was the first in New York State to receive Magnet Recognition for Excellence in Nursing Service from the American Nurses Credentialing Center four consecutive times. The global standard total knee replacement was developed at HSS in 1969. An affiliate of Weill Cornell Medical College, HSS has a main campus in New York City and facilities in New Jersey, Connecticut and in the Long Island and Westchester County regions of New York State. In addition, HSS will be opening a new facility in Florida in early 2020. In 2018, HSS provided care to 139,000 patients and performed more than 32,000 surgical procedures, and people from all 50 U.S. states and 80 countries travelled to receive care at HSS. There were more than 37,000 pediatric visits to the HSS Lerner Children’s Pavilion for treatment by a team of interdisciplinary experts. In addition to patient care, HSS leads the field in research, innovation and education. The HSS Research Institute comprises 20 laboratories and 300 staff members focused on leading the advancement of musculoskeletal health through prevention of degeneration, tissue repair and tissue regeneration. The HSS Global Innovation Institute was formed in 2016 to realize the potential of new drugs, therapeutics and devices. The HSS Education Institute is the world’s leading provider of education on musculoskeletal health, with its online learning platform offering more than 600 courses to more than 21,000 medical professional members worldwide. Through HSS Global Ventures, the institution is collaborating with medical centers and other organizations to advance the quality and value of musculoskeletal care and to make world-class HSS care more widely accessible nationally and internationally. www.hss.edu.

Journal

Science Immunology

DOI

10.1126/sciimmunol.aaw0693

Wealthy, white California counties--once considered the nation's hotbeds for autism spectrum disorder (ASD)--have seen prevalence flatten or fall in the last two decades, while rates among poor whites and minorities keep ticking up, new CU Boulder research has found.

The study, published March 19 in the Journal of Autism and Developmental Disorders, raises the possibility that parents in wealthier counties are successfully reducing environmental exposures that may contribute to autism risk, or taking other steps to curb its severity early on.

While that's a hopeful possibility, the authors say, the findings also illuminate a disturbing economic and racial divide.

"While autism was once considered a condition that occurs mainly among whites of high socioeconomic status, these data suggest that the brunt of severe autism is now increasingly being borne by low-income families and ethnic minorities," said lead author Cynthia Nevison, PhD, an atmospheric research scientist with the Institute of Arctic and Alpine Research, who also studies environmental health.

Adds co-author Willam Parker, PhD, an autism researcher at Duke University Medical Center:
"There is potentially good news here, but, unfortunately, not everyone is a beneficiary of this good news."

For the study, the researchers analyzed 20 years' worth of autism caseload counts from the California Department of Developmental Services, comparing data from 36 of the state's most populous counties.

Between birth years 1993 and 2000, autism prevalence increased steadily among all racial groups.

But around 2000, the trajectories started to diverge: Prevalence among whites in wealthy counties like Santa Clara (home to Silicon Valley) and from Monterey to the San Francisco coast started to decline.

In middle-income counties like Sacramento, Los Angeles and San Diego, prevalence among whites continued to increase, but at a slower rate.

Meanwhile, in lower income areas like Riverside and the South Central Valley, rates among whites climbed steeply.

By birth year 2013, prevalence among whites in the lowest income counties was at least double that of whites in the highest income counties. Generally speaking, the higher the county income, the lower the rate of autism among white children.

Notably, Santa Clara County had a surge in the rate of autism spectrum disorders between 1993 and 2000, with rates doubling among whites and Asians in just seven years. As Nevison and Parker recall in the new paper, that surge gave rise to controversial theories that men with poor social skills but strong math and engineering skills were increasingly able to find partners in the tech-age and were fathering "genetically autistic" children.

"Our data contradict that argument," said Nevison, noting that today Santa Clara County has one of the lowest prevalence rates of severe autism in the state among whites. Growth in prevalence among Asians has also flattened in the county.

Meanwhile, the study found, incidence among blacks has increased rapidly across California, marking the highest rates among any ethnic or racial group at 1.8%. That finding is in line with previous research finding that autism prevalence is rising rapidly nationwide among African Americans.

Some health experts have attributed such increases among minorities to better screening and diagnosis, but the authors believe environmental factors also play a role.

Just which factors may be at play is unclear, but Parker notes that many of the same things that fuel disease-causing inflammation--toxins, unhealthy food and emotional stress--are also associated with autism. And lower-income and minority families tend to have a harder time accessing or affording healthier lifestyle options.

Established risk factors associated with autism include: advanced parental age, challenges to the immune system during pregnancy, genetic mutations, premature birth and being a twin or multiple.

The authors cannot say if their findings would translate to other counties around the country or to milder forms of autism. They also cannot rule out that wealthy families are opting out of state services in favor of private services. More research is underway.

With autism affecting one in 59 children nationwide in 2018--a rate expected to be revised by the Centers for Disease Control later this spring--they hope the paper will encourage parents and policymakers to look beyond genetics and better outreach and diagnosis.

"There is an urgent need to understand what wealthy California parents are doing or have access to that may be lowering their children's risk," they conclude.

The virus that causes COVID-19 remains for several hours to days on surfaces and in aerosols, a new study published in the New England Journal of Medicine found.

The study suggests that people may acquire the coronavirus through the air and after touching contaminated objects. Scientists discovered the virus is detectable for up to three hours in aerosols, up to four hours on copper, up to 24 hours on cardboard and up to two to three days on plastic and stainless steel.

"This virus is quite transmissible through relatively casual contact, making this pathogen very hard to contain," said James Lloyd-Smith, a co-author of the study and a UCLA professor of ecology and evolutionary biology. "If you're touching items that someone else has recently handled, be aware they could be contaminated and wash your hands."

The study attempted to mimic the virus being deposited onto everyday surfaces in a household or hospital setting by an infected person through coughing or touching objects, for example. The scientists then investigated how long the virus remained infectious on these surfaces.

The study's authors are from UCLA, the National Institutes of Health's National Institute of Allergy and Infectious Diseases, the Centers for Disease Control and Prevention, and Princeton University. They include Amandine Gamble, a UCLA postdoctoral researcher in Lloyd-Smith's laboratory.

In February, Lloyd-Smith and colleagues reported in the journal eLife that screening travelers for COVID-19 is not very effective. People infected with the virus -- officially named SARS-CoV-2 -- may be spreading the virus without knowing they have it or before symptoms appear. Lloyd-Smith said the biology and epidemiology of the virus make infection extremely difficult to detect in its early stages because the majority of cases show no symptoms for five days or longer after exposure.

"Many people won't have developed symptoms yet," Lloyd-Smith said. "Based on our earlier analysis of flu pandemic data, many people may not choose to disclose if they do know."

The new study supports guidance from public health professionals to slow the spread of COVID-19:

Avoid close contact with people who are sick.

Avoid touching your eyes, nose and mouth.

Stay home when you are sick.

Cover coughs or sneezes with a tissue, and dispose of the tissue in the trash.

Clean and disinfect frequently touched objects and surfaces using a household cleaning spray or wipe.

Oncotarget Volume 11, Issue 11 reported that relapsed APL, particularly in the high-risk subset of patients, remains an important clinical problem.

The probability of relapse is significantly higher in the high-risk subset of patients undergoing treatment for APL; overall approximately 10-20% of APL patients relapse regardless of their risk stratification.

Alternative agents and approaches considering these clinical outcomes are needed to address ATO resistance as well as the relapse rate in high-risk APL.

Dr. Joaquin J. Jimenez from the Dr. Phillip Frost Department of Dermatology and The Department of Biochemistry and Molecular Biology, Miller School of Medicine at The University of Miami, in Miami Florida USA the first author on a paper with Dr. Andrew Schally, winner of The Nobel Prize in Physiology or Medicine and founding Oncotarget Editorial Board member said, "In recent decades, treatment of Acute Promyelocytic Leukemia (APL) has served as a representation of targeted therapy and has reflected the power of translational research."

"In recent decades, treatment of Acute Promyelocytic Leukemia (APL) has served as a representation of targeted therapy and has reflected the power of translational research."

- Dr. Joaquin J. Jimenez, Dr. Phillip Frost Department of Dermatology and The Department of Biochemistry and Molecular Biology, Miller School of Medicine at The University of Miami & Dr. Andrew Schally, winner of The Nobel Prize in Physiology or Medicine and founding Oncotarget Editorial Board member

The introduction of all-trans retinoic acid, as well as of arsenic trioxide in the treatment of APL, was crucial to achieving the current remarkable cure rates.

The initial evidence of the differentiating properties of retinoic acid and its potential to be used therapeutically came in 1980, first using the HL-60 cell line as a model for APL.

Shortly after the introduction of retinoic acid into the therapy regimen of APL, the need arose for addressing retinoic acid resistance.

Figure 1: PML-RARA transcriptional repression. he presence of the fusion protein interferes with the transcription of retinoic acid response elements and disrupts the formation of nuclear bodies. The fusion protein, in the absence of pharmacological doses of retinoic acid, recruits co-repressors to silence gene transcription related to differentiation and prevents apoptosis. NCOR: nuclear receptor corepressor, SMRT: silencing mediator for retinoid and thyroid hormone receptor, RARE: retinoic acid response elements, RARA: retinoic acid receptor alpha, PML: promyelocytic leukemia protein, HDAC: histone deacetylase.

Furthermore, up to 50% of patients undergoing treatment will develop differentiation syndrome; a common side effect of differentiating agents.

An evaluation of four clinical trials involving low-risk APL patients from 2010 2014 showed overall survival rates ranging from a low of 86% after three years to a high of 99% after 4 years.

The Jimenez Research Team concluded in their Oncotarget Review, "the biochemical and mechanistic research on APL over the past few decades has led to a unique understanding of this disease and the treatment options, ushering in an era of targeted therapy. Despite remarkable scientific advances in treating APL, some issues still remain, concerning high-risk patients and patients exhibiting an uncharacteristic translocation. The use of HI-60 and NB4 cell lines will continue to be beneficial for future studies on APL since they have already shown a remarkable translational potential and will help address the therapeutic needs of patients that do not respond to conventional treatment. Further studies, addressing aspects of differentiation, nuclear body formation, and degradation of the fusion protein are essential for advancing the treatment of APL and targeting it towards each affected individual. The investigation for alternative therapies for relapsed APL patients and the introduction of clear, defined treatment guidelines in each risk classified group are of particular concern to be addressed."

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DOI - https://doi.org/10.18632/oncotarget.27513

Full text - http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=27513&path[]=90088

Correspondence to - Joaquin J. Jimenez - j.jimenez@med.miami.edu

DOI

10.18632/oncotarget.27513