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Research news tip sheet: Story ideas from Johns Hopkins Medicine

STUDY SUGGESTS VR GAMES MAY HELP CHILDREN BETTER COPE WITH PAINFUL MEDICAL PROCEDURES

Media Contact: Michael E. Newman, mnewma25@jhmi.edu

Dealing with a painful medical procedure is difficult for anyone, but often more so if the patient is a child. For example, a venipuncture -- the penetrating of a vein for a procedure such as drawing blood or inserting an intravenous tube -- may make a young patient anxious or uneasy. Many hospitals, including Johns Hopkins Children's Center (JHCC), have a dedicated child life services team to help children cope with these procedures, while others depend on more traditional methods of diversions such as toys or books. Now, a recent study by Johns Hopkins Medicine researchers suggests that gameplaying using virtual reality (VR) headsets -- if the games are appropriate and carefully chosen for pediatric clinical situations -- may be an engaging and practical addition to the list of distraction therapy options.

Led by Therese Canares, M.D., director of pediatric emergency medicine digital health Innovation at JHCC and assistant professor of pediatrics at the Johns Hopkins University School of Medicine, the research team conducted a small-scale study to evaluate the therapeutic impact on pediatric patients of playing virtual reality games during a venipuncture procedure. Their findings were published online June 14, 2021, in the journal Hospital Pediatrics.

From June 2019 and March 2020, the researchers randomly assigned 55 patients -- ranging in age from 7 to 22 and receiving venipuncture procedures in the JHCC pediatric emergency department -- to three groups. The first group of 15 patients, played VR games in the presence of a child life specialist. The second group, consisting of 20 patients, did not use VR but was supported by a child life specialist. The remaining 20 patients in the third group did not have a child life specialist support or VR games.

Overall, the study found patients who played VR games during their venipuncture procedure benefitted from reduced pain and anxiety, and that the combination of VR and support from a child life specialist worked best. However, the researchers also found that children who used VR during venipunctures had significantly longer procedure times -- by 4-6 minutes on average -- than those who had only child life specialist support or no distraction therapy at all.

The most likely cause, say the researchers, was the nurse or technician having to repeatedly pause a game to correct a technical problem, provide guidance on game navigation or controller operation, or change a game.

"We feel that the extra time isn't a huge detriment, because it is hard to put a value on reducing a child's trauma during a venipuncture procedure," says Canares. "Even if VR adds five minutes, making a child more comfortable is well worth it."

Canares says the most surprising findings are how many adolescents needed help navigating the virtual reality games, and that a significant amount of "trial-and-error" was needed to determine which games were the best for distraction therapy.

"We found that games involving little movement of the head and arms, played without high anxiety scenarios -- such as military battles or zombie attacks -- and not requiring a controller or extensive menu options, worked best because they added the least amount of extra time to a venipuncture procedure," she says. "Hospitals considering the use of VR as distraction therapy -- especially those on a tight budget -- may want to look first at such 'clinically friendly games' before making the investment."

Canares says that although VR coupled with child life specialist support appears to be an excellent distraction therapy, "it isn't meant to replace child life professionals since games cannot take the place of human touch and compassion." However, she says, VR may be a solid option for community hospitals that don't have a child life services team.

Canares is available for interviews.

This news story was researched and written by Johns Hopkins Medicine communications intern Rachel Hackam.

JOHNS HOPKINS MEDICINE EXPERTS CREATE CLINICIAN RESOURCE FOR CHRONIC PAIN TREATMENTS

Media Contact: Rachel Butch, rbutch1@jhmi.edu

Researchers at Johns Hopkins Medicine have authored a series of articles in the journal The Lancet as part of an effort by the publication to help clinicians navigate the complexities of treating chronic pain.

The three articles by the Johns Hopkins Medicine experts -- part of a larger series in The Lancet published May 29, 2021 -- describes new research and treatment advances that include an emerging news category of chronic pain; the psychological, biological and social factors that contribute to a person's pain experience; and the potential risks and benefits of so-called neuromodulation therapies, which deliver electrical or chemical stimuli to the body's neurological areas to suppress pain.

"Rather than a strictly physical, clinical categorization of pain, the appropriate definition of pain should be based on a patient's psychological, biological and social factors," says series lead author Steven E. Cohen, M.D., chief of pain medicine and professor of anesthesiology and critical care medicine, neurology, physical medicine and rehabilitation, and psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine.

In the series, the Johns Hopkins Medicine experts advocate for personalized treatment plans that use a combination of therapies to manage a patient's chronic pain. Accounting for a person's age, medical history, and genetic and psychological factors when deciding on a treatment increases the likelihood of successful pain management and good health outcomes.

Additionally, the authors recommend that the invasiveness of procedures should be considered along with the patient factors.

Developing methods to identify patients that are likely to respond to a therapy, say the experts, is particularly important in invasive procedures, such as some neuromodulation therapies, the use of which has been on the rise in the last two decades. They emphasize that more high-quality research is needed to determine ideal patients for these therapies. However, this research often is difficult to perform due to practical limitations.

"We show that an interdisciplinary definition and approach -- one that incorporates a patient's individual experience and risk factors -- is crucial to properly categorize and effective treat pain with neuromodulation," says series co-author Eellan Sivanesan, M.D., director of neuromodulation and assistant professor of anesthesiology and critical care medicine at the Johns Hopkins University School of Medicine.

Sivanesan and Cohen are available for interviews.

Watch a video covering the articles here:

The Lancet Series on Chronic Pain: Video Abstract

HOW SHOULD PREDICTED LIFE EXPECTANCY GUIDE CANCER SCREENING DECISIONS FOR OLDER ADULTS?

Media Contact: Waun'Shae Blount, wblount1@jhmi.edu

Clinicians say timely and accurate screenings can facilitate early detection of and reduced death rates from cancer. However, for those age 65 and older, current guidelines for deciding if cancer screenings should be done are sometimes based on whether the person is likely to live 10 years -- the time usually needed to accrue benefits from the procedure. In a recent study, Johns Hopkins Medicine researchers examined a large group of older Americans to better understand the relationship between cancer screening and a person's likeliness of dying within a decade.

A report on the study findings was published June 1, 2021, in JAMA Network Open.

"Understanding the relationship between cancer screening and death can help inform how we should use a patient's chance of dying within 10 years to make cancer screening decisions," says study lead author Nancy Schoenborn, M.D., associate professor of medicine at the Johns Hopkins University School of Medicine.

For their study, Schoenborn and her colleagues used data from the Health and Retirement Study, an ongoing representative survey of more than 37,000 people over age 50 in 23,000 households in the United States. Included were 5,342 participants -- 3,257 women and 2,085 men -- age 65 and older who were eligible for a breast or prostate cancer screening. The average age for the women was 78 and for the men, 76.

The researchers used statistical methods to investigate the association between a person having a breast or prostate cancer screening, and whether that person either lived or died from any cause during the following 10 years. The researchers accounted for each person's age, health status, ability to carry out daily functions, and other factors currently used to predict life expectancy.

The researchers found that women receiving a mammogram and men who had a prostate screening both had lower risks of death, even after adjusting for age and the other health factors.

This, the researchers say, is likely due to differences between the types of people who complete cancer screening and those who do not, as opposed to being caused by the cancer screenings themselves. The researchers say this suggests that for people who get cancer screenings as recommended, the algorithms used to predict life expectancies can underestimate the outcomes.

"Based on our findings, we feel that cancer screenings should be individualized and not only based on predicted life expectancy," says Schoenborn. "The decision whether or not to screen should be made by the doctor and the patient working together in each individual situation."

Schoenborn says it is hoped that her team's future research in this precision medicine area will identify what is different about people who get cancer screenings from those who do not, and which differences may be associated with better survival.

"We can use that knowledge to improve how we predict life expectancy and, in turn, how those predictions are used in clinical decision making," she says.

Schoenborn is available for interviews.

Credit: 
Johns Hopkins Medicine

Unique christmas-tree-shaped palladium nanostructures for ascorbic acid oxidation

image: Figure 1: Unique Christmas-tree-shaped palladium nanostructures.

Image: 
JAIST

Ishikawa, Japan - Nanostructured metal surface has novel physical and chemical properties, which have sparked scientific interest for heterogeneous catalysis, biosensors, and electrocatalysis. The fabrication process can influence the shapes and sizes of metal nanostructures. Among various fabrication processes, the electrochemical deposition technique is widely used for clean metal nanostructures. Applying the technique, a team of researchers led by Dr. Yuki Nagao, Associate Professor at Japan Advanced Institute of Science and Technology (JAIST) and Md. Mahmudul Hasan, a PhD student at JAIST, succeeded to construct Pd-based catalysts having unique morphology.

In this study, the team has successfully synthesized Christmas-tree-shaped palladium nanostructures on the GCE surface for the first time by one-pot electrodeposition without using any additives (Figure 1). The controlled electrodeposition method creates many sharp edges of Christmas-tree-shaped palladium nanostructures (Pd/GCE) that enhanced the catalytic activity for AA electro-oxidation.

The unique nanostructures on the GCE exhibit excellent electrocatalytic oxidation of AA than the unmodified GCE in 1 M KOH solution (Figure 2). Multiple sharp edges observed in the nanostructures improved the electrocatalytic performance. This brings one step closer to the construction of alkaline AA-based Direct liquid fuel cell (DLFC.) "Improving the electrocatalytic performance of AA electro-oxidation could provide cleaner energy by constructing alkaline AA-based DLFC." explains Hasan.

To address the energy crises and climate change, clean energy sources need to be explored urgently. DLFC could be a potential candidate for the new energy source with its simple cell design. AA, known as vitamin C, is a feasible fuel source for DLFC. AA is environment-friendly and generates two electrons and two protons along with green dehydroascorbic acid during its electro-oxidation. AA is more affordable and, thus, can be used as a clean energy source widely.

This research could mark a firm step forward in achieving sustainable development goals.

Credit: 
Japan Advanced Institute of Science and Technology

Children's beat gestures predict the subsequent development of their oral skills

A study published on 21 May in Child Development shows that the early production of beat gestures with the hands (i.e., gestures normally associated with emphasis that do not represent the semantic content of speech) by infants between 14 and 58 months of age in natural interactions with their carers predicts that in their later development, nearing the age of five, these children obtain better results insofar as their oral narrative skills.

The authors analysed the predictive value of beat gestures, compared with flip gestures of the hands and iconic gestures

However, the study did not find these same effects when children produced other types of gestures, such as iconic gestures (gestures that visually represent the semantic content of discourse, such as moving the hands in the shape of a ball to express "ball") and hand flip gestures (gestures made by twisting the wrist, for example to express "don't know" with uncertainty while raising the shoulders).

The study is the result of collaboration between the UPF Prosodic Studies (GrEP) group and the Department of Translation and Language Sciences and the Goldin-Meadow Lab at the University of Chicago (Illinois, USA), research carried out by Ingrid Vilà-Giménez (UPF and UdG) and Pilar Prieto (ICREA, UPF) with the researchers Natalie Dowling and Susan Goldin-Meadow (University of Chicago, USA) and Ö. Ece Demir-Lira (University of Iowa).

A longitudinal database on language development was used

Through a longitudinal methodology, the study analysed data at different points in the children's development. The data belong to a large longitudinal database on language development belonging to the University of Chicago. The researchers analysed speech and the production of three types of gesture of 45 children aged between 14 and 58 months while interacting with their carers at mealtime or during games sessions or other activities such as reading books. Specifically, they examined the predictive value of beat gestures, compared with flip gestures of the hands and iconic gestures. At 5 years of age, the same children participated in a narrative task in which they had to tell a story from a cartoon without sound.

The study has shown that beat gestures produced by children aged 14 to 58 months play a very important role in narrative development at later stages

The results showed that beat gestures produced by children aged 14 to 58 months play a very important role in narrative development at later stages because they can predict improvements in children's oral skills some years later. Although the results of the study do not provide empirical evidence as to whether such beat gesture simply reflects that the child has the ability to structure speech or multimodally mark elements of speech associated with prominence of speech (i.e., to mark emphasis), the researchers argue that this kind of gesture plays a very important pragmatic role in children's early speech.

It should be noted that these pragmatic functions of beat gestures are related with the function of structuring narrative discourse. Therefore, as the study results would suggest, the authors highlight that it can be stated that the pragmatic functions of beat gestures in children's early narrative speeches may be highly important for the development of their initial speech as well as for developing their oral narrative skills at a later age.

This study contributes significantly to strengthening prior empirical evidence published by some of the same researchers on the benefits of a short intervention to improve the oral skills of children aged 5 and 6 years, in which they are asked to observe or produce beat gestures (Vilà-Giménez et al., 2019; Vilà-Giménez and Prieto, 2020; see also Vilà-Giménez and Prieto, 2021). Similarly, other complementary studies have also shown the positive impact of these gestures on other more complex language skills of children, such as understanding stories (Llanes-Coromina et al., 2018).

Credit: 
Universitat Pompeu Fabra - Barcelona

The molecular characteristics of the dissolved organic matter pool in a eutrophic coastal bay

image: Conceptual diagram of the dissolved organic matter pool.

Image: 
©Science China Press

Coastal bays are momentous transition zones connecting terrestrial and marine ecosystems. Xiangshan Bay is a typically eutrophic and semi-enclosed bay in the East China Sea. A recent study took Xiangshan Bay as an example, revealing the sources and transformation of dissolved organic matter (DOM) in this eutrophic bay.

Dissolved organic matter (DOM), consisting of a vast of complex compounds, has received much attention due to its significant contribution to the largest reduced organic carbon pool in the ocean, which is sizable to the atmosphere CO2 reservoir.

Coastal bays are known as semi-enclosed signature and long water retention time compared with river-dominated estuaries. In fact, they serve as links between rivers and oceans to transport organic carbon. However, they were universally exposed to high fluxes of nutrients from intensive anthropogenic activities such as sewage discharge and aquaculture industry with the rapid urbanization due to their locations near human settlements. Large nutrient fluxes could lead to coastal eutrophication with harmful algal blooms, which have been observed in a couple of coastal bays, such as Jiaozhou Bay and Xiangshan Bay in China. The high primary productivity, as well as subsequent biogeochemical processes, induced from eutrophication might impact the chemical composition and flux of organic matter transported to the open ocean. As such, coastal bays are supposed to be not only "conduits" where organic matter is transported to open oceans, but also "reactors" where organic matter is processed or transformed.

Describing Xiangshan Bay as "one of the most valuable testing places around the world", researchers from Zhejiang University pointed out the immense value of investigating the compositions of DOM pool in Xiangshan Bay: "It is recognized as a typically long, narrow coastal bay, with long water retention time, which would facilitate the biogeochemical processing of organic matter. Furthermore, it has been the largest aquaculture base in Zhejiang province, causing severe eutrophication with harmful algae blooms."

Biogeochemical researches conducted in other coastal bays, since the emergence of the spectroscopic, have revealed "Physical mixing, photo-oxidation, and tidal effects might affect the behaviors of DOM in such systems" according to Yu Pang and Chen Zhao, graduate students at the School of Earth Sciences, Zhejiang University, in the Chinese city of Hangzhou.

In an article coauthored with Yuping Zhou, Yanzhen Zhang, Wei Huang, Yuntao Wang, scholars at Zhejiang University and Second Institute of Oceanography, Ministry of Natural Resources, combined multiple approaches, these researchers stated: "Terrestrial, marine, and anthropogenic inputs collectively contribute to the whole DOM pool. The conclusion was confirmed by both optical and molecular approaches. One protein-like component and two humic-like components were identified by spectroscopic techniques and molecular groups associated with different sources were also determined."

These authors revealed in the study, which was published in the journal of Science China: Earth Sciences, that terrestrial signals gradually decrease from the upper to lower bay with increasing salinity due to seawater dilution effect while protein-like fluorescent component may derive from multiple sources because a similar linear relationship is lacking.

Research aimed at solving this issue faced an array of obstacles: The isolation, extraction, and chemical characterization of DOM are prerequisites to understand its cycling in aquatic systems. However, except for a few sugars, amino acids, and lignin phenols, compositions of most DOM are still largely uncertain because of its complexity, heterogeneity, and low concentration in natural environments. Understanding the chemical composition and sources is a prerequisite to determine the DOM cycling in aquatic environments.

"Traditional techniques could only be reflective of the bulk chemistry of the DOM while our knowledge of the molecular-level composition of DOM is still lacking. To date, limited studies have combined optical and molecular approaches to systematically investigate the DOM composition in coastal bays."

To solve this problem, these researchers applied Fourier Transform Ion Cyclotron Resonance Mass Spectrometry (FT-ICRMS), a state-of-the-art tool offering a possibility to precisely obtain molecular-level information of DOM. In the recent years, scientists have established a variety of indices to depict DOM based on the data obtained from FT-ICRMS.

The researchers found that the physical mixing resulting from seawater dilution effect still occurs in Xiangshan Bay during summer, which has been widely found in river-dominated estuaries around the world. Also, the detection of anthropogenic-associated S-containing compounds confirms the inputs from human activities. Anthropogenic inputs may be a significant source of DOM in coastal bays when comparing Xiangshan Bay with other Chinese bays.

The data obtained from FT-ICRMS suggested that photo-induced degradation play a critical role in altering DOM compositions, considering molecular compositions imprint pronounced labile signatures compared with other aquatic environments.

"To the best of our knowledge", wrote the seven researchers, "this work will also shed lights on future studies focusing on the estuarine carbon cycling."

Credit: 
Science China Press

Russian forests are crucial to global climate mitigation

Russia is the world's largest forest country. Being home to more than a fifth of forests globally, the country's forests and forestry have enormous potential to contribute to making a global impact in terms of climate mitigation. A new study by IIASA researchers, Russian experts, and other international colleagues have produced new estimates of biomass contained in Russian forests, confirming a substantial increase over the last few decades.

Since the dissolution of the USSR, Russia has been reporting almost no changes in its forests, while data obtained from remote sensing products indicate that Russian forests have in fact experienced an increase in vegetation productivity, tree cover, and above-ground biomass in the last few decades. This has led to inconsistencies in available data and a general decline in the reliability of information on Russian forests since 1988, which can be attributed to an information gap that appeared when Russia moved from the Soviet Forest Inventory and Planning system to its current National Forest Inventory (NFI) for the collection of forest information at the national scale. The first cycle of the Russian NFI was finalized in 2020. The authors of a new IIASA-led study published in Nature Scientific Reports have used this data in combination with research forest plots on the ground and remote sensing data, in an advanced analysis to produce a new estimate of the biomass of Russian forests, confirming these forests' climate change impact and their importance for climate change mitigation.

"We set out to determine the live biomass stock and sequestration rate of Russian forests. The joint efforts of our diverse team consisting of representatives from the Russian state forestry agency, forest survey, academic research institutes, and other educational institutions, made it possible for us to produce an important, reproducible scientific result. Even more importantly, our work contributed to building mutual trust, a policy of data sharing, and hopefully, the potential for fruitful future collaboration," says study lead author Dmitry Schepaschenko, a researcher with the IIASA Agriculture, Forestry, and Ecosystem Services Research Group in the Biodiversity and Natural Resources Program.

The team were the first to be given access to a portion of primary NFI plot data with precise location information, which, as in many other countries, is normally restricted for sharing and use, under the condition that the initial data processing was physically undertaken on site at the authorized division ("Roslesinforg") of the Federal Forestry. The researchers used this data in combination with remote sensing data to estimate the growing stock of Russian forests and to assess the relative changes in post-Soviet Russia. They calibrated models relating to two global remote sensing biomass data products and additional remote sensing data layers with around 10,000 ground plots from the NFI and the Forest Observation System to reduce uncertainties and produce an unbiased estimation at jurisdictional level. By combining these two sources of information, the team were able to utilize the advantages of both sources in terms of highly accurate ground measurements and the spatially comprehensive coverage of remote sensing products and methods.

"Quite often, practitioners simply use linear regression by default without checking the underlying statistical assumptions or worrying about the difference between the ability of a model to explain the observed data and the ability to predict the future or unobserved data. Because the aim of this study was to estimate the unobserved biomass, we have used modern computationally intensive methods to focus on the goodness-of-prediction of a range of plausible models," explains study coauthor and long-time IIASA collaborator, Elena Moltchanova from the School of Mathematics and Statistics at the University of Canterbury, New Zealand.

The findings indicate that Russian forests have in fact accumulated a large amount of biomass - in the range of 40% more than the value recorded in the country's State Forest Register and reported to the statistics of the Food and Agriculture Organization of the United Nations (FAO). Using the last Soviet Union report as a reference, the results show that the growing stock accumulation rate in Russian forests between 1988 and 2014 is of the same amplitude as the net forest stock losses in tropical countries. The study's estimate of carbon sequestration in live biomass of managed forests between 1988 and 2014 is 47% higher than reported in the National Greenhouse Gases Inventory.

The authors note that while Russian forests and forestry have great potential in terms of global climate mitigation as well as numerous potential co-benefits relating to the green economy and sustainable development, it is important to highlight that as the climate becomes more severe, as in recent years, resulting forest disturbances might nullify these gains. Close collaboration of science and policy would therefore be critical to elaborate and implement adaptive forest management.

"We are talking here about the largest country in the world hosting the largest share of the largest land biome globally - the circumboreal belt of forest - which is highly climate relevant. Imagine what just a few percent up or down with regard to the amount of forest biomass available and its consequent carbon sequestration potential can make globally," says Agriculture, Forestry, and Ecosystem Services Research Group Leader and study coauthor, Florian Kraxner. "This study once again highlights the important work done by researchers of the International Boreal Forest Research Association (IBFRA), which we would like to acknowledge particularly," he concludes.

Credit: 
International Institute for Applied Systems Analysis

Immunotherapy may be effective for subset of prostate cancer

Boston - In recent years, cancer immunotherapy has been effective in treating patients with immunogenic, or so-called "hot" tumors with increased levels of inflammation and the presence of immune cells in and around the tumors. Prostate cancer, however, is considered a "cold" tumor, with few immune cells recognizing and infiltrating prostate malignancies. Accordingly, prostate cancer has been found to respond poorly to the class of immunotherapies known as immune checkpoint inhibitors.

In previous work, a team led by medical oncologists at Beth Israel Deaconess Medical Center (BIDMC) identified a subset of prostate cancers that exhibited characteristics more typical of hot cancers. Now, in a paper appearing in the journal Clinical Cancer Research, researchers report that about a quarter of localized prostate cancers may demonstrate these immunologic traits, suggesting that a substantial number of patients with prostate cancer may, in fact, benefit from immunotherapies.

"We were surprised to find all the features of more traditionally immunogenic cancers in these prostate cancers, and that this is not a rare subtype, observed in about a quarter of high risk tumors," said co-corresponding author David J. Einstein, MD, a medical oncologist at BIDMC and an assistant professor of medicine at Harvard Medical School (HMS). "We're interested in whether there is a subset of patients with localized prostate cancer, especially more aggressive ones, whose cancers might be more recognized by the immune system and therefore more treatable with immunotherapies. These would also be some of the patients at greatest risk for relapse and metastatic spread."

Einstein and colleagues, including co-corresponding author Steven Balk, MD, PhD, a physician at BIDMC, focused on two characteristics that make traditionally immunogenic cancers susceptible to immunotherapy: PD-L1 expression and T cell infiltration. PD-L1 is a protein involved in tumor evasion of the immune system. T cells are the sentinels of the immune system, patrolling the body for potential pathogens or disease.

The researchers identified prostate cancers that had been removed from patients, looking for those that had areas of high PD-L1 expression and then looked for the presence of infiltrating T cells. Next, the team compared the T cell landscape in the more immunogenic prostate cancers to that of more typical prostate cancers, as well as to kidney cancer, one of the most immunogenic tumor types. Finally, the team used DNA sequencing to compare the genetic profiles from these immunologically hot areas to that of the so-called cold areas in the same tumors, as well as to the genomic landscape of immunogenic cancers in general.

The scientists were surprised to learn how many more T cells infiltrated the immunogenic prostate cancers compared with more typical prostate cancers, and to observe all the features of more traditionally immunogenic cancers like kidney cancer in these more immunogenic prostate cancers. They also noted significantly more loss of some key tumor suppressor genes in these immunogenic prostate cancers compared with typical prostate cancer, a difference that could potentially serve as markers to find cancers more treatable with immunotherapies.

"We're hoping to be able to identify patients with immunogenic tumors in advance of treatment, so that we can develop clinical trials for this subset of patients and offer a more personalized strategy than treating all-comers the same way," said Balk, who also a professor of medicine at HMS.

The team is currently conducting a clinical trial to test the effect of a PD-1 inhibitor in prostate cancer patients that will allow them to gather evidence as to whether any of these findings in immunogenic prostate cancer translate into clinical responses in response to PD-1 inhibition.

Credit: 
Beth Israel Deaconess Medical Center

Versatile, fast and reliable SARS-CoV-2 antibody assay

image: Based on the proven MCR microarray analysis platform of the Munich-based GWK Praezisionstechnik GmbH scientists at the Technical University of Munich have developed a new microarray-based rapid test for SARS-CoV-2 antibodies.

Image: 
Sebastian Kissel / TUM

During the continued progression of the Corona pandemic, rapid, inexpensive, and reliable tests will become increasingly important to determine whether people have the associated antibodies - either through infection or vaccination. Researchers at the Technical University of Munich (TUM) have now developed such a rapid antibody test. It provides the result in only eight minutes; the aim is to further reduce the process time to four minutes.

There are currently more than 20 different test procedures available for determining whether a person has antibodies against the new Corona virus. The waiting times for the results range between ten minutes and two and a half hours.

Matrix effects reduce the sensitivity of many of the methods. The more sensitive assays require numerous steps, making them expensive. In addition, most tests can identify only a single kind of antibody, forcing a choice between testing either for immunity through vaccination or through survived infection.

An interdisciplinary research team at the Technical University of Munich, led by the Chair of Analytical Chemistry and Water Chemistry, has now developed a low-cost automated rapid test that is highly sensitive and highly specific in detecting the three most important antibodies. The project, called CoVRapid, was funded by the Bavarian Research Foundation (BFS).

Modification of a proven process

The measurement is carried out on a foil-based sensor chip using the MCR microarray analysis platform of the Munich-based supplier GWK Präzisionstechnik GmbH. The device displays its measurement results within a few minutes after injecting a blood sample.

Today, the procedure still takes eight minutes, but building on current research, the waiting time will soon be reduced to just four minutes. IgG antibodies against a protein fragment of the SARS-CoV-2 receptor binding domain (RBD), the spike protein (S1 fragment) and the nucleocapsid protein (N) are simultaneously analyzed.

Deployable against new mutants

New mutant proteins can be very easily integrated into the chip. For this project, the research team is collaborating with the Planegg-based company ISAR Bioscience, which produces the respective viral proteins biotechnologically and modifies them for analytical use. The process used to fix the proteins onto the sensor chip has been tried and tested for many years.

"We have already developed reliable rapid tests for antibiotics in milk and for Legionella using this technology platform," says adjunct teaching professor Dr. Michael Seidel, head of the Bioanalytics and Microanalytical Systems group at TUM's Department of Analytical Chemistry and Water Chemistry. "The system has already proven itself in practical use. Our 'CoVRapid' rapid test may thus be deployed in clinics, medical offices and research laboratories in the very near future."

The new test will answer questions about corona immunity

However, the new rapid test can do even more: the microarray technology, which allows to accommodate up to 100 measurement points on a single chip, is so sensitive that it can even determine the concentration of antibodies in a sample.

"The present research begs questions like: How well do vaccinations work? How long does immunity last? When will vaccinations need to be readministered? With its high sensitivity, our CoVRapid will help us find the answers to these questions," says lead author Julia Klüpfel.

In the long term, the team is also planning on including other pathogens in the panel so the assay can be used, for example, to evaluate the effectiveness of an influenza vaccination.

Credit: 
Technical University of Munich (TUM)

Study highlights natural history and conservation importance of Chinese mountain cat

image: Chinese mountain cat.

Image: 
Song Dazhao, CFCA

FORT LAUDERDALE/DAVIE, Fla. - We know that the domestic cat has distant relatives that roam the earth - lions, tigers, cheetahs and mountain lions. Less familiar are the 38 distinct species in the Family Felidae, many with strange names like pampas cat, kodkod and rusty spotted cat. The new field of genomics - the unravelling of DNA genomes of separate species - is resolving old conundrums and revealing new secrets across the history of evolutionarily related species among cats, dogs, bears and ourselves.

In the largest-ever study undertaken of Chinese cats, genetic detectives highlight the evolutionary uniqueness and premier conservation importance of the elusive Chinese mountain cat (Felis silvestris bieti), found only in the Tibetan plateau of China. Also called Chinese desert cat or Steppe cat, the Chinese mountain cat has a distinctive appearance of sand colored fur, with faint dark stripes a thick tail and light blue pupils.

The research is published in Science Advances.

This new study compared three different felines living in China: the Chinese mountain cat, Felis silvestris bieti, the Asiatic wildcat Felis silvestris ornata, and feral domestic cats Felis silvestris catus. The Asiatic wildcat has distinguishing spotted coat pattern across a wide range extending from the Caspian Sea in the East through western India and southern Mongolia to parts of western China. Approximately 600 million domestic cats are found across the world.

The study was led by the Laboratory of Genomic Diversity at Peking University in Beijing and supported by an international team including lead genetic researchers at Nova Southeastern University, USA and in Malaysia. The genomic data resolves a taxonomic classification uncertainty, reveals the timing of evolutionary divergence and pinpoints the prospects for survival of an important endangered species.

Using 270 individual samples, the molecular genetic study finds that the Chinese mountain cat is a unique subspecies of the wide-ranging Wildcat, Felis silvestris. The wildcat species is found throughout Europe, Africa, and much of Western Asia. The Felis silvestris bieti subspecies, however, is found only in China, being adapted to the prey and alpine climate of the Tibetan plateau.

Applying the molecular clock hypotheses, the date of evolutionary split between F. s. bieti and F. s. ornata was a estimated at ~1.5 million years ago while the genetic distance from both to the closest Felis species relative, the black footed cat, Felis nigripes is twice that at 3.0 MY ago. These different times support the classification of F. s. ornata and F. s. bieti as subspecies of Felis silvestris. A closely related subspecies from Central Asia and north Africa, Felis silvestris lybica , is the clear predecessor of the world's domestic cats, including those throughout China. The cat domestication process happened 10-12,000 years ago in the Near East at around the same time and locale, when humankind ancestors morphed from peripatetic hunter-gatherers to sedentary farmers in the Fertile Crescent region.

The Chinese mountain cat faces several major threats, one from modern agricultural practices that divert precious habitat. A second, more existential threat, is from interbreeding with domestic cats brought by the growing human population in the cat's limited habitat. And finally, climate change, that may be expanding the range of neighboring wildcats into the mountain cat's core homeland.

"This study will help conservation scientists to identify threats and decide the best ways to conserve this special cat in its native range," said Stephen J. O'Brien, Ph.D., a world-renowned geneticist and research scientist at NSU's Halmos College of Arts and Sciences.

The study solidifies the taxonomic status of the mountain cat, Felis silvestris lybica, through an analysis of the cat's genome, placing the cat in an evolutionary context relative to other species and subspecies of cats. These arcane taxonomic distinctions are important for conservation because scientists have to be sure they are all talking about the same animal when discussing strategies, and no less important, because legal protections have to be specific to the group in question. Without an agreed-upon taxonomy, legal protections and conservation come to a stop.

Another important result of this study is the finding that domestic cats in China are derived from the same common stock and origin as domestic cats throughout the world, and that there was not an independent origin of domesticity in China. Previous studies have hinted at close associations between early Chinese farming communities and local wild animals, including Asian mountain cats, and that some of these animals may have begun the crossing from the wild to living with people in settled communities.

What the current study shows is that this did not happen with domestic cats; now the focus of research can move to determining - why? Why were some species domesticated in some place but not in others? Why did these processes happen when they did, and what were the conditions obtaining that allowed, maybe even promoted, the integration of wild animals into human societies? Answering these related questions will help us understand the history of early China, indeed helps us understand the history of the ancient anthropocentric world, in more detail.

Credit: 
Nova Southeastern University

New findings unveil a missing piece of human prehistory

image: Geographical and temporal distribution of newly sampled individuals

Image: 
IVPP

A joint research team led by Prof. FU Qiaomei from the Institute of Vertebrate Paleontology and Paleoanthropology (IVPP) of the Chinese Academy of Sciences sequenced the ancient genomes of 31 individuals from southern East Asia, thus unveiling a missing piece of human prehistory.

The study was published in Cell on June 24.

Prof. FU's team used DNA capture techniques to retrieve ancient DNA from Guangxi and Fujian, two provincial-level regions in southern China. They sequenced genome-wide DNA from 31 individuals dating back 11,747 to 194 years ago. Of these, two date back to more than 10,000 years ago, making them the oldest genomes sampled from southern East Asia and Southeast Asia to date.

Previous ancient DNA studies showed that ~8,000-4,000-year-old Southeast Asian Hòabìnhian hunter-gatherers possessed deeply divergent Asian ancestry, whereas the first Southeast Asian farmers beginning ~4,000 years ago show a mixture of ancestry associated with Hòabìnhian hunter-gatherers and present-day southern Chinese populations. In coastal southern China, ~9,000-4,000-year-old individuals from Fujian province show ancestry not as deeply divergent as the Hòabìnhian.

In Guangxi, FU and her team's sampling showed that the ancestry present was unlike that sampled previously in Fujian and Southeast Asia. Instead, they found a unique East Asian ancestral population (represented by the 11,000-year-old Longlin individual from Guangxi). Their findings highlight that 11,000 years ago, at least three genetically distinct ancestries composed the human landscape in southern East Asia and Southeast Asia: Fujian ancestry, Hòabìnhian ancestry, and Guangxi ancestry.

In addition to sharing Longlin ancestry, the Dushan and Baojianshan individuals in Guangxi also show strong evidence for admixture in southern China ~9,000 to 6,000 years ago. Dushan and Baojianshan were a mixture of local Guangxi ancestry, southern ancestry previously sampled in Fujian, and Deep Asian ancestry related to Southeast Asian Hòabìnhian hunter-gatherers.

Previously, it was shown that southern Chinese populations expanded to Southeast Asia, mixing with and eventually replacing Hòabìnhians in Southeast Asia. FU's team showed that the dynamics were more complex, since populations carrying Hòabìnhian ancestry either co-existed with populations carrying Guangxi ancestry in southern China or gene flow upwards from Southeast Asia to southern China also occurred as early as ~8,000-6,000 years ago.

The study fills a research gap in the region connecting East and Southeast Asia, revealing a new genetic ancestry different from that found in coastal areas of southern China and in Southeast Asia.

Furthermore, it shows the impact of migration and admixture of populations at the crossroads of East and Southeast Asia in the last 11,000 years, revealing a long history of intermingling between these two regions.

"While we now have a better understanding of the population history in the last 11,000 years at the crossroads of East and Southeast Asia, future sampling in regions near the Yangtze River and southwest China are needed for a comprehensive understanding of the genetic history of humans in southern China," said Prof. FU.

Genetic samples from ancient humans in these regions will likely further clarify the remarkably diverse genetic prehistory of humans in southeastern Asia, and inform the genetic shifts that occurred between 6,000 and 1,500 years ago and contributed to the genetic composition observed today in southern China.

Credit: 
Chinese Academy of Sciences Headquarters

Adolescent marijuana, alcohol use held steady during COVID-19 pandemic

Adolescent marijuana use and binge drinking did not significantly change during the COVID-19 pandemic, despite record decreases in the substances' perceived availability, according to a survey of 12th graders in the United States. The study's findings, which appeared online on June 24, 2021, in Drug and Alcohol Dependence, challenge the idea that reducing adolescent use of drugs can be achieved solely by limiting their supply. The work was led by researchers at the University of Michigan, Ann Arbor, and funded by the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health.

In contrast to consistent rates of marijuana and alcohol use, nicotine vaping in high school seniors declined during the pandemic, along with declines in perceived availability of vaping devices at this time. The legal purchase age is 21 for nicotine products and alcohol in all states, and for cannabis in states that have legalized nonmedical cannabis use.

"Last year brought dramatic changes to adolescents' lives, as many teens remained home with parents and other family members full time," said NIDA Director Nora D. Volkow, M.D. "It is striking that despite this monumental shift and teens' perceived decreases in availability of marijuana and alcohol, usage rates held steady for these substances. This indicates that teens were able to obtain them despite barriers caused by the pandemic and despite not being of age to legally purchase them."

The data for the study came from the annual Monitoring the Future (MTF) survey of substance use behaviors and related attitudes among adolescents in the United States. In a typical year, MTF surveys thousands of middle and high school students at more than a hundred schools across the country in the spring. MTF has been watching substance use trends for 46 years.

To assess the impact of the pandemic, the investigators issued a survey between mid-July and mid-August 2020, which 12th graders could complete outside of school. This summer survey followed up on investigators' standard MTF spring survey, which gathered responses between mid-February and mid-March 2020 before stopping prematurely due to school closures caused by COVID-19. Of the 3,770 12th graders who responded in the spring, 582 submitted a follow-up survey in the summer. All data and statistical analyses used in the study were weighted to be nationally representative.

Analysis of the responses revealed that students perceived a sharp decrease in availability of marijuana and alcohol in the months after the onset of the pandemic. For marijuana, the fraction of students who reported "fairly" or "very" easy access dropped by 17 percentage points, from 76% in the spring before the pandemic to 59% during the pandemic, and for alcohol it dropped by 24 percentage points, from 86% to 62%. These were the largest year-to-year decreases in perceived availability of marijuana and alcohol ever recorded since the survey began in 1975. Prior to 2020, the largest recorded decreases were only two percentage points for marijuana, and one percentage point for alcohol. Between the spring and summer of 2020, there was also a sharp decrease in respondents who said they could "fairly" or "very" easily obtain a vaping device, going from 73% before the pandemic to 63% during the pandemic.

Despite the reported declines in marijuana and alcohol availability, the levels of use of these substances did not change significantly. Before the pandemic, 23% of students said they had used marijuana in the past 30 days, compared to 20% during the pandemic. For alcohol, 17% reported binge drinking in the past two weeks pre-pandemic, compared to 13% during the pandemic. However, there was a moderate and significant decrease in nicotine vaping - before the pandemic, 24% of respondents said they had vaped nicotine in the past 30 days, compared to 17% during the pandemic.

The study authors cite the wide availability of alcohol and marijuana, even during the pandemic, as a factor in the continued use of these substances. While pandemic-related restrictions limited social interactions, and even with record-breaking decreases in perceived availability among participants, most students said they still had access to marijuana and alcohol. In addition, the authors suggest that when the substances became less available, the students may have intensified their efforts to obtain them.

While a dip in the perceived supply of vaping devices may have contributed to the decline in nicotine vaping that occurred during the pandemic, there may have been other factors as well. The federal minimum age for tobacco product purchases, including vaping devices and liquids, rose from 18 to 21 years and went into effect in early 2020. News reports on vaping-induced lung injuries may have also had a chilling effect on usage.

"These findings suggest that reducing adolescent substance use through attempts to restrict supply alone would be a difficult undertaking," said Richard A. Miech, Ph.D., lead author of the paper and team lead of the Monitoring the Future study at the University of Michigan. "The best strategy is likely to be one that combines approaches to limit the supply of these substances with efforts to decrease demand, through educational and public health campaigns."

Monitoring the Future continues to survey respondents as they progress through adulthood, providing the researchers with the opportunity to explore the impact of the pandemic and the social changes it brought about on future substance use trends.

Credit: 
NIH/National Institute on Drug Abuse

New microscopy method reveals single childhood cancer cells in unprecedented detail

image: Human fetal kidney imaged using multispectral Large-scale Single-cell Resolution 3D (mLSR-3D) and SegmenTation Analysis by ParaLlelization of 3D Datasets (STAPL-3D), developed by scientists at the Princess Máxima Center for pediatric oncology

Image: 
Ravian van Ineveld and Michiel Kleinneijenhuis, in the Rios lab at the Princess Máxima Center for pediatric oncology

A new technique to look at tumors under the microscope has revealed the cellular make-up of Wilm's tumors, a childhood kidney cancer, in unprecedented detail. This new approach could help understand how tumors develop and grow, and fuel research into new treatments for children's cancers.

Scientists at the Princess Máxima Center for pediatric oncology developed a new imaging technique and computational pipeline to study millions of cells in 3D tissue, revealing hundreds of features from each individual cell. Their research was published this month in Nature Biotechnology.

By offering a look at individual cells within an intact organ, the new technique helps scientists analyze the molecular profile of the cells, as well as their shape and position within an organ or tumor.

Other techniques to study individual cells require tissue to be cut up into small pieces, sacrificing important information about how tissue is organized.

Spatial information about cells is key in understanding how large tissues are organized, and the relationships between different cell types - to reveal differences between healthy tissue and childhood tumors. Linking such information to clinical outcome data could in future improve diagnosis.

New group of Wilm's tumor cells

The team led by co-first authors Ravian van Ineveld and Michiel Kleinnijenhuis applied their microscopy technique to compare Wilm's tumor tissue with healthy developing kidney tissue. They found a group of cells with higher levels of a gene called SIX2, linked to keeping cells in an immature state where they keep growing.

Other tumor cells with high SIX2 levels are linked with a poor outcome after chemotherapy treatment. Further research is needed to explore the clinical relevance of this new group of SIX2 Wilm's tumor cells - but this finding shows that the new imaging technique can lead to insights that could in future improve treatment.

More data in less time

Cells can be told apart from each other under the microscope by tagging specific molecules with fluorescent particles in different colors. The new imaging pipeline developed by the Rios group at the Princess Máxima Center (Dream3D Lab) doubles the number of colors that can be tagged at the same time from four to eight - meaning the researchers could distinguish cell types much more precisely.

The team also developed a brand new way of processing the enormous amounts of information generated by the microscopy technique. They cut up the information about the whole organ into smaller 3D blocks. These blocks were sent to many computers at once to analyze the data in parallel. This reduced the time to process the large volume of data from multiple days to about two hours - a requirement for bringing the new technique into practice. In addition, the team used deep learning approaches to identify each individual cell in the large dataset with high accuracy.

Link with clinical outcome

The scientists tested their new technique with different molecular tags to look at biopsy material from a childhood central nervous system tumor, as well as breast tumor tissue, confirming that it can be applied in multiple tissue types.

Next, the researchers aim to use their imaging pipeline to analyze more patient samples. Linking their 3D tissue analysis to clinical outcome could lead to better diagnostic tools for children's cancer.

Dr. Anne Rios, principal investigator at the Princess Máxima Center for pediatric oncology and senior author of the study, said:

'Our new single-cell technology marks a key step forward in unravelling the complexities of the way organs and tumors are organized. With our new microscopy technique, you get the best of both worlds: in-depth characterization of individual cells, in the full context of large-scale 3D tissue analysis.

'I look forward to seeing our new technique used to better understand how tumors develop and grow, and perhaps even discover leads for better treatment and diagnosis.'

Credit: 
Princess Máxima Center for Pediatric Oncology

New technique for studying cancer mutations - approaches for future therapies

FRANKFURT. Cancer and many other diseases are based on genetic defects. The body can often compensate for the defect of one gene; it is only the combination of several genetic errors that leads to the clinical picture. The 3Cs multiplex technique based on CRISPR-Cas technology developed at Goethe University Frankfurt now offers a way to simulate millions of such combinations of genetic defects and study their effects in cell culture. These "gene scissors" make it possible to introduce, remove and switch off genes in a targeted manner. For this purpose, small snippets of genetic material ("single guide RNA") are used as "addresses" that guide the gene scissors to specific sections of the DNA, where the gene scissors then become active.

The scientists from the Institute of Biochemistry II at Goethe University have expanded the 3Cs technique that they developed and patented three years ago. 3Cs stands for covalently-closed circular-synthesised, because the RNA elements used for CRISPR-Cas are generated with the help of a circular synthesis and are thus distributed more uniformly. With a whole library of such RNA rings, any gene in a cell can be specifically addressed in order to change it or switch it off.

The new 3Cs multiplex technique now even allows the simultaneous manipulation of two genes in one cell. Dr. Manuel Kaulich explains: "We can produce 'address' RNA libraries for all conceivable two-gene combinations. This allows up to several million combinations to be tested simultaneously in one experiment."

Until now, the cost and effort of such experiments was very high; the research group's new technique reduces it, including costs, by a factor of ten. This is because the team can produce the address libraries very uniformly and in high quality thanks to the new 3Cs multiplex technique. "Due to the mediocre quality of the CRISPR-Cas libraries previously available, very large experiments always had to be carried out to statistically compensate for any errors that arose," says Kaulich.

Using the example of various genes involved in degradation processes, the research group demonstrated the potential of the new 3Cs multiplex technique: they examined almost 13,000 two-way combinations of genes that are responsible for recycling processes (autophagy) in the cell. With their help, the cell breaks down and recycles "worn-out" cell components. Disturbances in autophagy can trigger cell proliferation.

"Using the 3Cs multiplex technique, we were able to identify, for example, two genes involved in autophagy whose switching off leads to an uncontrolled growth of cells," explains Kaulich. "These are precisely the autophagy mutations that occur in every fifth patient with squamous cell carcinoma of the lung. In this way, we can search very efficiently in cell culture experiments for genes that play an important role in cancer, and also in diseases of the nervous and immune systems, and that are suitable as possible targets for therapies."

Credit: 
Goethe University Frankfurt

Research shows Alaska infrastructure at risk of earlier failure

image: This illustration from the article shows the location of temperature sensors at the Dalton Highway research site.

Image: 
Drone photo by Soraya Kaiser; illustration distributed under Creative Commons 4.0 International

Roads, bridges, pipelines and other types of infrastructure in Alaska and elsewhere in the Arctic will deteriorate faster than expected due to a failure by planners to account for the structures' impact on adjacent permafrost, according to research by a University of Alaska Fairbanks Geophysical Institute permafrost expert and others.

The researchers say planners must account for the sideward repercussions of their projects in addition to the usual projection of the direct top-down effects.

The finding was presented in a May 31 paper in The Cryosphere, a publication of the European Geosciences Union.

UAF Geophysical Institute geophysics professor Vladimir Romanovsky is among the 13 authors of the paper. Principal researcher for the project is Thomas Schneider von Deimling of the Alfred Wegener Institute Helmholtz Centre for Polar and Marine Research in Potsdam, Germany.

The research focused on a portion of the Dalton Highway on Alaska's North Slope about 10 miles south of the Prudhoe Bay oil fields. Sensors monitored the temperature at seven locations, three to the west of the highway and four on the east.

The researchers found that top-down thawing isn't confined to the area beneath the road surface. They found instead that thawing spreads outward, leading to destabilization of the embankment and subgrade and that it is caused by the formation of taliks -- areas of ground that have thawed and remains unfrozen year-round -- under a roadway's toe, the prepared zone at the base of the embankment and abutting the natural terrain.

The result, the authors write, is an accelerating thaw rate and earlier than anticipated road failure -- and a warning that other types of Arctic infrastructure such as pipelines, fuel storage tanks and airports will fail sooner than projected.

The fieldwork and subsequent computer modeling of a gravel road built on continuous permafrost found that a slow and gradual thaw will lead to an accelerated "and likely irreversible permafrost degradation" and that "road failure is inevitable once a critical level of ground warming has been reached" absent extensive ground-cooling measures, the authors write.

The authors write that their findings show a shortcoming in other infrastructure risk assessment methods, which fail to adequately capture changes in permafrost and don't analyze the interaction between the infrastructure and the adjacent ground.

Those shortcomings make current estimates of infrastructure failure dates inaccurate.

"You cannot make blank decisions when you're dealing with permafrost," said Romanovsky, a longtime permafrost researcher. "You always have to be more specific about the region, about the amount of ice in permafrost and about the infrastructure itself. And when you take all of this into consideration -- and climate change -- you can make a much more educated decision."

The research will prove more beneficial in the planning of new roads than in the maintenance of existing roads, for which little can be done to change their initial construction. The research will, however, give transportation managers a better idea of when existing roads are likely to fail, Romanovsky said.

"The Department of Transportation can, using these results, understand how much they have to plan to spend to keep roads in good condition," he said. "They have a good idea in the near term, but they don't know what to expect, say, 10 years from now when the permafrost will be even more vulnerable than it is right now and how this thawing process will continue."

The authors conclude by saying it is "crucial to consider climate change effects when planning and constructing infrastructure on permafrost as a transition from a stable to a highly unstable state can well occur within the infrastructure's service lifetime (about 30 years)."

They add that their focus on the Dalton Highway illustrates that "such a transition can even occur in the coming decade for infrastructure built on continuous permafrost that displays cold and relatively stable conditions today."

Credit: 
University of Alaska Fairbanks

UCLA study reveals how immune cells can be trained to fight infections

image: In this image from a microscopy video, scientists track the activity of NFκB inside the cell as it responds to a stimulus.

Image: 
Brooks Taylor/UCLA

The body's immune cells naturally fight off viral and bacterial microbes and other invaders, but they can also be reprogrammed or "trained" to respond even more aggressively and potently to such threats, report UCLA scientists who have discovered the fundamental rule underlying this process in a particular class of cells.

In a study published June 18 in the journal Science, the researchers identified a key molecular mechanism within macrophages, infection-fighting cells of the innate immune system, that determines whether -- and how well -- the cells can be trained. Their findings could help pave the way for future targeted strategies to enhance the function of the immune system.

"Like a soldier or an athlete, innate immune cells can be trained by past experiences to become better at fighting infections," said lead author Quen Cheng, an assistant clinical professor of infectious diseases at UCLA's David Geffen School of Medicine. However, he noted, the researchers had previously observed that some experiences seemed to be better than others for immune training. "This surprising finding motivated us to better understand the rules that govern this process."

Whether immune training occurs depends on how the DNA of the cell is wrapped. In human cells, for instance, more than 6 feet of DNA must fit into the cell's nucleus, which is so small that it is not visible to the naked eye. To achieve this feat, the DNA is tightly wrapped into chromosomes.

Only selected regions of the DNA are exposed and accessible, and only the genes in those accessible regions are able to respond and fight infection, said senior author Alexander Hoffmann, UCLA's Thomas M. Asher Professor of Microbiology and director of the Institute for Quantitative and Computational Biosciences.

However, by introducing a stimulus to a macrophage -- for example, a substance derived from a microbe or pathogen, as in the case of a vaccine -- previously compacted DNA regions can be unwrapped. This unwrapping exposes new genes that will enable the cell to respond more aggressively, in essence training it to fight the next infection, Hoffmann said.

The new research reveals that the precise dynamics of a key immune signaling molecule in macrophages, called NFκB, determine whether or not this unwrapping and exposing of genes occurs. Moreover, the researchers report, the dynamic activity of NFκB itself is determined by the precise type of extracellular stimulus introduced to the macrophage.

"Importantly, our study shows that innate immune cells can be trained to become more aggressive only by some stimuli and not others," Cheng said. "This specificity is critical to human health because proper training is important for effectively fighting infection, but improper training may result in too much inflammation and autoimmunity, which can cause significant damage."

NFκB helps immune cells to identify incoming threats. When receptors on immune cells detect threatening external stimuli, they activate the NFκB molecule inside the cell. The dynamics of NFκB -- how it behaves over time -- form a language similar to Morse code by which it communicates the identity of the external threat to the DNA and tells it which genes to ready for battle.

The specific "word" of this code that NFκB uses to tell DNA to unwrap is dependent on whether NFκB is oscillatory or steady over eight or more hours after encountering a stimulus. Oscillating NFκB builds up in a macrophage's nucleus, then moves into the cytoplasm, then returns to the nucleus in cycles, much like a swinging pendulum. Non-oscillating, or steady, NFκB moves into the nucleus and stays there for several hours.

Using advanced microscopy, the researchers followed the activity of NFκB in macrophages derived from the bone marrow of healthy mice, tracking how the molecule's dynamics changed in response to several different stimuli. They discovered that NFκB was successful at training macrophages -- unwrapping DNA and exposing new infection-fighting genes -- only when the stimulus induced non-oscillating NFκB activity.

"For a long time, we've known intuitively that whether NFκB oscillates or not of must be important but had simply not been able to figure out how," Cheng said. "These results are a real breakthrough for understanding the language of immune cells, and knowing the language will help us 'hack' the system to improve immune function."

The researchers were also able to simulate this training process with a mathematical model, and the predictive understanding they gleaned may allow for future precision-targeted engineering of trained immunity, Hoffmann said. Mathematical modeling of immune regulatory systems is a key goal of his laboratory, in order to use predictive simulations for precision medicine.

Cheng earned his Ph.D. under Hoffmann's guidance through UCLA's Specialty Training and Advanced Research, or STAR, program for physician scientists.

Hoffmann and Cheng expect this research to inspire a wide range of additional studies, including investigations into human diseases caused by immune cells that are improperly trained, strategies to optimize immune training to fight infection and ways to complement existing vaccine approaches.

"This study shows how collaborations between researchers in the UCLA College and David Geffen School of Medicine can produce innovative and impactful science that benefits human health," Hoffmann said.

Credit: 
University of California - Los Angeles

Making citizen science inclusive will require more than rebranding

Scientists need to focus on tangible efforts to boost equity, diversity and inclusion in citizen science, researchers from North Carolina State University argued in a new perspective.

Published in the journal Science, the perspective is a response to a debate about rebranding "citizen science," the movement to use crowdsourced data collection, analysis or design in research. Researchers said that while the motivation for rebranding is in response to a real concern, there will be a cost to it, and efforts to make projects more inclusive should go deeper than that. Their recommendations speak to a broader discussion about how to ensure science is responsive to the needs of a diverse audience.

"At its heart, citizen science is a system of knowledge production that doesn't block entry based on credentials," said first author Caren Cooper, associate professor of forestry and environmental resources at NC State. "Those of us in citizen science have been saying 'science is for everyone, you don't need a degree or special training.' But, the sad irony is that it hasn't been for everyone. The overwhelming majority of participants resemble their academic counterparts, who are often white, affluent and have advanced degrees. We want to take the good intentions that are driving rebranding, and commit to long-term, sustained efforts to reimagine an inclusive citizen science."

The term "citizen science" was coined in the 1990s, researchers said, to describe science led by institutions that use volunteers to collect data. It has evolved to encompass many types of projects with public involvement in design, leadership or data collection and analysis. As a "citizen science campus," there are projects underway at NC State in which undergraduates, faculty, staff and the general public can help collect data. Examples include projects that rely on volunteers to help figure out the microbial content of sourdough bread or detect the presence of lead pipes in homes around the state.

In an effort to resolve concerns that the term is exclusionary to people who do not have citizenship status in a given nation, some organizations have moved toward using the term "community science," among other names. But researchers said community science is a distinct and existing research movement led and designed by communities, rather than institutions, to address environmental or social justice problems.

"It's a huge dis to community science to flippantly change the name like it isn't already being utilized, and could be considered disrespectful to people who are doing this work and have been for many years," said co-author Zakiya Leggett, assistant professor of forestry and environmental resources. "If you have a citizen science project, but you advertise it as 'community science,' it does a disservice to both practices."

In addition, there is a cost to losing the term "citizen science," they said, since the term has gained momentum globally. In the United States, the term is used in a federal law authorizing the government to include volunteers in scientific research irrespective of their credentials and citizenship status.

"There is a lot of work that has gone toward incorporating 'citizen science' as a part of policy, as well as being accepted into mainstream science," said co-author Madhusudan Katti, associate professor of forestry and environmental resources at NC State. "The name has been caught up in politicization of citizenship and nationalist politics, and rebranding is a little bit reactive. The concern is genuine, but the fix is not deep enough. Renaming something doesn't make it different from what it's been all along."

The researchers argued for strategic planning to advance accessibility, justice, equity, diversity and inclusion in citizen science.

"One approach that could work for citizen science is 'centering in the margins.' That can include centering research agendas based on the areas that are underserved by science," Cooper said.

Other tactics could involve ensuring there are diverse perspectives in project leadership, or overcoming economic barriers to participation. They also said there is a need for funding to support science that addresses interests, concerns and needs of people who have historically or are currently underserved by science.

They said rebranding, if needed, should only happen if it is called for as part of a broader strategic plan. They also said rebranding efforts should refrain from co-opting existing terminology, avoid exporting issues in the United States to the rest of the world, and identify terminology to help further clarify distinctions for different types of projects.

"We wanted the fact that diversity and inclusion in citizen science remains elusive to serve as a canary in the coal mine to the rest of the scientific community - it takes far more than words and good intentions to be inclusive," Cooper said. "We can learn from community science without co-opting it. We need to figure this out without expecting quick-fix solutions, because those can do more harm than good."

Credit: 
North Carolina State University