Culture

A UNSW Sydney-led medical research team has called for a new vaccine, improved strategies and enhanced monitoring to combat serious complications from childhood pneumonia.

The researchers examined the impact of the 13-valent pneumococcal conjugate vaccine (13vPCV) on childhood pneumonia and empyema - complicated pneumonia - after its introduction to the Australian National Immunisation Program about a decade ago.

The new study, published in Thorax recently, found that while 13vPCV resulted in a 21 per cent decrease in childhood pneumonia hospitalisations, there was a contemporaneous 25 per cent increase in admissions for empyema.

This incidence data for childhood empyema hospitalisations is similar to that reported in other countries.

Approximately 7000 Australians under the age of 18 are hospitalised with pneumonia each year.

Senior author Professor Adam Jaffe, Head of the School of Women's and Children's Health at UNSW Medicine & Health, said the researchers' findings suggested an emergence of non-vaccine serotypes - those which 13vPCV does not cover.

13vPCV was introduced to cover the 13 most common serotypes responsible for invasive pneumococcal infection, extending coverage to six additional serotypes including 1 and 3.

The previous vaccine (7vPCV) covered seven serotypes. A serotype is a distinct variation within a bacteria species.

Prof. Jaffe said: "Although we found a substantial reduction in serotype 1, serotype 3 is now the predominant organism which causes childhood empyema - in 76 per cent of cases - so, efforts must be made to create a vaccine which is more effective against serotype 3.

"In fact, Australia recently changed the vaccination dosage schedule to try and improve the effectiveness of 13vPCV against serotype 3, but we need to continue monitoring patients using molecular techniques to see if this change has had an impact.

"Childhood bacterial pneumonia and empyema are potentially preventable diseases through vaccination. So, if Australia can develop an effective vaccine, we could prevent children from being hospitalised with pneumonia and empyema."

Empyema is infected fluid around the lungs and about one per cent of children hospitalised with pneumonia develop it.

Although children are highly unlikely to die from empyema, they can expect a long stay in hospital for treatment with antibiotics and surgery, or the insertion of a drain. If adults develop empyema, about a third are likely to die.

Continuing enhanced surveillance needed

The researchers conducted a similar study during the period of the superseded 7vPCV. Their new study - which took four years to complete - is part of a broader research project on 13vPCV.

"Our new study had two parts," Prof. Jaffe said. "We analysed national hospitalisations for childhood empyema and childhood pneumonia, then we conducted an enhanced surveillance study on children with empyema."

The first part of the research used publicly available hospitalisations data - about 36,000 admissions - to assess whether the introduction of 13vPCV changed how many children were admitted to hospital with pneumonia and empyema.

The enhanced surveillance study involved the collection of blood and lung fluid samples from 401 children with empyema from February 2015 to September 2018.

The children were receiving treatment in 11 major children's hospitals across Australia.

Most children were boys (208 or 52 per cent) and the median age was four years old.
The researchers then conducted molecular testing on these samples and compared the results to their previous study undertaken during the period of 7vPCV.

The multidisciplinary team included Dr Nusrat Homaira, of the Discipline of Paediatrics at UNSW Medicine & Health, and paediatric research nurse Roxanne Strachan of Sydney Children's Hospital.

Prof. Jaffe said: "Our new research is the first of its kind in Australia - so, we now have the best data available for complicated childhood pneumonia to help guide future vaccination introductions and improve vaccine strategies.

"We are currently working on our larger study, of which this was a subset, to examine the effectiveness of 13vPCV on children with bacterial pneumonia. We will need to repeat the study in a few years' time to help with monitoring.

"In the meantime, it would make a big difference if molecular testing of patients' lung fluid was routine in laboratories, because that would ensure we had the best real-time data available which will help rationalise antibiotic choice; also, we would have no need to seek funding to undertake this much-needed research."

A joint research project between organizations in Japan and the US has demonstrated that zooplankton, a major food source for marine predators, can be located by following the concentration gradient of the chemical dimethyl sulfide (DMS) in ocean water and air. Currently, little is known about how marine predators search for and find enough food to maintain their body size. This study is expected to expand research into the chemical triggers of marine organisms while foraging.

Zooplankton, such as krill and copepods are the main energy source for many large marine animals. The big predators must consume a large amount of these tiny creatures to provide enough energy to power their enormous bodies. How they find their food is still not clearly understood.

Krill feed on phytoplankton which produce and retain water-soluble compounds in their bodies to cope with osmotic pressure. This is essential for survival in seawater. One of these compounds is dimethylsulfoniopropionate (DMSP). DMSP contains sulfur elements and is zwitterionic, meaning that it has both a positive and a negative charge like an amino acid. It is broken down by bacteria into DMS, a component of the familiar aromas associated with ocean air or dried seaweed. DMSP stored in phytoplankton is released into seawater when zooplankton graze on the phytoplankton, which is hypothesized to result in higher DMS concentrations in dense zooplankton areas. It is thought that marine predators could use DMS concentration to locate food sources. While attraction to artificially released DMS has been shown in some predatory species, whether natural gradients of DMS are used by predators and serve as a useful foraging cue remains unknown.

To investigate the phenomenon, an international team of researchers from Kumamoto University and Woods Hole Oceanographic Institution developed a new instrument to continuously and automatically analyze seawater and atmospheric concentrations of DMS. Together with a researcher from Stony Brook University, they then used the device to conduct a survey in June 2019 off the coast of Cape Cod, Massachusetts, a summer feeding grounds for many baleen whale species. Researchers took chemical measurements, recorded zooplankton and fish biomass, and whale locations over a series of transects across the ocean surface.

Their work revealed that, as hypothesized, zooplankton grazing on phytoplankton seems to result in higher localized concentrations of DMS compared to surrounding areas. In contrast, no association was found between fish biomass and DMS concentration. Simulations based on their measurements show that if large marine predators, such as whales, are able to detect the DMS concentration gradient, following increasing concentrations of DMS would allow them to reach denser zooplankton feeding areas than if they swam randomly.

"We plan to expand this research project in the future to investigate the relationship between DMS and predation by measuring the concentration of the chemical alongside marine predator movement trajectories," said Professor Kei Toda, who led the chemical measurements. "We also plan to explore other attractant chemicals and study their relationship with the behavior of marine predators like whales, seabirds and penguins. A pilot study tagging humpback whales to examine their movements in relation to DMS was conducted in Antarctica in February 2020, but there are still some issues that need to be addressed to pursue the relationship between chemical substances and predation. We believe that we will have some interesting findings in the near future."

Oncotarget recently published "Targeting an engineered cytokine with interleukin-2 and interleukin-15 activity to the neovasculature of solid tumors" by Mortensen, et al. which reported that there is a growing interest in the antibody-based delivery of cytokines to the tumor environment as a means to boost the anti-cancer activity of tumor-resident T cells and NK cells.

Here, the authors described the expression and characterization of fusion proteins, featuring the L19 antibody and an engineered cytokine with interleukin-2 and interleukin-15 properties.

The cytokine moiety was fused either at the N-terminal or at the C-terminal extremity and both fusion proteins showed a selective tumor accumulation in a quantitative biodistribution experiment.

The N-terminal fusion inhibited tumor growth in immunocompetent mice bearing F9 carcinomas or WEHI-164 sarcomas when used as a single agent.

These results indicate that the antibody-based delivery of engineered cytokines to the tumor neovasculature may mediate a potent anticancer activity.

Dr. Michael R. Mortensen from The Department of Chemistry and Applied Biosciences (D-CHAB) at The Institute for Pharmaceutical Sciences (IPW) in Zurich, Switzerland said, "Cancer immunotherapy relies on the activation of certain leukocytes (most typically, T cells and/or natural killer cells), with the aim to induce a selective biocidal activity against tumor cells."

IL2 muteins may alter the interaction of the cytokine with one or more of the IL2 receptor subunits, thus altering the selectivity towards the intermediate affinity receptor or towards the high-affinity receptor.

Since regulatory T cells predominantly express the high-affinity receptor, the selective activation of the intermediate affinity receptor has attracted considerable research efforts.

In a second approach, an increased selectivity towards the intermediate affinity IL2 receptor was achieved by blocking the interaction with CD25 either through IL2 mutations or by antibody blockade of the IL2 epitope involved in CD25 binding.

The Oncotarget authors described a series of engineered cytokines, which displayed biological features intermediate between those of IL2 and of IL15. IL15 interacts with CD122 and CD132 like IL2 but recognizes a different alpha subunit.

One of the new computationally designed cytokine variants, termed by the authors Neoleukin™-2/15, exhibited an increased affinity towards the receptor components shared by IL2 and IL15, with a complete absence of CD25 binding. Moreover, the newly engineered cytokine was much more stable compared to wild-type IL2.

The Mortensen Research Team concluded in their Oncotarget Research Paper that for certain cytokines the fusion with a tumor-homing antibody allows the creation of novel biopharmaceuticals, which display a preferential uptake in tumor lesions and which perform substantially better than the corresponding nontargeted cytokine in immunocompetent mouse models.

These authors and others have reported that not all cytokine payloads can be efficiently delivered to the tumor by fusion with antibodies.

Cytokine trapping at a low dose has been reported for fusion proteins based on interferon-gamma, but also for IL15 fusions.

Neo™-L19 is not glycosylated and the authors were pleased to see how the L19-based targeted delivery of the engineered IL2 and IL15 mimic led to an improved therapeutic effect for the F9 teratocarcinoma model. The contribution of L19-based targeting to an increased therapeutic index was less striking in the WEHI-164 model.

Collectively, the results presented indicate that a new fusion protein could be created, which displayed an excellent performance in biodistribution studies and which mediated a potent anticancer activity in two immunocompetent mouse models of cancer when used as a single agent.

The results suggest that this product, or similar fusion proteins featuring an N-terminal fusion in the diabody format, may deserve to be investigated in clinical trials.

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DOI - https://doi.org/10.18632/oncotarget.27772

Full text - https://www.oncotarget.com/article/27772/text/

Correspondence to - Michael R. Mortensen - michael.mortensen@pharma.ethz.ch

Keywords - immunotherapy, immunocytokines, EDB of fibronectin, antibody-cytokine fusion proteins, engineered cytokine

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The systemic balance that coordinates the growth of an organism and its progress through the different stages of development occurs across the animal world and is regulated by internal and external signals. Examples of this balance are puberty in humans and metamorphosis in flies. These are transitions characterised by the production of steroid hormones and they mark the turning point that will determine the halting of growth and entry into the adult state. Certain human diseases, such as cancer and inflammatory bowel diseases (IBDs), cause a delay in this transition.

Led by Dr. Marco Milán, scientists at IRB Barcelona have discovered the mechanism by which malignant epithelial tumours affect the production of steroid hormones. Specifically, these researchers have found that the Drosophila Upd3 protein (equivalent to human Interleukin-6) is the main signal produced by tumour cells to influence hormone production and activate signalling pathways that block the transition to adulthood.

"This finding is highly relevant and can help us understand delays in the transition to puberty caused by various medical conditions in adolescents. In the end, what happens is that a damaged organ sends signals to the body to warning that it is not prepared for a process of change," explains Dr. Milán, ICREA researcher and head of the Development and Growth Control laboratory at IRB Barcelona.

A model to study cancer

To carry out this study, Dr. Milán's group has used the genetic potential of the Drosophila fly to induce alterations in the epithelial tissue that simulate a tumour-like growth and mimic the capacity found in human carcinomas to send systemic signals.

"An animal model like the fly Drosophila allows us to study the entire phenomenon using a systemic approach. In this case, we have observed that tumour cells not only produce Upd3 to regulate the production of steroid hormones but also other molecules that act synergistically," says Daniela Romão, PhD student and first author of the article. "Interestingly, some of these signals cause a response from the body that resembles what happens in diabetic patients," says Daniela. These results open up new avenues to better understand why diabetes is a risk component in cancer patients.

Like its chemical relative carbon dioxide (CO2), nitrous oxide (N2O) is an important greenhouse gas and the dominant ozone-depleting substance emitted in the 21st Century. Consequently, strategies for limiting its emissions and its catalytic decomposition with metals are being developed. A recent study indicates that nitrous oxide can bind to metals similarly to carbon dioxide, which helps to design new complexes with even stronger bonding. This could allow the use of nitrous oxide in synthetic chemistry or help to degrade it to substances harmless to the atmosphere. The results were reported in the journal Angewandte Chemie International Edition as a Very Important Paper on February 17th 2021.

A comprehensive analysis of the global N2O budget has shown that its emissions have been increasing for the past four decades, with agricultural activities responsible for the growth. Even though N2O is present in the atmosphere at a concentration 1000 times less than CO2, it is approximately 300 times more potent as a greenhouse gas.

In nature, N2O is converted by enzymes into N2 and H2O. The process can be mimicked in a laboratory setting using catalytic metal complexes. Surprisingly, well-defined complexes of N2O with transition metals are exceedingly rare, even though CO2 has rich and well-documented coordination chemistry. The vastly dissimilar behaviour of these two related small molecules has been attributed to the poor ligand characteristics of N2O in comparison to CO2, but the origins and details of this justification are difficult to track.

"The more information we tried to find on the topic, the closer we headed to circular reasoning," says Dr. Heikki M. Tuononen from the University of Jyväskylä, Finland. "In many cases, some property of N2O was highlighted, but they are almost all characteristic to CO2 as well", he continues.

"This puzzle was one of the reasons why, during Dr. Tuononen's visit to Calgary as a Killam Scholar, our research teams decided to join forces and synthesize analogous metal complexes of N2O and CO2, and study the metal-ligand interaction in detail", tells Dr. Roland Roesler from the University of Calgary, Canada.

A rare metal complex of N2O stable even at room temperature

The results of the two-year investigation showed that, contrary to the general view, the metal binding ability of N2O is equally good or even better than that of CO2.

"It appears that the oxidizing character of N2O is mostly, if not entirely, responsible for the scarcity of metal complexes employing this ligand", says Dr. Tuononen.

"Once we had the right metal partner for N2O, their binding was strong enough that a rare side-on bound complex could be isolated and characterized even at room temperature", continues Dr. Chris Gendy, a former Ph.D. student at University of Calgary who was partially responsible of the synthetic work.

In addition to showing that N2O has better intrinsic ability to bind to metals than heretofore recognized, the work of the two research teams allows the rational design of N2O complexes that are even more stable than the ones characterized thus far. This could, in turn, open new avenues for using N2O in synthetic chemistry.

"N2O is in many ways a great oxidant. It is thermodynamically strong, relatively cheap, and gives N2 as the only side product", explains Dr. Tuononen.

"It would certainly be great to see more widespread use of N2O as an oxidant in metal-catalysed reactions. At the same time, we should not forget the role it plays in the atmosphere", adds Dr. Roesler.

"Nature has found elegant enzymatic pathways to convert N2O into products that are harmless to the atmosphere. We should aim for the same with our manmade emissions using novel catalysts", the research teams conclude.

UNIVERSITY PARK, Pa. -- The COVID-19 pandemic has prompted considerable investigation into how the SARS-CoV-2 Spike protein attaches to a human cell during the infection process, as this knowledge is useful in designing vaccines and therapeutics. Now, a team of scientists has discovered additional locations on the Spike protein that may not only help to explain how certain mutations make emerging variants more infectious but also could be used as additional targets for therapeutic intervention.

"Significant research is underway to examine how the receptor binding domain (RBD) at the tip of the club-shaped SARS-CoV-2 Spike protein attaches to an ACE2 receptor on a human cell, but little is known about the other changes that occur in the Spike protein as a result of this attachment," said Ganesh Anand, associate professor of chemistry, Penn State. "We have uncovered 'hotspots' further down on the Spike protein that are critical for SARS-CoV-2 infection and may be novel targets beyond the RBD for therapeutic intervention."

Anand and his colleagues used a process, called amide hydrogen-deuterium exchange mass spectrometry (HDXMS), to visualize what happens when the SARS-CoV-2 Spike protein binds to an ACE2 receptor. HDXMS uses heavy water or deuterium oxide (D2O), a naturally occurring, non-radioactive isotope of water formed from heavy hydrogen or deuterium, as a probe for mapping proteins. In this case, the team placed SARS-CoV-2 Spike protein and ACE2 receptors in heavy water and obtained footprints of ACE2 on the Spike protein.

"If you put the Spike protein and ACE2 receptor into a solution that's made with D2O, the surfaces and more floppy regions on both proteins will more readily exchange hydrogens for deuterium, compared to their interiors," said Anand. "And footprints of each protein on the binding partner can be readily identified from areas where you see little deuterium and only detect normal hydrogen."

Using this technique, the team determined that binding of the Spike protein and ACE2 receptor is necessary for furin-like proteases -- a family of human enzymes -- that act to snip off the tip, called the S1 subunit, of the Spike protein, which is the next step in the virus's infection of the cell. The findings published on Feb. 8 in the journal eLife.

"The Spike proteins on the surface of the virus swivel to search and latch onto the ACE2 receptor," said Anand. "ACE2 can be likened to a hand holding strands of hair -- the Spike protein clusters. Binding to Spike stabilizes it so it can be cut by furin protease scissors. After furin proteases clip the protein, the part that remains -- the S2 subunit -- is what fuses with the cell's membranes, allowing entry into the cell."

Anand noted that researchers have already learned much about how the Spike protein and ACE2 receptor bind together, but until now no one knew how this binding relayed the message to the furins to cut the protein. He explained that the phenomenon is called allostery, meaning "action at a distance."

"Our findings show ACE2 receptor binding to SARS-CoV-2 Spike protein causes long-range changes and allosterically enhances protease cutting at the distal S1/S2 cleavage site," he said.

Anand said that researchers are currently focusing only on therapeutics that block the Spike protein from binding to the ACE2 receptor.

"In this paper, we're suggesting that's not the only vulnerability that can be targeted," he said. "Maybe the S1/S2 cleavage that is necessary for furin cleavage can serve as a new target for inhibitory therapeutics against the virus. This study also may help in explaining how mutations in emerging variants might alter dynamics and allostery of ACE2 binding, potentially increasing infectiousness of the SARS-CoV-2 virus."

Philadelphia, February 22, 2021--In April 2020, pediatricians began recognizing a puzzling syndrome in children involving hyperinflammation that results in an array of symptoms, including fever, gastrointestinal distress and rash. The syndrome, thought to be a post-infectious complication of SARS-CoV-2 infection, was given the name Multisystem Inflammatory Syndrome Children, or MIS-C. However, diagnosing the condition has posed challenges, as many of its symptoms, including rash, are common in many other pediatric infections.

In a study published in Open Forum Infectious Diseases, researchers at Children's Hospital of Philadelphia (CHOP) describe the array of rashes seen in MIS-C patients at their hospital through late July 2020, providing photos and information that could help doctors diagnose future cases.

"We hope the information provided in this research letter will help general pediatricians and emergency department physicians who may wonder if a patient with a fever requires a more extensive examination," said Audrey Odom John, MD, PhD, Chief of the Division of Pediatric Infectious Diseases at CHOP and senior author of the paper. "Given that some rashes associated with MIS-C are distinctive, we also imagine these images could help many parents who are looking for signs that their child needs prompt evaluation."

The research team analyzed the MIS-C-associated rashes of seven patients seen at CHOP. Although the researchers did not observe a single, defining rash associated with COVID-19, there were several types of rashes that were common in these patients, both in appearance and location.

In terms of rash location, all patients in the study developed a rash on their lower body, and five of the seven patients had a rash on their inner thighs. Rashes on the chest and upper extremities were also common, occurring in four out of seven patients.

More than half of the patients presented with small-to-medium annular plaques, which look like dime-size circles, on their chest and back. More than half of the patients in the study also developed purpura, tiny red spots, often in the center of the dime-like annular plaques.

While some patients did develop a cherry-red rash on the bottoms of their feet and palms of their hands, this sort of rash was seen in less than half of the patients in the study. Rashes on the face were uncommon, and the rashes rarely itched.

"Depending on the age of the child, parents may not regularly look at the child's chest, back or thighs, but this is where the rashes associated with MIS-C tend to appear," said John. "Given that MIS-C is still largely a diagnosis of exclusion, parents and health care providers should look for rashes in these locations if the child has a fever that seems suspicious."

It has long been known that several chemicals used in plastic toys in different parts of the world can be harmful to human health. However, it is difficult for parents to figure out how to avoid plastic toys containing chemicals that may cause possible health risks to their children.

Regulations and labelling schemes are different across regions and countries, and there is no international agreement on which substances should be banned from use in toy materials. For the most part, regulations and international lists of 'chemicals of concern' in toys focus on certain substance groups with known harmful properties, such as phthalates, but do not cover the wider range of chemicals found in plastic toys.

Researchers from DTU and the University of Michigan together with UN Environment have looked into this important issue, analyzed data on chemical functions and amounts found in plastic toys, and quantified related children exposure and potential health risks. They ranked the chemicals according to their health risk and compared these results with existing priority substances lists from around the world. The study has been published with open access in the journal Environment International.

"Out of 419 chemicals found in hard, soft and foam plastic materials used in children toys, we identified 126 substances that can potentially harm children's health either via cancer or non-cancer effects, including 31 plasticizers, 18 flame retardants, and 8 fragrances. Being harmful in our study means that for these chemicals, estimated exposure doses exceed regulatory Reference Doses (RfD) or cancer risks exceed regulatory risk thresholds (all substances in the 'red zone' of below figure). These substances should be prioritized for phase-out in toy materials and replaced with safer and more sustainable alternatives," says Peter Fantke, Professor at DTU Management and the study's principle investigator.

Nicolò Aurisano, the study's first author and Peter's PhD student, explains that toy manufacturers usually do not provide any information on the chemical content in the toys, and toy composition databases are missing. Hence, the researchers had to collect and scrutinize information on chemicals contents in toy materials based on chemical test data for specific toys reported in 25 different peer-reviewed studies.

Nicolò further states: "We have combined the reported chemical content in toy materials with material characteristics and toy use patterns, such as how long a child typically plays with a toy, whether it puts it into the mouth, and how many toys are found in a household per child. We used this information to estimate exposure using high-throughput mass-balance models, and compared exposure doses with doses below which there is no unacceptable risk to the children."

The researchers find that children in Western countries have on average about 18 kilograms of plastic toys, which underlines the large amounts of plastic that children are surrounded by on a daily basis.

Chemicals that the researchers identified to be of possible concern for children's health include, for example, widely known phthalates and brominated flame retardants but also the two plasticizers butyrate TXIB and citrate ATBC, which are used as alternatives to some regulated phthalates.

"These alternatives showed indications for high non-cancer risk potentials in exposed children and should be further assessed to avoid 'regrettable substitutions', where one harmful chemical is replaced with a similarly harmful alternative. Overall, soft plastics cause higher exposure to certain harmful chemicals, and inhalation exposure dominates overall children exposure, because children potentially inhale chemicals diffusing out of all toys in the room, while usually only touching one toy at the time", Peter Fantke explains.

A way toward safe use of chemicals in plastic toys
Many lists exist that inform about 'chemicals of concern' across product and material applications. However, what is currently missing is any information about the levels at which the use of chemicals in the different applications would be safe and sustainable. Here, the researchers introduce a new metric to benchmark chemical contents in toy materials based on exposure and risk.

Peter Fantke explains: "Since the same chemicals can be found in different concentrations across toy materials, we have estimated the 'maximum acceptable chemical content (MACC)' for all the substances reported to be found in plastic toys. Such information will enable decision-makers to develop benchmarks for various chemicals in different applications, but will also help toy companies to evaluate the amount of chemicals used for a specific function against such benchmarks."

As a parent, it will continue to be difficult to avoid using plastic toys that can contain harmful chemicals, until regulators include all substances, and address exposure to toys that are produced outside Europe and imported to the European market. A good piece of advice from the researchers is hence to reduce the consumption of plastic materials in general, avoid the use of soft plastic toys, and remember to ventilate well every day your children's rooms.

About 70% of the world's main crops depend on insect pollination. Climate change is already affecting the abundance and distribution of insects, which could cause geographical mismatches between crops and their pollinators. Crops that rely primarily on wild pollinators (e.g., crops that cannot be effectively pollinated by commercial colonies of honey bees) could be particularly in jeopardy. However, limited information on plant-pollinator associations and pollinator distributions complicate the assessment of climate change impacts on specific crops. To study the potential impacts of climate change on pollination of a specific crop in North America, we use the case of open?field tomato crops, which rely on buzz pollinators (species that use vibration to release pollen, such as bumble bees) to increase their production. We aimed to (1) assess potential changes in buzz pollinator distribution and richness, and (2) evaluate the overlap between areas with high densities of tomato crops and high potential decrease in richness. We used baseline (1961-1990) climate and future (2050s and 2080s) climatic projections in ecological niche models fitted with occurrences of wild bees, documented in the literature as pollinators of tomatoes, to estimate the baseline and future potential distribution of suitable climatic conditions of targeted species and to create maps of richness change across North America. We obtained reliable models for 15 species and found important potential decreases in the distribution of some pollinators (e.g., Lasioglossum pectorale and Augochlorella aurata). We observed geographical discrepancies in the projected change in species richness across North America, detecting important declines in the eastern United States (up to 11 species decrease for 2050s). After overlapping the maps of species richness change with a tomato crop map for the United States, we found spatial correspondence between richness declines and areas with high concentration of tomato crops. Disparities in the effects of climate change on the potential future distribution of different wild pollinators and geographical variation in richness highlight the importance of crop?specific studies. Our study also emphasizes the challenges of compiling and modeling crop?specific pollinator data and the need to improve our understanding of current distribution of pollinators and their community dynamics under climate change.

The team of Professor Dongling Ma of the Institut national de la recherche scientifique (INRS) developed a new approach for foldable and solid devices.

Solid and flexible electrochromic (EC) devices, such as smart windows, wearable electronics, foldable displays, and smartphones, are of great interest in research. This importance is due to their unique property: the colour or opacity of the material changes when a voltage is applied.

Traditionally, electrochromic devices use indium tin oxide (ITO) electrodes. However, the inflexibility of metal oxide and the leakage issue of liquid electrolyte affect the performance and lifetime of EC devices. ITO is also brittle, which is incompatible with flexible substrates.

Furthermore, there are concerns about the scarcity and cost of indium, a rare element, which raises a question on its long-term sustainability. The fabrication process for the highest quality ITO electrodes is expensive. "With all these limitations, the need for ITO-free optoelectronic devices are considerably high. We were able to achieve such a goal," says Dongling Ma who led the study recently published in the journal Advanced Functional Materials.

A new approach

Indeed, the team has developed a new approach with a cost-effective and easy electrode fabrication that is completely ITO-free. "We reached high stability and flexibility of transparent conductive electrodes (TEC), even in a harsh environment, such as oxidizing solution of H2O2" she adds. They are the first to apply stable nanowires-based TCEs in flexible EC devices, using silver nanowires coated with a compact gold shell.

Now that they have a proof of concept, the researchers want to scale up the synthesis of TEC and make the nanowires fabrication process even more cost-effective, while maintaining high device performance.

COLUMBUS, Ohio - Fool the novel coronavirus once and it can't cause infection of cells, new research suggests.

Scientists have developed protein fragments - called peptides - that fit snugly into a groove on the SARS-CoV-2 Spike protein that it would normally use to access a host cell. These peptides effectively trick the virus into "shaking hands" with a replica rather than with the actual protein on a cell's surface that lets the virus in.

Previous research has determined that the novel coronavirus binds to a receptor protein on a target cell's surface called ACE2. This receptor is located on certain types of human cells in the lung and nasal cavity, providing SARS-CoV-2 many access points to infect the body.

For this work, Ohio State University scientists designed and tested peptides that resemble ACE2 enough to convince the coronavirus to bind to them, an action that blocks the virus's ability to actually get inside the cell.

"Our goal is that any time SARS-CoV-2 comes into contact with the peptides, the virus will be inactivated. This is because the virus Spike protein is already bound to something that it needs to use in order to bind to the cell," said Amit Sharma, co-lead author of the study and assistant professor of veterinary biosciences at Ohio State. "To do this, we have to get to the virus while it's still outside the cell."

The Ohio State team envisions delivering these manufactured peptides in a nasal spray or aerosol surface disinfectant, among other applications, to block circulating SARS-CoV-2 access points with an agent that prevents their entry into target cells.

"With the results we generated with these peptides, we are well-positioned to move into product-development steps," said Ross Larue, co-lead author and research assistant professor of pharmaceutics and pharmacology at Ohio State.

The study is published in the January issue of the journal Bioconjugate Chemistry.

SARS-CoV-2, like all other viruses, requires access to living cells to do its damage - viruses hijack cell functions to make copies of themselves and cause infection. Very rapid virus replication can overwhelm the host system before immune cells can muster an effective defense.

One reason this coronavirus is so infectious is because it binds very tightly to the ACE2 receptor, which is abundant on cells in humans and some other species. The Spike protein on the SARS-CoV-2 surface that has become its most recognizable characteristic is also fundamental to its success in attaching to ACE2.

Recent advances in crystallizing proteins and microscopy have made it possible to create computer images of specific protein structures alone or in combination - such as when they bind to each other.

Sharma and his colleagues closely examined images of the SARS-CoV-2 Spike protein and ACE2, zooming in on precisely how their interactions occur and what connections are required for the two proteins to lock into place. They took notice of a spiral ribbon-like tail on ACE2 as the focal point of the attachment, which became the starting point for designing peptides.

"Most of the peptides we designed are based on the ribbon contacting the Spike," said Sharma, who also holds a faculty appointment in microbial infection and immunity. "We focused on creating the shortest possible peptides with the minimum essential contacts."

The team tested several peptides as "competitive inhibitors" that could not only securely bind with SARS-CoV-2 Spike proteins, but also prevent or lower viral replication in cell cultures. Two peptides, one with the minimum contact points and another larger one, were effective at reducing SARS-CoV-2 infection in cell studies compared to controls.

Sharma described these findings as the beginning of a product-development process that will be continued by the team of virologists and pharmaceutical chemists collaborating on this work.

"We are taking a multipronged approach," Sharma said. "With these peptides, we have identified the minimal contacts needed to inactivate the virus. Going forward we plan to focus on developing aspects of this technology for therapeutic purposes.

"The goal is to neutralize the virus effectively and potently, and now, because of the emergence of variants, we're interested in assessing our technology against the emerging mutations."

Intravenous injection of bone marrow derived stem cells (MSCs) in patients with spinal cord injuries led to significant improvement in motor functions, researchers from Yale University and Japan report Feb. 18 in the Journal of Clinical Neurology and Neurosurgery.

For more than half of the patients, substantial improvements in key functions -- such as ability to walk, or to use their hands -- were observed within weeks of stem cell injection, the researchers report. No substantial side effects were reported.

The patients had sustained, non-penetrating spinal cord injuries, in many cases from falls or minor trauma, several weeks prior to implantation of the stem cells. Their symptoms involved loss of motor function and coordination, sensory loss, as well as bowel and bladder dysfunction. The stem cells were prepared from the patients' own bone marrow, via a culture protocol that took a few weeks in a specialized cell processing center. The cells were injected intravenously in this series, with each patient serving as their own control. Results were not blinded and there were no placebo controls.

Yale scientists Jeffery D. Kocsis, professor of neurology and neuroscience, and Stephen G. Waxman, professor of neurology, neuroscience and pharmacology, were senior authors of the study, which was carried out with investigators at Sapporo Medical University in Japan. Key investigators of the Sapporo team, Osamu Honmou and Masanori Sasaki, both hold adjunct professor positions in neurology at Yale.

Kocsis and Waxman stress that additional studies will be needed to confirm the results of this preliminary, unblinded trial. They also stress that this could take years. Despite the challenges, they remain optimistic.

"Similar results with stem cells in patients with stroke increases our confidence that this approach may be clinically useful," noted Kocsis. "This clinical study is the culmination of extensive preclinical laboratory work using MSCs between Yale and Sapporo colleagues over many years."

"The idea that we may be able to restore function after injury to the brain and spinal cord using the patient's own stem cells has intrigued us for years," Waxman said. "Now we have a hint, in humans, that it may be possible."

ITHACA, N.Y. - In the same way that Lego pieces can be arranged in new ways to build a variety of structures, genetic elements can be mixed and matched to create new genes, according to new research.

A long-proposed mechanism for creating genes, called exon shuffling, works by shuffling functional blocks of DNA sequences into new genes that express proteins.

A study, "Recurrent Evolution of Vertebrate Transcription Factors by Transposase Capture," published Feb. 19 in Science, investigates how genetic elements called transposons, or "jumping genes," are added into the mix during evolution to assemble new genes through exon shuffling.

Transposons, first discovered in the 1940s by Cornell alum and Nobel Prize-winner Barbara McClintock '23, M.A. '25, Ph.D. '27, are abundant components of genomes - they make up half of human DNA - and have the ability to hop and replicate selfishly in the genome. Some transposons contain their own genes that code for enzymes called transposase proteins, which cut and paste genetic material from one chromosomal location to another.

The study, which focused on tetrapods (four-limbed vertebrates), is important because it shows that transposons represent an important force in the creation of new genes during evolution. The work also explains how genes critical for human development were born.

"We think it's very likely this mechanism may extend beyond vertebrates and could be more of a fundamental mechanism that occurs in non-vertebrates as well," said first author Rachel Cosby, Ph.D. '19, a postdoctoral researcher at the National Institutes of Health. Cosby is a former graduate student in the lab of senior author Cedric Feschotte, professor in the Department of Molecular Biology and Genetics in the College of Agriculture and Life Sciences.

"You are putting the bricks in in a different way and you construct a whole new thing," Feschotte said. "We are looking at the question of how genes are born. The originality is that we are looking at the role of transposons in creating proteins with novel function in evolution."

In the study, the researchers first mined existing databases for genomes of tetrapods, because genomes for more than 500 species have been fully sequenced. Cosby and colleagues searched for combinations of DNA sequences known to be characteristic of transposons fused to host sequences to find good candidates for study. They then chose genes that evolved relatively recently - within tens of millions of years ago - so they could trace the history of the gene's development through the vertebrate tree of life.

Though genes fused with these transposases are relatively rare, the researchers found them all over the vertebrate tree of life. The researchers identified more than 100 distinct genes fused with transposases born in the past 350 million years along different species lineages, including genes in birds, reptiles, frogs, bats and koalas, and a total of 44 genes born this way in the human genome.

Cosby and colleagues selected four recently evolved genes and performed a wide range of experiments in cell culture to understand their functions. They found the proteins derived from these genes are able to bind to specific DNA sequences and turn off gene expression. Such genes are known as transcription factors and act as master regulator genes for development and basic physiology. One such gene, PAX6, is well studied, plays a key role as a master regulator in the formation of eyes in all animals and is highly conserved throughout evolution.

"If you put a PAX6 gene from a mouse into a Drosophila [fruit fly], it works," Feschotte said. Though others have proposed before that PAX6 is derived from a transposase fusion, the researchers in this study further validated the hypothesis.

Cosby and colleagues isolated one of these recently evolved genes in bats, called KRABINER, and then used CRISPR gene-editing technology to delete it from the bat genome and see what genes were affected, before adding it back in. The experiment revealed that when KRABINER was removed, hundreds of genes were dysregulated, and when they restored it, normal functioning returned. The protein expressed by the KRABINER gene bound to other related transposons in the bat genome, Cosby said.

"The experiment revealed that it controls a large network of other genes wired through the past dispersion of related transposons throughout the bat genome - creating not just a gene but what is known as a gene regulatory network," Feschotte said.

ITHACA, N.Y. - A new study identifies a mechanism that makes bacteria tolerant to penicillin and related antibiotics, findings that could lead to new therapies that boost the effectiveness of these treatments.

Antibiotic tolerance is the ability of bacteria to survive exposure to antibiotics, in contrast to antibiotic resistance, when bacteria actually grow in the presence of antibiotics. Tolerant bacteria can lead to infections that persist after treatment and may develop into resistance over time.

The study in mice, "A Multifaceted Cellular Damage Repair and Prevention Pathway Promotes High Level Tolerance to Beta-lactam Antibiotics," published Feb. 3 in the journal EMBO Reports, reveals how tolerance occurs, thanks to a system that mitigates iron toxicity in bacteria that have been exposed to penicillin.

"We're hoping we can design a drug or develop antibiotic adjuvants that would then basically kill off these tolerant cells," said senior author Tobias Dörr, assistant professor of microbiology in the Weill Institute for Cell and Molecular Biology in the College of Agriculture and Life Sciences.

Co-authors included Ilana Brito, the Mong Family Sesquicentennial Faculty Scholar and assistant professor in the Meinig School of Biomedical Engineering in the College of Engineering, and Lars Westblade, associate professor of pathology and laboratory medicine at Weill Cornell Medicine.

Some bacteria, including the model bacterium used in the study, Vibrio cholerae, which causes cholera in humans, are remarkably tolerant to penicillin and related antibiotics, known as beta lactam antibiotics. It has been known for a long time that beta-lactam antibiotics break down bacterial cell walls, but how bacteria survive loss of their cell walls was poorly understood.

In the study, the researchers developed a V. cholerae mutant that lacked a two-component damage repair response system that controls a gene network encoding diverse functions. Without the system, known as VxrAB, when the cell wall is damaged by antibiotics, the transfer of electrons across the cell membrane goes awry, leading to electrons ending up on the wrong molecules. This misdirection causes hydrogen peroxide to accumulate in the cell, which changes the oxidation state of cellular iron and disrupts signals for the cell to tell how much iron it has.

In the presence of hydrogen peroxide, the mutant bacteria cannot sense how much iron has been acquired, and it behaves as if it is iron-starved and seeks to acquire more iron. Left unchecked, these circumstances cause iron toxicity, which will kill the cell, according to the experiments the researchers conducted. In further tests with mutant V. cholerae bacteria, both in test tubes and in mice, the researchers showed that reducing the influx of iron increased the bacteria's tolerance to beta lactams.

Fortunately for normal V. cholerae, exposure to antibiotics and the breakdown of the cell's walls activate the VxrAB system, which works to repair cell walls and downregulates iron uptake systems, and thereby creates antibiotic tolerance. More study is needed to understand what triggers the VxrAB system in the presence of beta-lactam antibiotics.

The research opens the door for developing new drugs that could be combined with antibiotics to exploit oxidative damage and iron influx in tolerant bacteria. In future work, the researchers will search for parallel mechanisms of tolerance in other bacterial pathogens.

COLUMBIA, Mo. -- When teachers encounter disruptive or noncompliant students in the classroom, they typically respond by focusing on the negative behavior. However, new research from the University of Missouri found that offering students more positive encouragement not only reduces disruptive classroom behavior, but can improve students' academic and social outcomes.

"As educators, we often focus on communicating what we don't want our students to be doing in class, but we have found that just doesn't work," said Keith Herman, a professor in the University of Missouri College of Education. "Instead, we need to be setting clear expectations of what behaviors we do want to be seeing."

To help teachers provide a nurturing and structured environment for students in the classroom, Herman implemented CHAMPS, a classroom behavior management training intervention, into a St. Louis County school district's middle school classroom over the course of five years. The intervention resulted in decreased disruptive classroom behavior and student concentration problems. The intervention also improved both completed class work and standardized test scores, as well as increased the amount of time students remained on task with classroom assignments.

"The intervention is based off principles and practices research has shown to be helpful in creating successful classroom management, such as communicating clear expectations to students, giving more positive encouragement compared to negative reprimands and moving around the classroom to monitor student behavior," Herman said.

One of the coaches that helped implement the intervention was Julia Burke, former assistant superintendent for student services in the Hazelwood School District. She conducted classroom observations to help coach and mentor the teachers receiving the training. She observed that the intervention helped increase student engagement and boosted the teachers' confidence in their ability to manage disruptive behaviors.

"I have always been committed to removing barriers that prevent student success in schools," Burke said. "We can positively impact our children and prepare them for the future if we have strong teachers that are equipped not only with knowledge, but with a toolbox of skills and strategies to provide the best instruction possible in a respectful, engaged classroom climate."

As a former special education instructor, Burke emphasized the need to connect with all types of students, regardless of educational background.

"We have a wide variety of student demographics, and we have to meet the needs of all our students," Burke said. "We can't just meet the needs of the kids who come in prepared and ready to learn. We also need to connect with the students who may not have had the same opportunities growing up or who might be dealing with other struggles outside the classroom."

The classroom behavior management intervention ties into Herman's overall research objective, which is to improve the mental health of children who may be suffering with a variety of issues like stress, anxiety and depression.

"I want to help kids develop a positive view of themselves and see their own value as contributing members of society," Herman said. "Too often we just think of mental health as sending a kid who may have concerns to a counselor. But even before we get to that point -- how can we set these kids up for success so that fewer of them develop these problems that require further intervention in the first place."