Culture

Kyoto, Japan -- In mere milliseconds trillions of chemical reactions ignite signals that travel across the billions of neurons in our brain. As we go through our daily lives and absorb new knowledge these neurons begin to modify themselves and change their signaling properties.

However, the mechanisms of how signals are integrated into the neurons to establish such flexibility, also known as plasticity, remains elusive.

Publishing in the Journal of Neuroscience, Gen Ohtsuki of Kyoto University's Hakubi Center reports that Purkinje cells -- the primary output neurons in the cerebellum -- have the ability to modulate and filter incoming signals. The findings bring new insight into the learning mechanisms of the cerebellum and the brain.

The cerebellum is a structure located at the base of the brain, and is known to play a vital role in motor control and cognitive function. Recent findings have even revealed its contributions in mental illnesses. One of the most vivid features of Purkinje cells are their long complex branches called dendrites.

It is thought that the plasticity of these Purkinje-cell dendrites is the basis for cerebellar learning. However, validation of this hypothesis was difficult due to the challenge of measuring signals within a single cell.

Thankfully in a prior study, Ohtsuki was successful in measuring the electrical activity on dendrites of a single Purkinje cell utilizing the patch-clamp method.

"To measure how electrical signals travel through the Purkinje cell membrane, I applied this method using rats and measured the spontaneous synaptic activity between the dendrite and the 'soma' or cell body," explains Ohtsuki.

What he found was that signals coming from dendrites far away from the soma, known as distal dendrites, were not being registered. This suggests the dendrites have a mechanism that limits electroconduction, and that individual branches can choose whether an input passes through or not. In fact, the same signals were registered when they came from proximal dendrites -- the ones closer to the soma.

After further analysis it was found that these distal dendrites modulated their incoming signals through intrinsic plasticity associated with the down-regulation of an ion channel called SK channels.

"One of the reasons for this new finding is because similar experiments used cesium ions in the intracellular fluid, so the phenomena itself could not be observed at all," states Ohtsuki. "The results reveal a new learning mechanism at the dendritic level."

He hopes to further verify these results and determine whether similar findings can be obtained with animals other than rodents, such as fishes and reptiles, or higher mammals.

Ohtsuki concludes, "Studying these fundamental processes should help us understand the reasons for the mechanism of intelligence."

Pseudomonas putida is a bacterium occuring in soil, aquatic environments and plants. Although the virulence of Pseudomonas p. -- the ability of the bacterium to infect its host and inflict a disease -- is considered to be low, infection in severely ill patients can be lethal. P. putida strains (also called isolates) have been found in hospitals, e.g. in urine, blood or wound discharge from patients, and such clinical isolates have been found to display resistance to drugs. Now, Kohei Ogura from Kanazawa University and colleagues have performed gene sequencing for various P. putida isolates originating from both environmental and clinical sites.

Genetic typing of different P. putida strains enables to determine which are the more virulent ones. This is important because P. putida has high biotechnological value. Indeed, P. putida is a perfect microbiological platform for 'metabolic engineering', in which selected biochemical processes within the cells of an organism are stimulated so that the cells produce more of a particular substance. (Examples of metabolic engineering include the industrial production of beer, wine and cheese.)

The researchers applied a technique known as multilocus sequence typing (MLST), a method used in molecular biology for the genetic typing of more than one locus -- a locus refers to the position on a chromosome where a specific gene is located.

The MLST technique is based on obtaining DNA sequences of several so-called 'housekeeping genes': genes that are needed for the maintenance of the basic functioning of a cell. In order to arrive at a valid MLST scheme, typically 100 isolates are required. Ogura and colleagues used 106 isolates, with 16 having an environmental origin and 90 coming from clinical sites. For the MLST scheme, the scientists used 8 housekeeping genes.

The scientists not only obtained the first MLST scheme for P. putida, they also were able to deduce that the studied bacterium isolates are clonal, meaning that they share common ancestry. At the same time, the researchers found that "our MLST scheme reflects the genetic diversity of P. putida group isolated from both clinical and environmental sites".

The Montreal Protocol, an international agreement signed in 1987 to stop chlorofluorocarbons (CFCs) destroying the ozone layer, now appears to be the first international treaty to successfully slow the rate of global warming.

New research published today in Environmental Research Letters has revealed that thanks to the Protocol, today's global temperatures are considerably lower. And by mid-century the Earth will be - on average - at least 1°C cooler than it would have been without the agreement. Mitigation is even greater in regions such as the Arctic, where the avoided warming will be as much as 3°C - 4°C.

"By mass CFCs are thousands of times more potent a greenhouse gas compared to CO2, so the Montreal Protocol not only saved the ozone layer but it also mitigated a substantial fraction of global warming," said lead author of the paper Rishav Goyal.

"Remarkably, the Protocol has had a far greater impact on global warming than the Kyoto Agreement, which was specifically designed to reduce greenhouse gases.
Action taken as part of the Kyoto Agreement will only reduce temperatures by 0.12°C by the middle of the century - compared to a full 1°C of mitigation from the Montreal Protocol."

The findings were made inadvertently when the team set out to quantify how the Montreal Protocol had affected atmospheric circulation around Antarctica. To get their results, the researchers modelled global climate under two scenarios of atmospheric chemistry - one with, and one without the Montreal Protocol being enacted. They then extended these simulations into the future using conservative estimates for unmitigated CFC emissions - set to 3% growth per annum, much less than the observed CFC growth rates at the time of establishment of the Montreal Protocol. Their results therefore likely underestimate the actual impact of the international treaty to reduce CFCs.

The success of the Montreal Protocol in mitigating climate change is even more striking when focusing on regional domains. For example, warming of between 0.5°C - 1°C has already been avoided over North America, Africa and Eurasia. By midcentury avoided warming in some of these areas will be 1.5°C - 2°C and over the Arctic avoided warming will be as much as 3°C - 4°C.

The researchers also found an amount of avoided ice melt due to the Protocol, with the extent of sea ice around the Arctic during summer around 25% greater today than it would have been without any reduction in CFC emissions. The avoided warming over Greenland also suggests that the observed accelerating ice sheet melt there and the associated sea level rise has also been reduced by the Protocol.

"Without any fanfare the Montreal Protocol has been mitigating global warming impacts for more than three decades, surpassing some treaties that were specifically aimed to ameliorate climate change impacts," said co author Dr Martin Jucker.

Looking ahead, co-author Prof Matthew England said, "The success of the Montreal Protocol demonstrates superbly that international treaties to limit greenhouse gas emissions really do work; they can impact our climate in very favourable ways, and they can help us avoid dangerous levels of climate change.

"Montreal sorted out CFC's, the next big target has to be zeroing out our emissions of carbon dioxide."

Many organic molecules are chiral, which means that they are non-superimposable on their mirror image. Those mirror images are called enantiomers and can have different properties when interacting with other chiral entities, for example, biomolecules. Selectively producing the right enantiomer is therefore important in for example the pharmaceutical. University of Groningen chemists Ruth Dorel and Ben Feringa have now devised a method that not only achieves this but that also controls which version is being produced using light. The results were published online by the journal Angewandte Chemie on November 17.

The process is based on the use of a molecular motor created by Professor Feringa, for which he was awarded the 2016 Nobel Prize in Chemistry. The motor molecule was used to produce the first switchable catalyst for asymmetric anion-binding catalysis. Dr Ruth Dorel explains: 'We attached anion-binding arms on both sides of the motor molecule to create an anion receptor that can act as a catalyst. This receptor will adopt a helical structure in the presence of anions that, depending on the relative position of the arms, will exist in different forms.'

Switch

In this study, a very slow-turning motor molecule was used so that different stages of the rotation cycle could be used in catalysis. The molecular motor is made up of two identical halves, linked by a double carbon-carbon bond that acts as the axle. By sequentially exposing the molecule to UV-light and heat, unidirectional rotation around the axle is achieved. Consequently, the anion-binding groups on both halves of the motor are able to switch from being apart from each other (trans) to being in close proximity on the same side of the motor molecule (cis). In the cis configuration, the arms can adopt two different configurations leading to two different helices with opposite handedness. Dorel: 'The helicity dictates the enantiomer of the product that this catalyst will produce.'

Drugs or polymers

The new catalyst was tested on a benchmark reaction for anion-binding catalysis. 'We now have a proof of principle,' Dorel explains. Practical applications are a long way off but could potentially be found both in fundamental research and in the production of drugs or polymers. For many drugs, only one of the two mirror images is the active substance - the other may do nothing, or even cause side effects. 'And in polymer production, a catalyst like this could alter the shape and properties of the polymer chain on demand.'

In remote areas with low literacy rates, showing animated videos in the local language demonstrating agricultural techniques results in high retention and adoption rates of those techniques, found researchers from Michigan State University.

The study, published in the journal Information Technology for Development, demonstrated that two years after being shown an educational animated video on a postharvest bean storage method, farmers in Mozambique had a 97% retention rate and 89% adoption of the storage solution.

According to Julia Bello-Bravo, the study's lead author, these results are crucial since developing and deploying scalable educational solutions for farmers in developing countries remains an elusive goal.

"These animated intervention strategies are viable for scaling since they can be produced in the local languages of the farmers and distributed through readily available resources such as smartphones," said Bello-Bravo, assistant professor in the Department of Food Science and Human Nutrition. "It's a cost-effective approach to reach isolated communities that might not otherwise have access to these important agricultural solutions."

In most African countries, agriculture is a major economic industry; in Mozambique, 90% of rural households farm. However, poverty, low literacy rates, lingering effects of war and environmental threats keep farmers from receiving the proper education to improve their crop yield and means of support.

"We are dealing with the Last Mile Problem - how to get information to people in hard-to-reach places so they are aware of the techniques that can improve their own lives," said Barry Pittendrigh, an MSU Foundation professor in the Department of Entomology, who co-founded of Scientific Animations Without Borders with Bello-Bravo.

SAWBO is a university-based program that transforms extension information on agriculture, health and women's empowerment into animated videos, which are translated into many languages.

Bello-Bravo said two major barriers to education are language and gender, especially in countries where women may do much of the farming but aren't given equal access to traditional learning opportunities.

"Our videos can be adapted to a diversity of cultural scenarios, allowing women, men and a great diversity of age groups to view them and learn the proper techniques," Bello-Bravo said. "In this study we observed women taking an active role in learning and sharing the information they gained from the animations. Add to this, many people started using the technique. We were excited to see that people both learned from the materials and used the technique presented in the animation."

In 2015, the researchers taught farmers in the Gurue District in Mozambique, using animated videos or traditional lectures, how to use jerrycans to secure stored beans for future planting seasons. Jerrycans, containers often used in Africa to store water, were chosen because they are easily and cheaply obtained, yet they keep the seeds dry and protected from pests.

In 2017, the researchers analyzed the farmers' ability to recall the eight steps in the process, if they had used the new storage technique, and if they had shared the technique with other farmers.

These videos have applications around the world, Bello-Bravo said.

"Animations can also be useful for explaining complex ideas to the general population or those that speak diverse global languages to share information around medical needs, such as cancer screening," she said. "We recognize that this is one animation on one technique in one experimental situation; however, the results are encouraging, and we hope to test these outcomes under different topic areas, groups and circumstances."

This study was funded in part by the United States Agency for International Development as part of the Feed the Future Innovation Lab for Collaborative Research on Grain Legumes. Robert Mazur and Eric Abbott from Iowa State University, and Sostino Mocumbe and Ricardo Maria from the Mozambique Institute of Agricultural Research contributed to this research.

The video used in the survey was translated into the local language of Lomwe and also is available in Portuguese, the native language of Mozambique.

(Note for media: Please include a link to the original paper in online coverage: https://www.tandfonline.com/doi/full/10.1080/02681102.2019.1697632)

Pioneering research gives fresh insight into one of the pivotal building blocks of life

The quest to better understand how genomic information is read has taken a new step forward, thanks to pioneering new research.

A team of scientists, led by Dr Steven West at the University of Exeter's Living Systems Institute, have revealed a fresh insight into how genes are copied.

The human genome - or the entire set of DNA - comprises of thousands of genes. These units of information are copied into a messenger molecule, called RNA, by a complicated process known as 'transcription'.

For the process, a factory molecule called RNA polymerase attaches to DNA at the beginning of a gene, copies the information in the gene into an RNA molecule, before finally terminating the transcription process at the end of a gene.

Crucially, in order for this process to be carried out safely to the host organism, it is vital to start and stop in the correct place or else the message - in this case the RNA transcript - may make no sense or even cause harm.

The new research, published in Genes & Development, has given a fresh insight into how the transcription process stops - or is terminated.

Traditionally, there have been two models that are thought to explain this - the allosteric model that suggests that the properties of RNA polymerase are changed at the ends of genes to cause it to stop; and the torpedo model that suggests that, at the ends of genes, a molecular torpedo jumps onto the RNA and gives chase to the RNA polymerase bumping it off the DNA when it catches it.

These two models have been debated now for over thirty years in a bid to understand this elusive final step in the transcription cycle. The new research, however, suggests a combination of the two processes is actually more likely to explain the phenomenon. The research shows that the allosteric component of the mechanism applies a brake that slows down the RNA polymerase, which can be thought of as a juggernaut. Once slowed, it represents a much easier target for the molecular torpedo.

Dr West explained - "for many years these two models were pitted against one another. The fact that they work together is satisfying and explains why evidence had built up to support both. This will help us to better understand the transcription cycle, and how cells use their genetic information correctly".

Artificial intelligence and machine learning (AI/ML) are increasingly transforming the healthcare sector. From spotting malignant tumours to reading CT scans and mammograms, AI/ML-based technology is faster and more accurate than traditional devices - or even the best doctors. But along with the benefits come new risks and regulatory challenges.

In their latest article Algorithms on regulatory lockdown in medicine recently published in Science, Boris Babic, INSEAD Assistant Professor of Decision Sciences; Theodoros Evgeniou, INSEAD Professor of Decision Sciences and Technology Management; Sara Gerke, Research Fellow at Harvard Law School's Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics; and I. Glenn Cohen, Professor at Harvard Law School and Faculty Director at the Petrie-Flom Center look at the new challenges facing regulators as they navigate the unfamiliar pathways of AI/ML.

They consider the questions: What new risks do we face as AI/ML devices are developed and implemented? How should they be managed? What factors do regulators need to focus on to ensure maximum value at minimal risk?

Until now regulatory bodies like the U.S. Food and Drug Administration (FDA) have approved medical AI/ML-based software with "locked algorithms" - that is algorithms that provide the same result each time and do not change with use. However, a key strength and potential benefit from most AI/ML technology is derived from its ability to evolve as the model learns in response to new data. These "adaptive algorithms", made possible because of AI/ML, create what is in essence a learning healthcare system, in which the boundaries between research and practice are porous.

Given the significant value of this adaptive system, a fundamental question for regulators today is whether authorisation should be limited to the version of technology that was submitted and evaluated as being safe and effective, or whether they permit the marketing of an algorithm where greater value is to be found in the technology's ability to learn and adapt to new conditions.

The authors take an in-depth look at the risks associated with this update problem, considering the specific areas which require focus and ways in which the challenges could be addressed.

The key to strong regulation, they say, is to prioritise continuous risk monitoring.

"To manage the risks, regulators should focus particularly on continuous monitoring and risk assessment, and less on planning for future algorithm changes," say the authors.

As regulators move forward, the authors recommend they develop new processes to continuously monitor, identify, and manage associated risks. They suggest key elements that could help with this, and which may in the future themselves be automated using AI/ML - possibly having AI/ML systems monitoring each other.

While the paper draws largely from the FDA's experience in regulating biomedical technology, the lessons and examples have broad relevance as other countries consider how they shape their associated regulatory architecture. They are also important and relevant for any business that develops AI/ML embedded products and services, from automotive, to insurance, financials, energy, and increasingly many others. Executives in all organisations have a lot to learn about managing new AI/ML risks from how regulators think about them today.

"Our goal is to emphasise the risks that can arise from unanticipated changes in how medical AI/ML systems react or adapt to their environments," say the authors, warning that, "Subtle, often unrecognised parametric updates or new types of data can cause large and costly mistakes."

"Being crabby" might have a whole new meaning.

A crab's nervous system could help scientists learn what causes single neurons in the human brain to become "out of whack," which can contribute to the development of neurological diseases like Alzheimer's disease. Knowing exactly how a single neuron operates among the billions housed in the human brain could one day help scientists design innovative ways to prevent and treat these diseases, such as targeted therapies.

The study, conducted by researchers at the University of Missouri, Brandeis University and the University of Texas at Austin, was published in the journal Proceedings of the National Academy of Sciences.

Researchers worked to validate a popular research method called RNA sequencing used to identify unknown neurons in the brain and sort them into various subtypes. Neurons are a basic element of all animal nervous systems, allowing scientists to draw comparisons in animal models like crabs when studying the human nervous system.

"There are billions of neurons in the human brain, yet we still don't know how many distinct types there are," said David Schulz, a professor of biological sciences in the College of Arts and Science. "We are finally at a technological point where we can ask the incredibly complex question -- what are the brain's building blocks?"

Schulz believes the answer to that question will drive everything we know about diseases in the brain for the next 50 to 100 years. However, in order to answer that question he said we must first know how neurons are different from one another, and how healthy neurons differ from diseased ones.

Using a crab's nervous system as a model, the researchers compared and validated the results of previous human RNA sequencing methods. Since crabs have already identifiable subtypes of neurons, the researchers knew what they were looking for, so they were able to work backward from the published results and use the RNA sequencing method to validate those findings.

Schulz said he was both surprised and reassured by what they found.

"If you don't know what you are looking for in the complex human brain, then early efforts using RNA sequencing are going to need some refinement before we can answer this fundamental question," Schulz said. "This study is one of those refinements. Until we can understand each component, we can't expect to take the brain apart and put it back together again in order to figure out how it works."

Scientists of Far Eastern Federal University (FEFU) and the G.B. Elyakov Pacific Institute of Bioorganic Chemistry (FEB RAS) together with German colleagues spotted six new and three already known biologically active compounds in a new strain of the fungus Penicillium piltunense first time isolated. One compound has a pronounced anti-inflammatory activity, others have herbicidal potential, i.e., possibly, can become components of new chemicals for weed control. A related study is published in Marine Drugs.

The spotted compounds are the derivatives of aspterric acid which herbicidal activity was previously highlighted in a scientific report published in Nature journal. The authors of the report noted that the acid has a mediocre ability to inhibit plant growth, suggested its analogs promise to be more effective.

"We believe that the compounds isolated could potentially have herbicidal activity since they are the very analogs of aspterric acid, which our foreign colleagues wrote about in Nature. We have not yet been able to check how strongly these properties are expressed in the substances found, but we plan to find it out further. Worth noting, the new herbicidal compounds have not been introduced onto the market for about 30 years", said Olesya Zhuravleva, Ph.D., Head of the Laboratory of Biologically Active Compounds, FEFU School of Natural Sciences.

The scientist went on that one of the compounds has a pronounced anti-inflammatory activity confirmed by an experiment on macrophage cell lines of mice. In the future, new substances can be useful to the developing of anti-inflammatory drugs.

Scientists are also planning to test all the compounds obtained for antimicrobial activity. If it confirms, the compounds will also become candidates for the development of new antibiotics.

Fungi of the genus Penicillium are one of the most common fungus species on our planet. They grow both on land and in the ocean, where they are associated with seagrass, algae, soil, vertebrate and invertebrate animals.

The previously unknown strain of the fungus Penicillium piltunense KMM4648 was isolated from sea soil collected near the northeast shelf of the Sakhalin Island, The Sea of Okhotsk during a marine expedition on the "Akademik Oparin" research vessel. The strain was described by mycologists of the Laboratory of Microbiology PIBOC FEB RAS, Dr. Mikhail V. Pivkin and Dr. Natalya Kirichuk.

Subsequently, the fungal strain was investigated by researchers of the Laboratory of Biologically Active Compounds of the FEFU School of Natural Sciences, together with colleagues from the Laboratory of Microbial Metabolites of the PIBOC FEB RAS.

Gel-like materials have a wide range of applications, especially in chemistry and medicine. However, their usefulness is sometimes limited by their inherent random and disordered nature. Researchers from the University of Tokyo's Institute for Solid State Physics have found a way to produce a new kind of gel which overcomes this limitation. It is still malleable and adaptable like existing gels, but it has a more ordered structure, which can open up a new range of possible uses in various fields.

When you hear the word "gel," you probably conjure up the image of something wobbly and viscous like some cosmetic substance or the inside of a memory-foam mattress. But in the world of scientific research, gels have a more specific definition. Strictly speaking, gels are three-dimensional networks of polymers -- chains of molecules -- with microscopic pores between these chemical strands. The nature and arrangement of these polymers give gels different functions leading to common applications, such as chemical filtration or drug delivery.

The creation of polymer network gels is difficult to control, so they are very disordered and contain many structural inconsistencies or defects. They are said to be heterogeneous, meaning their forms vary widely throughout their structures. However, Research Associate Xiang Li and colleagues have found a novel way to maintain a high level of order while fabricating polymer gels. The result is a homogeneous gel, one that is more consistent throughout its structure whilst still providing the benefits of a highly porous and malleable material.

"We demonstrated that it's actually quite easy to synthesize an extremely homogeneous gel network," said Li. "First, we tightly packed some star-shaped polymers together in a solvent and added some chemicals which, when activated, join these star polymers together. We activated the joining or 'cross-linking' chemicals in a controlled manner; this in turn led to a more ordered polymer gel network than one might ordinarily expect from this kind of process."

The fabrication process, based on a concept known as bond percolation, is very effective at producing ordered gel networks -- so much so that researchers feel it forces them to redefine what actually constitutes a gel. Previously a gel was assumed to contain disorder and defects, however these are no longer key properties. But all this work is not just for the sake of making something new; it has a strong purpose and it could lead to some interesting advancements.

"Ordered yet flexible gel networks could be used in applications like high-performance chemical filters, flexible sensors, mechanical actuators, controlled drug release and even ultraclear optical fibers," explained Li. "We want to encourage others to build on our work here and find other ways to synthesize new polymer gels based on what we have started. Although our method was very specific, it lays the foundations for a more general experimental platform."

Scientists at Johns Hopkins Medicine report they have created a tiny, nanosize container that can slip inside cells and deliver protein-based medicines and gene therapies of any size -- even hefty ones attached to the gene-editing tool called CRISPR. If their creation - constructed of a biodegradable polymer -- passes more laboratory testing, it could offer a way to efficiently ferry larger medical compounds into specifically selected target cells.

A report on their work appears in the Dec. 6 issue of Science Advances.

"Most medicines spread throughout the body in an indiscriminate way and don't target a specific cell," says biomedical engineer Jordan Green, Ph.D., leader of the research team. "Some medicines, such as antibodies, latch on to targets on the cell's surface receptors, but we don't have good systems for delivering biological medicines straight to the inside of a cell, which is where therapies would have the best chance at working properly and with fewer side effects."

Many academic and commercial scientists have long sought better transit systems for therapies, says Green, professor of biomedical engineering, ophthalmology, oncology, neurosurgery, materials science and engineering, and chemical and biomolecular engineering at the Johns Hopkins University School of Medicine, and a member of the Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins.

Some commercially available techniques use stripped down forms of viruses - known for their ability to "infect" cells directly -- to deliver therapies, although the noninfectious versions of these delivery systems can unleash an unwanted immune system response. Other therapies aimed at diseased blood cells, for example, are more cumbersome, requiring patients' blood to be removed, then zapped with an electric current that opens pores in the cell membrane to gain entry.

The nanosize container that Green and his team developed at Johns Hopkins borrows an idea from the properties of viruses, many of which are nearly spherical in shape and carry both negative and positive charges. With a more neutral overall charge, viruses can get close to cells. That's not the case with many biological medicines, which consist of highly charged, large proteins and nucleic acids that tend to repel off cells.

To overcome this, graduate student Yuan Rui developed a new biodegradable polymer material. Polymer is the general term for a substance made up of many molecules. To make the polymer, Rui strung together -- like the branches of a tree -- four component molecules that, over time, break down and dissolve in water. The molecules contain both positive and negative charges.

With a balance of positive and negative charges, the molecules push and pull according to their charge and their hydrogen atoms bond with a biological therapy in the vicinity. The result is a nano-structure containing the biological therapy.

The nanosize container's positive charges interact with the membrane of a cell, and the container is engulfed in a cellular package called an endosome.

Once inside, the nanosize container breaks open the endosome, and the polymers degrade, leaving the medicine to work inside the cell.

To test their invention, Rui made a nanocontainer of a small protein and fed it to mouse kidney cells in culture dishes. She attached a green fluorescent tag to the small protein and saw bright green splashes throughout most of the cells, indicating that the protein was successfully delivered.

Then, Rui packaged a bigger protein: human immunoglobulin, a therapy typically used to strengthen the immune system and a model for antibody therapies. This time, she found that 90% of the kidney cells she treated lit up with the green fluorescent tag attached to the immunoglobulin.

"When nanoparticles enter a cell, they often get sequestered into endosomes, which degrade its contents, but our experiments show the protein packages uniformly spread throughout most of the cells and were not stuck in the endosomes," says Rui.

For an even greater challenge, Rui created a nanopackage containing a CRISPR-based protein and nucleic acid complex that could turn off a green fluorescence signal or cause the cells to glow red when the CRISPR compound cut part of a cell's genome. The researchers saw that the gene editing to disable a gene worked in up to 77% of cells grown in the laboratory and to add or repair a gene in about 4% of cells.

"That's pretty effective considering, with other gene editing systems, you might get the correct gene-cutting result less than 10 percent of the time," said Rui. CRISPR-based therapies have the potential to make medicines far more precise with their ability to precisely target genetic flaws that contribute to disease. Some CRISPR therapies are being tested in clinical trials.

In a final experiment, Rui and her colleagues implanted brain cancer cells into the brains of mice. She injected the nanocontainers with gene editing components directly into the mouse brains and analyzed their cells for a red glow indicating successful gene editing. She found brain cancer cells that glowed red several millimeters away from where she injected them.

'When I first started this project five years ago, scientists didn't think that you could use something other than a virus to deliver these therapies into cells," says Rui. "Developing new technologies can help us understand more about disease, but also more about making new drugs."

Rui and Green are trying to make the nanocontainers more stable so they can be injected into the bloodstream and targeted to cells with certain genetic signatures.

The scientists are filing for patents related to this work.

New Rochelle, NY, December 6, 2019 -The role of adenosine in neurodegeneration and neuroregeneration has led to growing attention on adenosine receptors as potential drug targets in a range of brain disorders, including neuroregenerative therapy and treatment for amyotrophyic lateral sclerosis (ALS). These are just two areas of focus in the upcoming special issue on Adenosine and Neurodegeneration - Part II published in Journal of Caffeine and Adenosine Research, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. Visit the Journal of Caffeine and Adenosine Research website to read the articles free until January 6, 2020.

Guest Editor David Blum, University of Lille, Inserm, has compiled a wide-ranging collection of articles on the emerging role of adenosine and neurodegeneration and the implications it has for therapeutic drug development.

Sara Xapelli, PhD, Universidade de Lisboa (Portugal), Ricardo Rodrigues, PhD, University of Coimbra (Portugal), and colleagues coauthored an article entitled "Neurogenesis and Gliogenesis: Relevance of Adenosine for Neuroregeneration in Brain Disorders." In this article the authors review the current understanding of the role of adenosine and caffeine as modulators of neuronal activity and as potential targets for the formation of new neurons and oligodendrocytes. They consider these concepts in the setting of their relevance to brain regeneration.

Ana Sebastião, Universidade de Lisboa (Portugal), Yijuang Chern, PhD, Academia Sinica (Taipei, Taiwan) and colleagues coauthored the article entitled "Adenosine and its Receptors as Potential Drug Targets in Amyotrophic Lateral Sclerosis." The researchers review the growing body of evidence showing changes in adenosine metabolism and adenosine receptor function as ALS develops and progresses. They discuss how adenosine homeostasis and adenosine receptors are altered in ALS patients and experimental models of ALS, and the potential for targeting these factors as drug targets.

"These authoritative reviews will help our quest to increase awareness of the fundamental role of adenosine for the normal brain development and function as well as in the pathogenesis of neuropsychiatric disorders," says Editor-in-Chief of Journal of Caffeine and Adenosine Research Sergi Ferré, MD, PhD, Chief of the Integrative Neurobiology Section at the National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD.

MIAMI--Scientists working on the next frontier of weather forecasting are hoping that weather conditions 3-to-4 weeks out will soon be as readily available as seven-day forecasts. Having this type of weather information--called subseasonal forecasts--in the hands of the public and emergency managers can provide the critical lead time necessary to prepare for natural hazards like heat waves or the next polar vortex.

Scientists like University of Miami (UM) Rosenstiel School of Marine and Atmospheric Science Professor Ben Kirtman and Assistant Professor Kathleen Pegion at George Mason University are leading the way to close this critical gap in the weather forecast system through the SubX project. SubX--short for The Subseasonal Experiment--is a research-to-operations project to provide better subseasonal forecasts to the National Weather Service.

"Subseasonal predictions is the most difficult timeframe to predict," said Kirtman, a professor of atmospheric sciences and director of the NOAA Cooperative Institute for Marine and Atmospheric Studies (CIMAS). "The hardest part is taking all the observations and putting them into the model."

SubX is filling the gap between the prediction of weather and the prediction of seasonal conditions, which is guided by slowly evolving ocean conditions like sea surface temperatures and soil moisture and variability in the climate system that work on time scales of weeks. To get to the subseasonal scale, scientists need information on conditions that affects global weather such as large-scale convective anomalies like the Madden-Julian Oscillation in the tropical Indian Ocean into their computer models.

"The SubX public database makes 3-4 week forecasts available right now and provides researchers the data infrastructure to investigate how to make them even better in the future," said Pegion.

SubX has already shown great promise forecasting weather conditions. It accurately predicted the amount of rainfall from Hurricane Michael---roughly 50 mm, the 4th of July heat wave in Alaska where temperatures reached over 90 degrees Fahrenheit--20 to 30 degrees above average in some locations --and the polar vortex that hit the midwestern U.S. and eastern Canada in late January and killed 22 people.

For Kirtman and his team, the power to make these predictions requires the capacity to compute and store a large amount of data. This means they depend heavily on the UM Center for Computational Science's (CCS) computing capability to handle the complex computation needed for their models. CCS resources are critical for Kirtman and Pegion to meet the on-time, in-real-time, all-the-time deadlines required for SubX to be successful.

SubX's publicly available database contains 17 years of historical reforecasts (1999-2015) and more than 18 months of real-time forecasts for use by the research community and the National Weather Service.

As Kirtman and his research team pointed out in an Oct. 2019 article in the American Meteorological Society's journal BAMS, "early warning of heat waves, extreme cold, flooding rains, flash drought, or other weather hazards as far as 4 weeks into the future could allow for risk reduction and disaster preparedness, potentially preserving life and resources. Less extreme, but no less important, reliable probabilistic forecasts about the potential for warmer, colder, wetter, or drier conditions at a few weeks lead are valuable for routine planning and resource management."

SAN DIEGO, December 5, 2019 -- One of the first things new viewers of the cartoon "Rick and Morty" might notice about Rick Sanchez is his penchant for punctuating his speech with burps. Linguistics can provide a new way to read into the dimension-hopping grandfather's midsentence belching.

Researcher Brooke Kidner has analyzed the frequency and acoustics of belching while speaking. By zeroing in on the specific pitches and sound qualities of a midspeech burp in "Rick and Morty," the work takes aim at finding what latent linguistic meaning might be found in the little-studied gastrointestinal grumbles.

"There has not been any serious attempts to acoustically or phonetically describe the characteristics of belching in over 60 years," Kidner said.

Kidner will present her findings at the 178th Meeting of the Acoustical Society of America, which will be held Dec. 2-6, at the Hotel del Coronado in San Diego.

Human speech contains a wide soundscape of nontraditional words, such groans and gasps, that still convey meaning and make up what is called a paralanguage. Belching during speech is a relatively less common paralinguistic item.

Less common, of course, unless you are Rick Sanchez. Kidner's initial count from the scripts of the show found the character belched more than 200 times.

She needed to acoustically define what was burping. For that, she turned to recent work that described the qualities of belching, such as jitter and shimmer, which denote how unstable are the frequency and amplitude of sounds.

Burps tend to rumble at a relatively low 300 hertz, jitter 4% more than normal speech and shimmer 15% more.

Cross-referencing the scripted belches with those that fit the definition showed the majority of the original 200 sounds she identified as potential burps weren't burps at all but some other kind of paralinguistic sound, like the actor running out of air.

The findings shed light on new ways we use nonword sounds. "This area was ignored by linguistics for decades," Kidner said. "But there are more and more papers being published on these types of phenomena, and what important implications they have for the speech communities that utilize them."

Kidner's poster 4aSC14, "Acoustic Characteristics of Belching in Speech," will be presented 8:00 a.m.-12 noon PT, Thursday, Dec. 5, in the Crown room of the Hotel del Coronado in San Diego.

Medical practitioners routinely outfit patients with devices ranging from cardiovascular stents, pacemakers, catheters, and therapeutic lenses to orthopedic, breast, dental, and cochlear implants and prostheses. These accessories restore mobility and improve the lifestyles of millions of people. Yet despite the creation of new biocompatible materials, medical implants remain especially vulnerable to bacterial infection. Bacteria are either preexistent or inoculated during the surgical procedure, which weakens the host's defense mechanisms. In fact, nearly 15 percent of all in-hospital infections among surgical patients are related to indwelling medical devices.

Upon adhering to an implant's smooth surface, the bacteria aggregate and produce a biofilm -- a protective environment comprised of DNA, proteins, and polysaccharides. It is important to inhibit formation of a biofilm because it greatly increases a bacterium's resistance to both the host's immune system and antibacterial agents. In many cases, the only way to effectively eradicate an infection once a biofilm has formed is to remove the implant entirely, clear out the bacteria with antibiotics, and ultimately replace the implant. This process is time-consuming and expensive, and poses a significant health risk to the patient.

Implant infections are typically highly resistant to systemic antibiotherapy and natural host defenses. Traditional systematic administration of antibiotics results in a low concentration at the target site, rendering many of these drugs ineffective. Yet while higher concentrations kill more bacteria, they also cause adverse side effects--like toxicity and renal or liver complications--in patients. Implants with anti-adhesive surface coatings, which release antibacterial drugs while simultaneously limiting adherence, may seem like an effective way to combat bacterial infections. However, these coatings can negatively affect the fusion between implant and bone by preventing bone cells from adhering to the prostheses.

A recent advancement in the medical community involves the use of clinical, drug-eluting coatings that disperse therapeutic agents into the polymeric surface of metallic implants. Upon contact with the interstitial fluid that surrounds cells, the biocompatible polymers in the porous coating release the drugs to targeted organs or tissues over an extended period of time. In an article publishing this Thursday in the SIAM Journal on Applied Mathematics, Raquel Bernardes, José Ferreira, Paula de Oliveira, Mario Grassi, and Manuel Nhangumbe present a mathematical model that explores the interactions between bacterial populations, the materials they colonize, and drugs delivered from the medical devices to which they adhere. In short, they are interested in polymer porosity and bacteria's dependence on and reaction to both the polymeric coating and the drug.

"One of the most common approaches for preventing biofilm formation is the dispersion of antimicrobial agents in an implant's polymeric coating," de Oliveira said. "In medical devices like drug-eluting cardiovascular stents, therapeutic lenses, and intraocular implants, the drug is dispersed in biocompatible and biodegradable polymeric matrices and the release obeys a predefined pattern."

When constructing their model, the authors make a handful of assumptions pertaining to the biological, chemical, and physical interactions on the surface of the drug-eluting implant. One such assumption is that an initially-solid drug is dispersed in the biodegradable polymeric coating of the implanted medical device. "When in contact with the interstitial fluid, the drug dissolves and diffuses," Ferreira said. "To consequently govern the behavior of the solid and dissolved drug respectively, we need two partial differential equations (PDEs). The solid drug dissolves because the interstitial fluid permeates the polymeric coating and enters in contact with the solid drug. So a third PDE is needed for the interstitial fluid."

The researchers' model is therefore comprised of a system of PDEs--of the convection-diffusion-reaction type--coupled with an ordinary differential equation (ODE). The ODE controls the time evolution of the population density of the bacteria attached to the implant's surface, meaning that its solution depends on the solution of the PDE. For the sake of simplicity, the authors describe the bacteria's density only as a function of time. An integral function, which represents the mass of drug released by the polymeric coating at a given time, connects the PDEs with the ODE.

The authors note that the porosity of the device's coating does not in any way compromise the strength of the medical device itself. However, polymer porosity is certainly complex. "As porosity increases, two opposite events occur," de Oliveira said. "A larger porosity leads to higher drug release levels, and we can expect a subsequent decrease in bacterial density. On the contrary, a higher porosity provides the bacteria with larger surfaces to adhere to and a higher likelihood of survival." The team therefore treats the bacterial growth rate as a function of porosity to account for bacterial proliferation's dependence on porosity.

Their model indicates that successful drug therapy depends on a delicate balance between the drug's action and bacterial proliferation. "The larger the effective diffusion, the smaller the bacterial population," Grassi said. "Effective diffusion is contingent upon both drug diffusion and polymeric coating properties. Consequently, a successful fight depends not only on drug properties but also on the degradation rate and porosity of the coating where the drug is dispersed. If effective diffusion is not large enough, the bacterial density explodes."

Use of indwelling medical devices, implants, and prostheses will continue to grow with time and progressively incorporate innovative technologies such as tissue engineering, subcutaneous microsensors, and artificial extracellular matrices. Practitioners will therefore be increasingly reliant upon mathematical models that examine drug delivery from the polymeric coatings of these devices, test mechanical properties, and simulate various drug release scenarios. Such models bridge the gap between theoretical analysis and more practical outcomes, and help doctors understand patients' immediate post-surgery responses and long-range defense abilities.

The team is currently advancing its present work by studying the influence of sepsis during surgery, the insertion of a contaminated implant, and its interplay with the preexisting foci of infection in the patient. "The bacterial population is now described by a PDE because space is of crucial importance in this context," de Oliveira said. "We are addressing questions about the topology of preexistent infection foci and the degree and 'shape' of implant contamination."