Culture

Stanford scientists' software turns 'mental handwriting' into on-screen words, sentences

Call it "mindwriting."

The combination of mental effort and state-of-the-art technology have allowed a man with immobilized limbs to communicate by text at speeds rivaling those achieved by his able-bodied peers texting on a smartphone.

Stanford University investigators have coupled artificial-intelligence software with a device, called a brain-computer interface, implanted in the brain of a man with full-body paralysis. The software was able to decode information from the BCI to quickly convert the man's thoughts about handwriting into text on a computer screen.

The man was able to write using this approach more than twice as quickly as he could using a previous method developed by the Stanford researchers, who reported those findings in 2017 in the journal eLife.

The new findings, to be published online May 12 in Nature, could spur further advances benefiting hundreds of thousands of Americans, and millions globally, who've lost the use of their upper limbs or their ability to speak due to spinal-cord injuries, strokes or amyotrophic lateral sclerosis, also known as Lou Gehrig's disease, said Jaimie Henderson, MD, professor of neurosurgery.

"This approach allowed a person with paralysis to compose sentences at speeds nearly comparable to those of able-bodied adults of the same age typing on a smartphone," said Henderson, the John and Jene Blume -- Robert and Ruth Halperin Professor. "The goal is to restore the ability to communicate by text."

The participant in the study produced text at a rate of about 18 words per minute. By comparison, able-bodied people of the same age can punch out about 23 words per minute on a smartphone.

The participant, referred to as T5, lost practically all movement below the neck because of a spinal-cord injury in 2007. Nine years later, Henderson placed two brain-computer-interface chips, each the size of a baby aspirin, on the left side of T5's brain. Each chip has 100 electrodes that pick up signals from neurons firing in the part of the motor cortex -- a region of the brain's outermost surface -- that governs hand movement.

Those neural signals are sent via wires to a computer, where artificial-intelligence algorithms decode the signals and surmise T5's intended hand and finger motion. The algorithms were designed in Stanford's Neural Prosthetics Translational Lab, co-directed by Henderson and Krishna Shenoy, PhD, professor of electrical engineering and the Hong Seh and Vivian W. M. Lim Professor of Engineering.

Shenoy and Henderson, who have been collaborating on BCIs since 2005, are the senior co-authors of the new study. The lead author is Frank Willett, PhD, a research scientist in the lab and with the Howard Hughes Medical Institute.

"We've learned that the brain retains its ability to prescribe fine movements a full decade after the body has lost its ability to execute those movements," Willett said. "And we've learned that complicated intended motions involving changing speeds and curved trajectories, like handwriting, can be interpreted more easily and more rapidly by the artificial-intelligence algorithms we're using than can simpler intended motions like moving a cursor in a straight path at a steady speed. Alphabetical letters are different from one another, so they're easier to tell apart."

In the 2017 study, three participants with limb paralysis, including T5 -- all with BCIs placed in the motor cortex -- were asked to concentrate on using an arm and hand to move a cursor from one key to the next on a computer-screen keyboard display, then to focus on clicking on that key.

In that study, T5 set what was until now the all-time record: copying displayed sentences at about 40 characters per minute. Another study participant was able to write extemporaneously, selecting whatever words she wanted, at 24.4 characters per minute.

If the paradigm underlying the 2017 study was analogous to typing, the model for the new Nature study is analogous to handwriting. T5 concentrated on trying to write individual letters of the alphabet on an imaginary legal pad with an imaginary pen, despite his inability to move his arm or hand. He repeated each letter 10 times, permitting the software to "learn" to recognize the neural signals associated with his effort to write that particular letter.

In numerous multi-hour sessions that followed, T5 was presented with groups of sentences and instructed to make a mental effort to "handwrite" each one. No uppercase letters were employed. Examples of the sentences were "i interrupted, unable to keep silent," and "within thirty seconds the army had landed." Over time, the algorithms improved their ability to differentiate among the neural firing patterns typifying different characters. The algorithms' interpretation of whatever letter T5 was attempting to write appeared on the computer screen after a roughly half-second delay.

In further sessions, T5 was instructed to copy sentences the algorithms had never been exposed to. He was eventually able to generate 90 characters, or about 18 words, per minute. Later, asked to give his answers to open-ended questions, which required some pauses for thought, he generated 73.8 characters (close to 15 words, on average) per minute, tripling the previous free-composition record set in the 2017 study.

T5's sentence-copying error rate was about one mistake in every 18 or 19 attempted characters. His free-composition error rate was about one in every 11 or 12 characters. When the researchers used an after-the-fact autocorrect function -- similar to the ones incorporated into our smartphone keyboards -- to clean things up, those error rates were markedly lower: below 1% for copying, and just over 2% for freestyle.

These error rates are quite low compared with other BCIs, said Shenoy, who is also a Howard Hughes Medical Institute investigator.

"While handwriting can approach 20 words per minute, we tend to speak around 125 words per minute, and this is another exciting direction that complements handwriting. If combined, these systems could together offer even more options for patients to communicate effectively," Shenoy said.

What The Study Did: Researchers describe overdose deaths in San Francisco before and after the initial COVID-19 shelter-in-place order to try to make clear whether characteristics of fatal overdoses changed during this time in an effort to guide future prevention efforts.

Authors: Luke N. Rodda, Ph.D., of the Office of the Chief Medical Examiner for the city and county of San Francisco, is the corresponding author.

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

(doi:10.1001/jamanetworkopen.2021.10452)

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

What The Study Did: Researchers used registry data to examine the number, characteristics and outcomes of patients with sunburns severe enough to warrant admission to specialist burn services in Australia and New Zealand.

Authors: Lincoln M. Tracy, Ph.D., of Monash University in Melbourne, Australia, is the corresponding author.

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

(doi:10.1001/jamadermatol.2021.1110)

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

What The Study Did: Delayed localized injection-site reactions to the Moderna COVID-19 vaccine for 16 patients are described in this report.

Authors: Alicia J. Little, M.D., Ph.D., of the Yale University School of Medicine in New Haven, Connecticut, is the corresponding author.

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

(doi:10.1001/jamadermatol.2021.1214)

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

LA JOLLA, CALIF. - May 12, 2021 - Scientists at Sanford Burnham Prebys Medical Discovery Institute have taken a deep dive into a previously overlooked family of proteins and discovered that they are essential to maintaining the energy that cells need to grow and survive. The proteins, known as lipid kinases, produce messengers that help balance cellular metabolism and promote overall health. The findings, published in Developmental Cell, provide further support to pursue lipid kinases as promising therapeutic targets for diseases that demand excess energy, such as cancer.

"Cancer cells are hungry--they grow faster than most cell types and need energy to support their aggressive attempts to metastasize," says Brooke Emerling, Ph.D., assistant professor in the Cell and Molecular Biology of Cancer Program at Sanford Burnham Prebys and corresponding author of the study. "Our study is one of the first to look at how PI5P4Ks--lipid kinases with known links to sarcomas and certain types of breast cancer--facilitate communications within the cell and maintain an energy balance to support cell growth."

For years scientists have tried to halt cancer by blocking nutrients from reaching tumor cells. But these attempts have been disappointing because cancer cells are tricky and create back up routes to source food to sustain their growth. Emerling's approach is to find and attack metabolic vulnerabilities within cells, which would deprive them of energy even in an abundance of nutrients and special tactics.

Using a combination of cell lines, imaging technology and mouse tumor models, Emerling's team revealed that PI5P4Ks produce an active messenger that coordinates communications between peroxisomes and mitochondria--two organelles intimately involved in making and using fuel to support cellular growth. In the absence of the messenger, the interplay between the organelles breaks down, mitochondria become overworked, and cells starve and die.

"Mitochondria are the powerhouses of the cell, says Archna Ravi, Ph.D., a postdoctoral researcher in Emerling's lab and first author of the paper. "They play an essential role in generating energy to drive cellular function and basically all biological processes. This research supports targeting PI5P4Ks as a cancer treatment strategy because it would deprive tumors of the one thing they can't live without: energy."

Emerling's team previously discovered the essential role of PI5P4K in tumor formation. The new study indicates a role for PI5P4Ks not only in tumor establishment, but for the first time in tumor maintenance.

"We use sarcomas as a tumor model because PI5P4Ks are highly expressed in high grade sarcomas, and their expression correlates with patient survival," says Emerling. "Sarcomas are a rare group of cancers that affect the body's connective tissues, and about half of all cases can be cured, but for the other half, better therapies are desperately needed."

Targeting PI5P4K may also be valuable for other tumor types that have developed profound metabolic alterations to source nutrients, such as triple negative breast cancer. Like sarcomas, triple negative breast cancer therapies remain woefully inadequate.

"Our goal is to develop drugs in the near future that inhibit PI5P4K and test the drugs in mice. If successful, we hope to advance to human clinical trials. I think the future for our research is very bright now," concludes Emerling.

Social anxiety disorder can cause considerable suffering in children and adolescents and, for many with the disorder, access to effective treatment is limited. Researchers at Centre for Psychiatry Research at Karolinska Institutet and Region Stockholm in Sweden have now shown that internet-delivered cognitive behavioural therapy is an efficacious and cost-effective treatment option. The study is published in the journal JAMA Psychiatry.

Social anxiety disorder (SAD, previously known as social phobia) has a typical onset during childhood and is characterised by an intense and persistent fear of being scrutinised and negatively evaluated in social or performance situations.

The fear typically leads to avoidance of such anxiety triggering situations or are endured under great distress, resulting in an impaired ability to function in everyday life.

The disability can lead to underperformance in school, social isolation from peers and, inability to partake in leisure activities.

As one of the most common anxiety disorders among youth, the disorder affects 5 to 10 percent of the youth population and without effective treatment it has been linked to long-term psychosocial adversity and persistence into adulthood.

Despite known evidence-based treatments for SAD, such as cognitive behavioural therapy (CBT), the access to effective treatment is very limited.

As a means to increase access, researchers at Centre for Psychiatry Research at Karolinska Institutet and the Child and Adolescent Mental Health Services in Region Stockholm have now developed and evaluated a 10-week internet-delivered CBT (ICBT) programme for young people with SAD.

The study was conducted between 2017 and 2020, and included 103 youths aged 10 to 17 along with their parents. Participants were randomly assigned to either internet-delivered CBT or an active control group, internet-delivered supportive therapy.

Both interventions included ten online treatment modules with weekly therapist support and, three video sessions with the therapist. Parents parallelly received five online modules with therapist support.

The results showed that ICBT was significantly more effective than supportive therapy in reducing social anxiety and comorbid psychiatric symptoms, as well as in increasing the level of global functioning.

The superiority of ICBT was shown in assessments of participants' symptoms made by masked assessors as well as in ratings by participants themselves and their parents.

According to the researchers, the digital format can also increase access to evidence-based treatment for children and adolescents with SAD.

"Offering treatment digitally means that children and parents don't have to take time off school and work to travel to a health care facility," says the study's first author Martina Nordh, psychologist and researcher at the Centre for Psychiatry Research, part of Karolinska Institutet's Department of Clinical Neuroscience, and Region Stockholm. "We also believe it may lower the threshold to seeking treatment, as young people with SAD can find it too challenging to meet with unfamiliar people and to be in a new setting."

The total time spent by the therapists in ICBT was about a quarter of the time normally required by face-to-face CBT for SAD.

"Shorter therapist time enables each therapist to treat more patients and may lead to reduction of waiting times," says principal investigator Eva Serlachius, child and adolescent psychiatrist and adjunct professor at the Centre for Psychiatry Research, part of Karolinska Institutet's Department of Clinical Neuroscience, and Region Stockholm. "This also makes digital CBT less costly for the healthcare services and resources can be redistributed to those with greater need of more intensive treatment."

The acidity of the atmosphere is increasingly determined by carbon dioxide and organic acids such as formic acid. The second of these contribute to the formation of aerosol particles as a precursor of raindrops and therefore impact the growth of clouds and pH of rainwater. In previous atmospheric chemistry models of acid formation, formic acid tended to play a small role. The chemical processes behind its formation were not well understood. An international team of researchers under the aegis of Forschungszentrum Jülich has now succeeded in filling this gap and deciphering the dominant mechanism in the formation of formic acid. This makes it possible to further refine atmosphere and climate models. The results of the study have now been published in the peer-reviewed journal Nature.

In Germany, we are familiar with acid rain, particularly from our experience in the 1980s. The cause of it was that nitrogen oxides and sulfur oxides released into the atmosphere by human beings reacted with the water droplets in the clouds to form sulfuric acid and nitric acid. Acid rain has a pH of about 4.2-4.8, lower than that of pure rainwater (5.5-5.7), which results from the natural carbon dioxide content of the atmosphere.

However, the chemical process that forms the bulk of the formic acid present in the atmosphere was unknown up to now. Dr. Bruno Franco and Dr. Domenico Taraborrelli from Jülich's Institute of Energy and Climate Research - Troposphere have now deciphered it: Formaldehyde is formed naturally by photo-oxidation of volatile organic compounds. Formaldehyde reacts in cloud droplets with water molecules to form methanediol. The majority of this is outgassed and reacts with OH radicals, sometimes called the "detergent of the atmosphere", in a photochemical process to form formic acid. A smaller portion reacts with the liquid phase of the water droplets to also form formic acid that is spread by rain.

"According to our calculations, the oxidation of methanediol in the gas phase produces up to four times as much formic acid as what is produced in other known chemical processes in the atmosphere," says Domenico Taraborrelli. This amount reduces the pH of clouds and rainwater by up to 0.3, which highlights the contribution of organic carbon to the natural acidity in the atmosphere.

As a first step, the two scientists tested their theory using MESSy, a global atmospheric chemistry model, and compared the results with remote sensing data. To carry out the modelling, they used the Jülich supercomputer JURECA. Subsequent experiments in Jülich's SAPHIR atmosphere simulation chamber confirmed the results. "We assume that the mechanism demonstrated is also active in aqueous aerosols and applies to other organic acids such as oxalic acid, which are not adequately accounted for in atmospheric chemistry models to date," says Taraborrelli. One of the effects of this could be an improved understanding of the growth of aerosol particles and the development of clouds.

Since the discovery of Alzheimer's disease over a century ago, two hallmarks of the devastating illness have taken center stage.

The first, known as amyloid plaques, are dense accumulations of misfolded amyloid protein, occurring in the spaces between nerve cells. Most efforts to halt the advance of Alzheimer's disease have targeted amyloid protein plaques. To date, all have met dispiriting failure.

The second classic trait has, until recently, received less scrutiny. It consists of string-like formations within the bodies of neurons, produced by another crucial protein-- tau. These are known as neurofibrillary tangles.

In a new study, researchers with the ASU-Banner Neurodegenerative Disease Center at the Biodesign Institute and their colleagues investigate these tangles in the brain -- pathologies not only characteristic of Alzheimer's but other neurodegenerative conditions as well.

The research homes in on a particular protein known as Rbbp7, whose dysregulation appears linked to the eventual formation of tau protein tangles and the rampant cell death associated with Alzheimer's and other neurodegenerative diseases.

"We had a hunch that this protein was involved in Alzheimer's disease, particularly because we know that the protein was decreased in Alzheimer's disease post-mortem brain tissue when compared with normal brains," says Nikhil Dave, lead author of the new study.

The research shows a correlation between decreased Rbbp7 levels and increased tangle formation and associated neuronal loss and brain weight reduction in Alzheimer's diseased brains. Intriguingly, cell loss and tangle formation were reversed in transgenic mice whose levels of Rbbp7 were restored to baseline levels.

The findings open a new avenue of research that could aid in the development of effective treatments for Alzheimer's disease along with a broad range of tau-related afflictions, collectively known as tauopathies, including Pick's disease, frontotemporal dementia and traumatic brain injury.

The new study appears in the current issue of the journal Acta Neuropathologica.

Infernal assault

Alzheimer's disease remains one of the most enigmatic illnesses known to medical science. Its clinical symptoms stealthily appear over a period of years and can be masked by the normal processes of aging. Once it has taken command of the brain however, the advance of the disease is often swift and merciless.

Patients may experience a bewildering range of symptoms including confusion, physical disorientation, delusions, forgetfulness, aggression, agitation, and progressive loss of motor control.

Researchers now know that by the time the first outward appearances of the disease become apparent, Alzheimer's disease has been silently ravaging the brain for decades, typically leaving its calling card in the form of plaques and tangles.

Alzheimer's disease remains the leading cause of dementia, with advancing age being the primary risk factor. The disease has been on a frightening upward trajectory, as life expectancy increases and other once-deadly illnesses have become treatable, if not curable. Currently, 5.8 million people in the United States alone suffer from Alzheimer's disease, with the number expected to swell to 14 million by 2060, according to the Centers for Disease Research.

Many other factors apart from advancing age play a role in this complex disorder, from hereditary predisposition to vascular afflictions such as diabetes and obesity. Lifestyle choices, including diet and exercise, can also affect vulnerability. The disease typically afflicts those over 65, though early onset versions of the disorder can strike much sooner.

Genome 2.0

The new study examines another area of risk for neurodegenerative illness, one bearing on an individual's genes and how they are expressed. Although the three billion letter DNA code making up an individual's genome remains fixed throughout life, researchers now know that chemical messengers of great variety and complexity can act on the genome, delivering instructions to the DNA and guiding its behavior.

These epigenetic changes as they are known can turn genes on and off or regulate the amount of protein these genes produce. Earlier notions in biology emphasizing a static view of genomic destinies have given way to a new picture of life in which environmental changes can profoundly affect the way our genes behave. Scientists are just beginning to learn the far-reaching influence of the epigenome on human health and disease.

The current research describes epigenetic changes that take place in the brain when the level of the protein Rbbp7 is reduced, something the researchers detected in post-mortem brain tissue from Alzheimer's patients.

One function of Rbbp7 is to regulate gene expression. It does this by altering the interaction of DNA with proteins known as histones, which DNA wraps around like sewing thread around a spool. When the DNA thread is loosely wrapped around the histone spool, the cell machinery can read the exposed DNA message and transcribe it into mRNA, which is then translated into protein. If the DNA thread is tightly wrapped around the histone however, the DNA genes are hidden from view and transcription maybe partially or entirely blocked, thereby reducing or disabling protein expression.

The researchers observed that when Rbbp7 levels are reduced, the level of another protein known as p300 increases, causing a post-translational modification of tau protein, known as acetylation. The effect of this is to cause tau protein to detach from cell structures known as microtubules, which tau typically binds with. The detached tau is then free to accumulate within neurons, eventually forming the telltale tangles associated with Alzheimer's disease. (See accompanying graphic.)

The acetylation of tau caused by low Rbbp7 results in increased phosphorylation of tau, further promoting tangle formation and subsequent neuronal loss in the brain.

In the new study, transgenic mice displaying tau pathology showed decreased levels of Rbbp7 and increased neuronal loss. Restoring Rbbp7 to normal levels in the mice reversed these pathologies, though the cognitive deficits remained.

Ramon Velazquez, corresponding senior author of the new study, speculates that the reason for this is that the study targeted only a small subregion of the hippocampus, while other brain areas associated with cognition were still rampant with tangle formation. "We plan to look at the global effect of overexpressing Rbbp7 in our future research to see if we can rescue learning, memory and other facets of cognition."

Light at the end of the tunnel?

The associations outlined in the study between Rbbp7 levels and the formation of tau tangles, cell death and loss of cognitive function in the brain are compelling. The results suggest that Rbbp7 may be an attractive target for drug discovery and the development of effective therapies for Alzheimer's disease and other tau-associated afflictions. Treatments based on studies of this kind could be ready for clinical trials within the next five years.

Nevertheless, the authors stress that other molecular players are likely involved in these complex processes. In future studies, the researchers plan to perform extensive, unbiased probing of protein interactions, transcription pathways from DNA to mRNA and the epigenetic modifications that can lead to neurodegenerative disease.

Acetone, a volatile solvent used for everything from removing nail polish and cleaning textiles to manufacturing plastics, could get a sustainability boost from a new strain of bacteria engineered by a research team based in Japan.

They published the details of the heat-loving, acetone-producing bacteria called Moorella thermoacetica on April 23 in AMB Express.

Acetone is typically produced through the widely used cumene method, which is cost-effective but not sustainable. The process, developed in 1942, involves converting two non-renewable resources into acetone and phenol, another chemical that helps manufacture a number of materials, including plastics.

More environmentally friendly options exist -- including gas fermentation, a bioprocess that converts carbon dioxide, monoxide and hydrogen into chemicals and fuels -- but they tend to be cumbersome and costly, according to Yutaka Nakashimada, professor in the Graduate School of Integrated Sciences for Life, Hiroshima University, who led the research. One of the major expenses is the downstream processing, which involves separating out the desired chemicals from the other materials.

"We thought the key is a simultaneous separation of the product from the ongoing fermentation," Nakashimada said. "Our choice was to produce volatile chemicals by using a group of bacteria thriving at high temperatures."

The bacteria, M. thermoacetica, eat the gaseous feedstocks of hydrogen, carbon dioxide and monoxide -- which can be procured from renewable resources -- to produce acetone. Since they grow at a temperature higher than the boiling point of acetone, the acetone produced is a gas that evaporates and can be distilled as the bacteria make it. It streamlines the traditional system into a simultaneous process.

"Our development of the engineered bacteria could pave the way for developing a consolidated process with simplified and cost-effective recovery via condensation following gas fermentation on a large scale suitable for industrial production," said paper co-first author Junya Kato, specially appointed assistant professor in the Graduate School of Integrated Sciences for Life, Hiroshima University.

To develop this productive bacteria strain, the researchers genetically engineered bacteria with modified metabolism processes.

"To our knowledge, this is the first study to provide strains of bacteria that thrive at high temperatures for gas fermentation of acetone," Kato said. "Although further study would be needed to improve the productivity for realization of the industrial applications, the gas fermentation process can be simpler and more cost-effective than before."

The researchers plan to scale their work and study the productivity of their bacteria in industrial conditions.

"We may need to genetically engineer the metabolism of the strain further," Nakashimada said. "Our ultimate goal is the industrialization of the gas fermentation of the 'gas-to-gas' process that is simpler and lower-cost."

PHILADELPHIA--A low-cost, rapid diagnostic test for COVID-19 developed by Penn Medicine provides COVID-19 results within four minutes with 90 percent accuracy. A paper published this week in Matter details the fast and inexpensive diagnostic test, called RAPID 1.0 (Real-time Accurate Portable Impedimetric Detection prototype 1.0). Compared to existing methods for COVID-19 detection, RAPID is inexpensive and highly scalable, allowing the production of millions of units per week.

Despite the urgency of the pandemic, most available methods for COVID-19 testing use RT-PCR--reverse transcription polymerase chain reaction--to detect SARS-CoV-2. Though effective, the technique requires large laboratory space and trained workers to employ. These tests are also costly, they run a risk of cross-contamination, and can take hours or days to provide results.

RAPID was developed by a team led by César de la Fuente, PhD, a Presidential Assistant Professor in Psychiatry, Microbiology, Chemical and Biomolecular Engineering, and Bioengineering, to quickly and accurately detect the virus while remaining cheap enough to be widely accessible. An electrode printed using a screen printer--thousands of which can be printed in a day at very low cost--can detect the virus in nasal swab or saliva samples. The results can be read on a benchtop instrument or on a smartphone.

"Prior to the pandemic, our lab was working on diagnostics for bacterial infections. But then, COVID-19 hit. We felt a responsibility to use our expertise to help--and the diagnostic space was ripe for improvements," de la Fuente said. "We feel strongly about the health inequities witnessed during the pandemic, with testing access and the vaccine rollout, for example. We believe inexpensive diagnostic tests like RAPID could help bridge some of those gaps."

The RAPID technology uses electrochemical impedance spectroscopy (EIS), which transforms the binding event between the SARS-CoV-2 viral spike protein and its receptor in the human body, the protein ACE2 (which provides the entry point for the coronavirus to hook into and infect human cells), into an electrical signal that clinicians and technicians can detect. That signal allows the test to discriminate between infected and healthy human samples. The signal can be read through a desktop instrument or a smartphone.

The team assessed the performance of RAPID using both COVID-19 positive and negative clinical samples from the Hospital of the University of Pennsylvania, including samples of the highly contagious UK B117 variant. In blinded tests, they analyzed 139 nasal swab samples--109 of which were COVID-19 positive and 30 COVID-19 negative, as determined by standard RT-PCR clinical assessments. The team also analyzed 50 saliva samples from patients. For the nasal swab samples, RAPID was 87.1 percent accurate. For saliva samples, RAPID was 90 percent accurate.

RAPID provides results in four minutes, which is faster than most methods currently available for diagnosing COVID-19. For example, serological tests can take around 15 to 20 minutes, and they are about 60 to 70 percent accurate. In addition, RAPID is able to detect COVID-19 at extremely low concentrations (1.16 PFU mL), which corresponds to a viral load that correlates with the initial stages of COVID-19 (about two to three days after onset of symptoms). This is beneficial for detecting individuals at the earliest stages of infection, allowing for rapid care and the potential decrease of further viral spread.

"Quick and reliable tests like RAPID allow for high-frequency testing, which can help identify asymptomatic individuals who, once they learn they are infected, will stay home and decrease spread. We envision this type of test being able to be used at high-populated locations such as schools, airports, stadiums, companies--or even in one's own home," said first author Marcelo Der Torossian Torres, PhD, a postdoctoral researcher at Penn.

Importantly, the technology is affordable and scalable. Each test, which can be performed at room temperature, costs $4.67 to produce. Additionally, the electrodes used in the test can be quickly mass-produced using commercially available screen-printers to print the circuit board (named eChip). One laboratory-sized unit is able to produce 35,000 electrodes daily (about 1.05 million per month).

The team also constructed an electrode for RAPID composed of filter paper, which is a more accessible and inexpensive material. Named ePAD, the researchers demonstrated the applicability of ePAD for RAPID in a portable method, connected to a smart device, which may enable further scale and on-demand testing capabilities at the point-of-care.

"Having low-cost tests which are quick and easy to read extends testing to not only people who can afford it, but to remote or disadvantaged areas," de la Fuente said.

De la Fuente lab's research focuses primarily on developing technologies that help understand, prevent, and treat infectious diseases. Though RAPID was developed as a COVID-19 test, the technology can be used to detect other viruses and diagnose a variety of diseases such as the flu or sexually transmitted diseases.

The inhibition of pathological protein-protein interactions is a promising approach for treating a large number of diseases, including many forms of cancer. A team of researchers has now developed a bicyclic peptide that binds to beta-catenin--a protein associated with certain types of tumor. The secret of their success is the cyclic nature and the hairpin shape of the peptide, which mimics a natural protein structure, they report in the journal Angewandte Chemie.

Because of the extensive protein regions involved in protein-protein interactions, therapeutic approaches involving small molecules are often unsuccessful. Protein mimetics are alternatives that imitate the spatial structure of binding segments of natural protein binding partners. Although beta-sheets--protein structures made of several stretched out peptide chains arranged side by side, resembling a sheet of paper folded like an accordion--often play a role in the interaction of proteins, they have rarely been used as a basis for mimetics. This is partly because they have problems entering the target cell, and thus, cannot reach the pathogenic protein.

Led by Tom N. Grossmann, an international team from the Vrije Universiteit Amsterdam (Netherlands), Università degli Studi di Napoli "Federico II" (Italy), as well as AstraZeneca (Cambridge, UK), has now reported the design of β-sheet mimetics that inhibit the intracellular oncogenic protein beta-catenin. beta-Catenin is a component of the Wnt signaling pathway and activates T-cell factors (TCF), which ultimately stimulate cell growth and proliferation. Hyperactivation of the Wnt pathway is associated with various forms of cancer. Inhibition of the interaction between beta-catenin and TCF is thus an appealing therapeutic approach.

Based on the known structure of beta-catenin when it is in a complex with a protein, the team first produced a binding partner for beta-catenin. This partner is a ring-shaped peptide that forms a short, antiparallel beta-sheet--known as a beta-hairpin structure--when it is bound to beta-catenin, as demonstrated by an analysis of its crystal structure. The idea was to fix this cyclic peptide in the hairpin form by introducing an additional bridge. This generates a bicyclic structure that strengthens binding to beta-catenin. By using a series of different synthesized variants, the team was able to identify several bicyclic peptides with a high affinity for beta-catenin. Among these, they found a compound that (other than the original cyclic peptide) successfully penetrates cells and significantly inhibits the oncogenic Wnt signal cascade.

This newly developed bicyclic beta-sheet mimetic thus represents a possible starting point for the development of new antitumor drugs that inhibit cellular Wnt signaling. This strategy could also be used for the design of further inhibitors of other protein-protein interactions mediated by beta-sheets.

In a new study from Lund University and the University of Gothenburg, patients were interviewed about their experiences ten years after undergoing obesity surgery. The results show that the effect on eating and weight regulation persisted, whereas other problems, such as feelings of guilt about still not being healthy enough, remained.

"This is one of few follow-ups from a patients perspective so long after surgery", says My Engström, researcher in nursing at the University of Gothenburg.

18 patients were interviewed in the study. All of them experienced that their eating habits and appetite were still affected after the operation: their bodies still objected, preventing them from eating as much as before surgery, and the reduction in cravings for unhealthy foods was maintained. Several participants also reported still being more easily affected by alcohol, which had consequences for their social life.

However, while the operation had brought several changes, many described their existence with their surgically altered body as the new normal, or their new everyday life.

"Several respondents found that one reason why they managed their lives with a gastrointestinal modification as well as they did was that they had been warned, and expected more complications than they actually suffered", says My Engström.

"This was interesting to hear as just over 70 per cent of those we interviewed actually did experience an event that healthcare classified as a complication, such as malnutrition, abdominal pain, gall-bladder surgery or ileus."

The participants reported still struggling to manage their lives and their weight after the surgery. This concerned aspects like how to support their children who were often also overweight. Some of the parents said that they felt resigned to their children's weight problems; they tried to provide the best possible guidance but found it difficult.

Several respondents also spoke about physical activity as a continuous cause for bad conscience. They were well aware that they should be physically active, but struggled with this. As a reason, they stated pain or their personal history of always having been bad at physical activity.

"Even if the excess weight was no longer there or did not constitute a real hindrance, the old self-image persisted as an obstacle to progress", says My Engström.

One response common to most of the patients interviewed was the great gratitude they expressed for the procedure itself and towards society for bearing the cost of it. Some participants blamed themselves when something did not work optimally, and thought that they were not "conscientious patients".

"Follow-up of these patients is often insufficient and must improve", says Kajsa Järvholm, researcher in psychology at Lund University.

"The patients should be called back to their primary healthcare centre once a year but this is seldom the case. The patients are instead expected to remember to contact their healthcare provider themselves. When they did get in touch, they often found that knowledge about the surgery was poor."

In summary, the researchers think that long-term follow-up of bariatric surgery patients must improve both within specialist and primary healthcare.

"Those who encounter bariatric surgery patients in the course of their work need both to help create realistic expectations of what the operation can change, and to take into account that many patients blame themselves and therefore hesitate to raise problems with their healthcare providers", says Kajsa Järvholm. "This process is facilitated if the healthcare providers have a non-judgemental attitude and take the time to ask the patients how they are managing in their everyday lives."

Mycobacterium tuberculosis is incredible in that it can survive for decades within its human host. It does this by varying its diet to successfully steal nutrients from the human host including immune cells; it is known to acquire and absorb multiple carbon sources from the body during infection.

In a paper published in the journal Molecular Systems Biology, Surrey scientists detail how they measure the flow of metabolites or "fluxes" through metabolic pathways when Mycobacterium tuberculosis is consuming some of its favourite nutrients. Measuring these 'fluxes' could help scientists advance new tuberculosis drugs as well as understand why the bacterium survives so long in humans and why current antibiotics are often ineffective.

By growing Mycobacterium tuberculosis in specialised bioreactors that allow the environmental conditions and growth rates to be tightly controlled, and then analysing the resulting data with bespoke, cutting-edge computing, Surrey scientists were able to determine the speed of the chemical processes that the bacterium uses to turn the host's nutrients into new bacteria. By measuring these metabolic fluxes, scientists can identify which reactions are critical for the bacteria's growth and thus direct the design of new tuberculosis drugs to effectively kill the bacterium.

The work is a collaboration between Surrey scientists Dr Khushboo Borah, Dr Tom Mendum, Professor Johnjoe McFadden and Dr Dany Beste.

Dr Dany Beste, the lead author of the study and Senior Lecturer in Microbial Metabolism at the University of Surrey, said:

"The decline of tuberculosis deaths in recent years is positive news. However, the current Covid-19 pandemic is estimated to set back TB control decades and therefore we urgently need novel treatments. Our basic science study advances our understanding of the metabolism of this pathogen which can ultimately be capitalised in developing more effective tuberculosis drugs and accelerate progress towards eliminating this infection globally."

The DNA sequences produced are also called oligonucleotides. These are widely used for disease identification, for the manufacture of oligonucleotide-based drugs, and for several other medical and biotechnological applications. 

The high demand for oligonucleotides therefore requires an efficient automated method for their chemical production.This process relies on phosphoramidites, which are chemical compounds that have the disadvantage of being unstable unless stored at the ideal -20 degrees Celsius.

Instruments used for DNA synthesis are not able to cool down the phosphoramidites, and consequently it is unavoidable that some of them degrade after being added to the instrument. 

Avoiding unwanted degradation of important ingredients

Professor Kurt Gothelf and Professor Troels Skrydstrup are each heading a research group in organic chemistry, which have worked together to develop a relatively simple but efficient technology where the production of phosphoramidites can be automated and integrated directly into the instrument for DNA synthesis.

This avoids both the manual synthesis of these, which normally would take up to 12 hours, as well as the problem of storing unstable phosphoramidites. Gothelf's group has contributed with their expertise in automated DNA synthesis and Skrydstrup's group has contributed with their know-how with chemical reactions that take place in continuously flowing liquids (flow chemistry).

"It has been a very rewarding collaboration which is precisely one of the core values of iNANO", says Kurt Gothelf, who adds "and I would also like to attribute to Alexander Sandahl a large part of the credit for this project being successful, as he has established the collaboration and has developed and realized a large part of the ideas for the project.” 

The results have just been published in the journal, Nature Communications. 

In the method of producing phosphoramidites, nucleosides (starting materials) are flushed through a solid material (resin), which can potentially be fully integrated into an automated process in the instrument for DNA synthesis. The resin ensures that the nucleosides are rapidly phosphorylated, whereby the nucleosides are converted to phosphoramidites within a few minutes. From the resin, the phosphoramidites are automatically flushed on to the part of the instrument which is responsible for the DNA synthesis.

This avoids the degradation of the phosphoramidites, as they are first produced just before they are to be used (on-demand), in a faster, more efficient flow-based way that can potentially be automated and operated by non-chemists.

The research is financially supported by the Lundbeck Foundation, the Novo Nordisk Foundation (CEMBID), the Independent Research Fund Denmark, and the Danish National Research Foundation (CADIAC).

Read more about the research results in Nature Communications:

Alexander F. Sandahl, Thuy J. D. Nguyen, Rikke A. Hansen, Martin B. Johansen, Troels Skrydstrup, and Kurt V. Gothelf. On-Demand Synthesis of Phosporamidites. Nature Commun. 2021. doi: /10.1038/s41467-021-22945-z. 

Patent

Phosphoramidite synthesis on-demandPriority application EP20186197.8Patentees: Sandahl, A. F.; Nguyen, T. J. D.; Gothelf, K. V.

For further information, please contact:

Professor Kurt Vesterager Gothelf Department of Chemistry and Interdisciplinary Nanoscience Center (iNANO) kvg@chem.au.dk - +45 60202725 –

Journal

Nature Communications

DOI

10.1038/s41467-021-22945-z

"We're meant to be crossing over ... but the bridge is broken": 2020 university graduates' experiences of the pandemic in Ireland

A new study from Trinity College Dublin investigating the impact of the COVID pandemic on young adults finds that they are vastly more affected than older people, and the reverberations of the disruption to some will last decades. Researchers say this group have paid a high price in the form of foregone opportunities for education, social networks, and labour market integration.

The research, involving university graduates in Ireland, is published in YOUNG: the Nordic Journal of Youth Research (Wednesday, 12th May, 2021) here: https://journals.sagepub.com/doi/full/10.1177/11033088211004792

The impact of major crises in our lives is dependent on many things, but the timing of the crisis relative to our life course transitions is one of the most important aspects that influences how we are affected.

Older people have - understandably - been at the centre of attention during the pandemic, as COVID affects them more directly. Now that large parts of the older population (in the Global North) are effectively shielded by vaccination, attention is turning to young adults - a group that has been largely neglected or even vilified.

The quote 'We're supposed to be crossing over.....but the bridge is broken," that comes from one of the research participants is apt - the sense that 'the bridge is broken' at a crucial stage when major transitions are supposed to happen in their lives. In terms of such critical junctures and transitions, young adults are vastly more affected than older people, and the reverberations of the disruption to some will last decades.

Young adults are disadvantaged in facing the pandemic in several different ways. They have not yet developed the coping mechanisms and perspective that allow for, by and large, more successful regulation of negative affective states - whereas older adults have such 'armour' due to their longer time perspective and greater accumulated experience and resources.

KEY FINDINGS OF THE RESEARCH

Participants of the study:

- demonstrated a keen awareness of their mental health, adopting self-care practices such as mindfulness.

- reported positive experiences of life in their 'lockdown homes' with supportive families.

- (some) were embarking on normative adult pathways sooner than anticipated while others opted for postgraduate study to bide time.

- reported heightened worry and anxiety, and most had limited their media use in response.

- experienced a degree of resignation as their plans did not extend beyond the immediate future.

- accepted strict constraints associated with the management of the pandemic in Ireland during the early stages of the pandemic.

- did not view themselves as members of a group that was likely to experience the long-term costs of the pandemic but rather were attempting to negotiate their own pathway through labour market uncertainty.

- demonstrated high levels of solidarity towards family members and other vulnerable groups in society.

Professor Virpi Timonen, School of Social Work and Social Policy, Trinity College and Senior Author said:

" At the start of the pandemic, I found the absence of attention to young adults quite baffling and alarming, and this sense grew as it became clear that the pandemic was going to last for a long time and as the associated restrictions turned out to be comparatively long-lasting and extensive in Ireland.

Working in third-level education, I am attuned to the importance of the final year of college and the immediate aftermath of graduation as a juncture that can have a profound impact on subsequent trajectories. Young adults have - relative to older age groups - weak resources to adapt at a point in their lives that is especially crucial for subsequent social integration and employment pathways.

The fact that this group has received very little positive attention from policymakers is alarming as young adults are the future of any society and extended disruptions in their developmental pathways carry a long-term cost not just to the individuals but society as a whole."

Professor Timonen makes some recommendations for moving forward to limit the damage to young adults as we move beyond the COVID crisis. She said:

" Young adults have paid a high price in the form of foregone opportunities for education, social networks, and labour market integration; yet the large majority continue to evince astonishing levels of solidarity towards older and other vulnerable groups in society. However, the adverse impacts of the pandemic for many will continue for decades, in some cases throughout their lives. It is of utmost urgency for the future of Ireland to turn attention to normalising young adults' lives and ensuring that they have better labour market opportunities.

Among the strategies that I would propose, both arising from this research and in more general terms, include immediate initiation of systematic planning for a number of scenarios for the return to colleges in the autumn; programmes that combat loneliness at younger ages; greatly enhanced mental health supports; and much stronger focus on labour market openings at entry-level. In the absence of such measures, 'Generation COVID'' will struggle and some of its members might even become a lost generation."