Culture

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."

Researchers at the Francis Crick Institute and the Latvian Institute of Organic Synthesis have designed a drug-like compound which effectively blocks a critical step in the malaria parasite life cycle and are working to develop this compound into a potential first of its kind malaria treatment.

While drugs and mosquito control have reduced levels of malaria over recent decades, the parasite still kills over 400,000 people every year, infecting many more. Worryingly, it has now developed resistance to many existing antimalarial drugs, meaning new treatments that work in different ways are urgently needed.

In their research, published in PNAS, the scientists developed a set of compounds designed to stop the parasite being able to burst out of red blood cells, a process vital to its replication and life cycle. They found one compound in particular was highly effective in human cell tests.

"Malaria parasites invade red blood cells where they replicate many times, before bursting out into the bloodstream to repeat the process. It's this cycle and build-up of infected red blood cells which causes the symptoms and sometimes fatal effects of the disease," says Mike Blackman, lead author and group leader of the Malaria Biochemistry Laboratory at the Crick.

"If we can effectively trap malaria in the cell by blocking the parasite's exit route, we could stop the disease in its tracks and halt its devastating cycle of invading cells."

The compound works by blocking an enzyme called SUB1, which is critical for malaria to burst out of red blood cells. Existing antimalarials work by killing the parasite within the cell, so the researchers hope this alternative drug action will overcome the resistance the parasite has acquired.

Importantly the compound is also able to pass through the membranes of the red blood cell and of the compartment within the cell where the parasites reside.

The team is continuing to optimise the compound, making it smaller and more potent. If successful, it will need to be tested in further experiments and in animal and human trials to show it is safe and effective, before being made available to people.

Chrislaine Withers-Martinez, author and researcher in the Malaria Biochemistry Laboratory, says: "Many existing antimalarial drugs are plant derived and while they're incredibly effective, we don't know the precise mechanisms behind how they work. Our decades of research have helped us identify and understand pathways crucial to the malaria life cycle allowing us to rationally design new drug compounds based on the structure and mechanism of critical enzymes like SUB1.

"This approach, which has already been highly successful at finding new treatments for diseases including HIV and Hepatitis C, could be key to sustained and effective malaria control for many years to come."

Multiple sclerosis, or MS for short, manifests itself slightly differently in each person - which is why some call it "the disease of a thousand faces." Arguably the worst manifestation of MS is its chronic progressive form. Unlike the more common relapsing-remitting variant (RRMS), in which sufferers are often symptom-free for months or even years, patients with the primary progressive form of the disease (PPMS) see their condition steadily deteriorate with no remissions.

Poorly insulated neurons die off

Today's therapeutic approaches are based on the assumption that the immune system is making a mistake and waging an inappropriate attack on the layer of myelin that surrounds and insulates the nerve cells' long, cable-like branches called axons. "In progressive MS, neurodegenerative processes steadily multiply and cause more and more neurons in the brain and spinal cord to die," explains Dr. Alexander Brandt, lead author of the study that has now been published in the journal JAMA Neurology. "However, we still do not know what exactly causes this disease variant."

Together with Professor Friedemann Paul from the Experimental and Clinical Research Center (ECRC), a joint institution of Charité - Universitätsmedizin Berlin and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), as well as eleven colleagues from Berlin, Irvine and Toronto, Brandt now hopes he has shed some more light on the subject. As the team reports in their study, it appears that the simple sugar N-acetylglucosamine, or GlcNAc for short, could play an important role in the development of progressive MS. Inside an organism, GlcNAc and other sugar molecules attach to proteins on the cell surface in the form of chains. This mechanism, which is known as glycosylation, controls various cell functions by forming branched structures from these sugar chains.

The sugar molecule could serve as a biomarker

"We studied 120 subjects from Irvine and were able to show that, in this particularly severe form of the disease, there are significantly lower concentrations of N-acetylglucosamine in the blood serum than there are in healthy people or patients with relapsing-remitting MS," reports Brandt. At the time of this study, the physician was head of the Translational Neuroimaging laboratory in Paul's Clinical Neuroimmunology group at Charité. Brandt has since moved to the School of Medicine at the University of California, Irvine (UCI) as an associate professor of neurology, but remains a guest researcher at Charité.

"In another study of 180 patients from Berlin with relapsing-remitting or progressive MS, we also found that low serum levels of GlcNAc are associated with the development of the progressive form of the disease, clinical disability and neurodegeneration," adds the study's corresponding author, Professor Michael Demetriou of UC Irvine. "This opens up potential new avenues for identifying, at an early stage, which patients are at higher risk of progressive MS and adjusting their treatment accordingly."

Human treatment studies now in the pipeline

Back in autumn 2020, Brandt, Demetriou and other researchers working with the then lead author Dr. Michael Sy from UC Irvine published a study in the Journal of Biological Chemistry. They had administered GlcNAc to lactating mice and found that the animals passed on this simple sugar, which incidentally is also contained in human breast milk, to their offspring. This stimulated primary myelination of the neuronal axons in the young animals. "We also observed in the mouse experiments that N-acetylglucosamine activates myelin progenitor cells, thus promoting both primary myelination and the repair of damaged myelin," says Brandt.

The researchers therefore hope that GlcNAc not only has potential as a suitable biomarker for progressive MS, but could also pave the way for new therapeutic strategies. "Our hope is that we can use GlcNAc and the associated glycosylation mechanism to promote myelin repair and thus reduce neurodegeneration," summarizes Brandt. An initial, as-yet-unpublished phase I trial has just been completed with around 30 subjects, where the scientists investigated the safety of taking GlcNAc in certain doses. If it is shown to be safe, the scientists hope to be able to conduct further studies into this simple sugar's possible efficacy as an MS therapy.

A giant mosasaur from the end of the Cretaceous period in Morocco that could have reached up to eight metres long is the third new species to be described from the region in less than a year, bringing the total number of species up to at least 13.

The high diversity of the fauna shows how mosasaurs, giant marine lizards related to snakes and Komodo dragons, thrived in the final million years of the Cretaceous period before they, and most of all species on Earth, were wiped out by the impact of a giant asteroid 66 million years ago.

The new species, named Pluridens serpentis, had long, slender jaws with over a hundred sharp, fanglike teeth to grab small prey like fish and squid. Compared to related species, it had small eyes, suggesting poor vision. But the snout had dozens of openings for nerves, hinting at the ability to hunt by sensing water movements and changes in pressure. These nerves may have been sensitive to tiny variations in water pressure, an adaptation seen in sea snakes.

"Typically, when animals evolve small eyes, it's because they're relying more heavily on other senses," said Dr Nick Longrich, senior lecturer at the Milner Centre for Evolution at the University of Bath, who led the study.

The fact that Pluridens had so many nerves in the face may mean that it was using changes in water pressure to detect animals in low-light conditions, either at night or in deep, dark water. Mosasaurs may also have had other senses at their disposal.

"If it wasn't using the eyes, then it's very likely that it was using the tongue to hunt, like a snake," he said. "Many aquatic snakes and lizards - sea snakes, filesnakes, water monitors- flick their forked tongues underwater, using chemical cues to track their prey. Mosasaurs would have resembled whales and dolphins, so it's tempting to assume they lived like them.

"But they're very different beasts - they're huge lizards - so they probably acted like them."

While most of its relatives were small, just a few meters long, Pluridens got big, perhaps eight meters long. The largest individuals had thick, heavily built jawbones.

"It's possible that big males were fighting with these jaws," said Dr Longrich. "In some beaked whales, the males have massive jaws they use to fight with, and male sperm whales can be highly aggressive. Some Pluridens jaws show healing injuries, which suggests some violent fights."

The Moroccan mosasaurs were wildly diverse. Some had small teeth for seizing fish and squid, others evolved blunt teeth to crush crustaceans, clams, and ammonites, while others had teeth designed to cut or tear apart other marine animals - including other mosasaurs.

Pluridens brings the number of mosasaurs known from latest Cretaceous of Morocco up to 13, but the researchers suggest it's unlikely to be the last new species.

Dr Longrich said: "The diversity in these fossils is just astonishing. Far from declining in diversity, the mosasaurs seem to be peaking just before they went extinct.

"We're not seeing any evidence that this group was struggling before they went extinct - From an evolutionary standpoint, they were succeeding, they did everything right- but nothing can prepare you for an asteroid."

Co-author on the study, Dr Nour-Eddine Jalil from the Natural History Museum of Sorbonne University (France) said: "It's a new species of a large predator which, with its eight metre length, comes to confirm the diversity of the faunas of the seas just before the Cretaceous crisis.

"Pluridens serpentis highlights the importance of the paleontological heritage of Morocco to help illustrate the history of life."

Dr Nathalie Bardet, a specialist in mosasaurs, particularly those from the Phosphates of Morocco, at the Muséum National d'Histoire Naturelle of Paris, was also co-author on the paper.

She said: "Working on this group of marine reptiles since more than 20 years, I never stop being surprised by the incredible diversity of these predators, who all lived there and shared the available space and food resources.

"These latest discoveries show perfectly that the list of species present here is far from being closed and that the future still holds great surprises and discoveries!"

A study published in the journal Scientific Reports reveals the genetic structure of the land snail Xerocrassa montserratensis and it provides new scientific tools for the improvement of the conservation of this endemic and threatened species in Catalonia. This land mollusc, identified in the late 19th century in the Montserrat mountain, has a reduced geographical distribution limited to the province of Barcelona, and it is a protected species in the area of the natural parks of Montserrat and Sant Llorenç del Munt i l'Obac.

The study is led by the lecturer Marta Pascual, from the Faculty of Biology and the Biodiversity Research Institute of the University of Barcelona (IRBio), and signed by Cristina Català (UB-IRBio), Vicenç Bros (Barcelona Provincial Council), Xavier Castelltort (University of Lleida), and Xavier Santos (Research Center in Biodiversity and Genetic Resources - CIBIO, Portugal). Both the paper and its publication received the collaboration of the team of the Office of the Natural Park of Sant Llorenç del Munt i l'Obac, and the economic support of the Technical Office of the Natural Parks from the Barcelona Provincial Council park network.

An endemic species described more than a hundred years ago in Montserrat

The species Xerocrassa montserratensis --previously named Helix montserratensis--, is a uniqueness of the terrestrial malacological fauna in Catalonia described by Joaquín González Hidalgo in 1870 in the Montserrat mountain. Also, in the late 19th century, Artur Bofill had described two sub-species according to the morphological character of the shell: X. m. betulonensis and X. m. delicatula.

This Catalan endemism, considered to be an excellent model in phylogeographical studies, is found in open spaces of typical bare stony slopes of conglomerate lithology, but not in forestal areas. Surprisingly, the species was detected in areas that had been previously burnt, "which would indicate a high ability to survive or colonize which is not described yet in the scientific literature", notes the expert Xavier Santos, from CIBIO.

As part of the research study, the team applied the methodology based on the so-called DNA barcoding, which uses a short and standardized fragment of DNA --in this case, the mitochondrial gen Cytochrome Oxidase I (COI)-- to facilitate the identification of species and detection of differenced evolutionary groups. This methodology allows researchers to classify most of the species with a high resolution, and in many cases, it provides a great intraspecific variability to detect barriers in the genic flow between populations.

"Since these molluscs have a low mobility, from the from a scientific perspective it was quite interesting to determine whether this endangered species had a populational structure", reveals Marta Pascual, lecturer at the Department of Genetics, Microbiology and Statistics.

The study enabled the researchers to test the hypothesis from a hundred years ago, which related the population of the mountain chain of Marina --in the Catalan littoral mountain chain-- with populations in the upstream waters in the Besòs River.

The team identified genetic groups in areas where different sub-species had been described, a hypothesis that had been under doubts recently by several morphological studies. The results show that the genetically differenced groups are in those populations where the different sub-species had been described more than a century ago. Moreover, researchers also identified a new area where the groups are strongly differenced --Munts, in the Catalan transversal mountain chain--, which should be studied in detail in future studies.

"Our study provides information favouring the validity of these sub-species but we need to advance with the research studies and to conduct morphometric and genomic studies to determine whether there is a reproductive isolation among the different mitochondrial groups", notes Marta Pascual.

A genetic diversification situation during the Pleistocene

According to the authors, the process of diversification of the genetic groups --combined with the specificity of their natural habitat-- could be related to the geological and paleoclimate processes during the Pleistocene, which finally contributed to shaping the current genetic structure of the species. These processes could explain the origins of the vast radiation of species of the gender Xerocrassa in some Mediterranean islands, such as Crete or the Balearic Islands, as stated by the authors.

"It is shocking to find that close populations are that genetically differenced, and at the same time, that a species with such a reduced distribution area can present genetically differenced groups at a mitochondrial level", notes Xavier Santos.

Skeletal muscles make a tremendous variety of actions stabilizing the body in different positions. Despite their endurance during daily activities, they can undergo several mild injuries caused by sport, accidental overstretching, or sudden overtwisting. Luckily mild injuries can be quickly healed; however, when a large part of muscles is damaged or resected surgically, the full recovery can be impossible. Muscle regeneration is challenging, but the development of innovative biocompatible materials tackles that problem. Recently, a multinational team of scientists led by dr. Marco Costantini from the Institute of Physical Chemistry, Polish Academy of Sciences (IPC PAS), and dr. Cesare Gargioli from the University of Rome Tor Vergata (Italy) presented a biofabricated myo-substitutes to restore significantly injured skeletal muscles with unprecedented efficiency.

3xM - muscles, myofibers, and myogenesis

Muscles are the largest tissue in the body. They are essential for motion, and without them, we would be unable even to stand up, walk or pick a food from the table. Every day, our muscular system performs an endless variety of movements that engage millions of fiber-like tissues into the contracting, shortening, returning to their original shape, relaxing, and even lengthening passively when the other muscles contract. There are two types of muscles: involuntary and voluntary muscles. Involuntary muscles are automatically controlled by the brain, like the muscles shrinking during heartbeats or breathing, while voluntary muscles are actioned when deciding to make a move. Some of them are short like muscles in the ear, while others are long, like the calf muscle controlling the ankle, foot, and toes movement. Each one is highly resistant to stretching and pressure, while there are some limits to their performance. Likewise all tissues in the body, muscles can be injured. Sudden pulling or twisting occurring by accident or in sports can lead to muscle strains, tears, or even ruptures. In some diseases like cancers, dystrophy, or mechanical damage, they can be affected entirely or mechanically cut.

Despite our body's impressive ability to regenerate itself daily, skeletal muscles in some cases cannot be fully revived. When they are damaged, just after the inflammation and swelling, the body tries to bundle, contracting individual muscle fibers step by step, activating them to grow. These tiny fibrils called myofibers are generated to create the new muscle tissue within the myogenesis process. When the muscles' damage is slight, they can recover completely, although repairing significant mass defects complicates the total healing. That makes muscle restoration and their functionalities improvement one of the biggest biomedical challenges of our times.

Let's get starting - regeneration in progress.

Recently, Marco Costantini from IPC PAS with a multinational team presented a biofabrication solution to tackle volumetric muscle loss. They have created a biocompatible spaghetti-like gel resembling a native muscle structure that can be easily made using a 3D bioprinting process. Researchers have synthesized such a gel from an aqueous solution containing natural polymers and encapsulated muscle progenitors, forming a matrix for natural fibers growth. Such highly biomimetic gel was created using a new bioprinting platform that combines a microfluidic printing head with a wet-spinning technology.

Dr. Marco Costantini remarks, "Our bioprinting system has been envisioned to precisely mimic the highly anisotropic architecture of skeletal muscles, resulting in an improved guidance and differentiation of muscle progenitors into functional structures".

Then, the gel was pre-cultured for a week in vitro to stimulate cell growth and then was implanted into the damaged tissues of a mouse patient having resected muscle. The injury presented in this work was significant as it would need up to several months for healing without restoring the full spectrum of initial functions. The bioprinted skeletal muscle substitute enabled restoring up to 90% of the actual functionalities. Moreover, the muscles were recovered within just 20 days making the synthesized gel a promising material for biomedical application supporting tissue regeneration.

"Restoring the mass and functionalities of a 90% ablated muscle in just 20 days is an absolute record that motivates us in further exploring this approach in the near future. Now, we need to upscale our platform to biofabricate constructs that could support the regeneration of muscles in large-size animals, proving that this technology could be ready in a reasonable time for clinical use in humans." - claims dr. Marco Costantini

The technology presented by scientists from IPC PAS makes it possible to bioprint living materials on-demand, offering a new alternative of a faster and better recovery to those who suffer from severe skeletal muscle mass loss.

The research was published on 15th February in EMBO Molecular Medicine, opening new horizons for the regeneration of tissues that would not be recovered at all in natural conditions.

This study was supported by the National Science Centre Poland (NCN) within SONATA 14 Project No. 2018/31/D/ST8/03647 to dr. Marco Costantini.

Tuberous Sclerosis Complex (TSC) affects between one and two of every 10,000 new-born babies. This genetic disease leads to the formation of benign tumours which can massively impair the proper functioning of vital organs such as the kidneys, the liver and the brain. The disease affects different patients to varying degrees and is triggered by mutations in one of two genes, the TSC1 or TSC2 gene. An interdisciplinary team of researchers led by biochemists Prof. Daniel Kümmel and Dr. Andrea Oeckinghaus from the University of Münster (Germany) examined the "tumour suppressor protein TSC1" and, for the first time, gained insights into its hitherto unclear functions. The team identified a new mechanism, in a central cellular process, which regulates cell growth. The results can also help in understanding how Tuberous Sclerosis Complex arises. The results of the study have now been published in the journal Molecular Cell (advance publication online).

Mutations concern a "burr effect"

The TSC1 protein and the TSC2 protein together form the TSC protein complex. This has the task of controlling cell growth and, as a result, of suppressing the emergence of tumours - hence the term "tumour suppressor". Previously, it had largely been unclear what the functions of TSC1 were. Similarly, little was known about the mechanism which is affected by certain mutations in the TSC1 gene in the occurrence of the disease. The researchers have now found out that one part of the TSC1 protein, a so-called domain, can bind to the surfaces of lysosomal membranes. Lysosomes are small compartments in the interior of the cell, surrounded by a membrane, which contain digestive enzymes. On their surface there are certain control centres which are important for the regulation of cell growth. The TSC1 protein ensures that the entire TSC complex arrives at these control centres and prevents any uncontrolled cell growth by inhibiting the activity of an important signal protein called "mTOR" - "Mechanistic Target of Rapamycin".

"In this process," Daniel Kümmel explains, "TSC1 uses a strategy reminiscent of the principle of the burr. The burr's individual hooks stick to material only very weakly, but lots of hooks together provide a firm attachment." The study shows that TSC1's individual membrane binding domain only forms a weak attachment. However, a strong attachment becomes possible with a controlled aggregation of a large number of TSC1 molecules. "Mutations occur particularly frequently in the membrane binding domain," says Andrea Oeckinghaus. "We assume that some of the pathogenic effects can now be explained by a loss of the correct localization of the TSC complex."

Membrane component regulates cell growth

Another discovery the team made is that the properties of the membrane surface can influence the way the TSC complex functions and, as a result, the growth processes in the cell. More precisely, the team identified a special component in the membrane: a lipid called phosphatidylinositol 3,5-bisphosphate (PI3,5P2), which is necessary for the activity of the TSC complex. Depending on how often it occurs on the membrane's surface, it has different effects on the activity. "As the production and breakdown of this lipid are regulated," says Daniel Kümmel, "this opens up entirely new perspectives on how cell growth can be controlled. This means that our results are an exciting starting point for further studies."

The team of researchers used a broad range of methods in its investigations, starting from approaches using structural biology and biochemistry, and also involving cell-biological experiments. "The resulting insights into mechanistic and physiological aspects were only possible through our interfaculty collaboration," says Kümmel.

The work was carried out jointly by the team headed by Dr. Andrea Oeckinghaus (Münster University Faculty of Medicine and Münster University Hospital, Institute of Molecular Tumour Biology) and the team led by Prof. Daniel Kümmel (Münster University Faculty of Chemistry and Pharmacy, Institute of Biochemistry). Important contributions were made by partners at the Max Planck Institute for the Biology of Ageing, Cologne (team headed by Dr. Constantinos Demetriades) and at the Max Planck Institute for Molecular Physiology, Dortmund (team led by Prof. Stephan Raunser).

Meat that is certified organic by the U.S. Department of Agriculture is less likely to be contaminated with bacteria that can sicken people, including dangerous, multidrug-resistant organisms, compared to conventionally produced meat, according to a study from researchers at the Johns Hopkins Bloomberg School of Public Health.

The findings highlight the risk for consumers to contract foodborne illness--contaminated animal products and produce sicken tens of millions of people in the U.S. each year--and the prevalence of multidrug-resistant organisms that, when they lead to illness, can complicate treatment.

The researchers found that, compared to conventionally processed meats, organic-certified meats were 56 percent less likely to be contaminated with multidrug-resistant bacteria. The study was based on nationwide testing of meats from 2012 to 2017 as part of the U.S. National Antimicrobial Resistance Monitoring System (NARMS).

In order for meat to be certified organic by the USDA, animals can never have been administered antibiotics or hormones, and animal feed and forage such as grass and hay must be 100 percent organic. A longstanding concern about antibiotic use in livestock and livestock feed is the increased prevalence of antibiotic-resistant pathogens. To monitor this trend, in 1996 the federal government developed NARMS to track antibiotic resistance in bacteria isolated from retail meats, farmed animals, and patients with foodborne illness in the U.S.

For their study, the Bloomberg School research team analyzed U.S. Food and Drug Administration-NARMS data from randomly sampled chicken breast, ground beef, ground turkey, and pork for any contamination and for contamination by multidrug-resistant organisms. The analysis covers four types of bacteria: Salmonella, Campylobacter, Enterococcus, and Escherichia coli.

The study covered a total of 39,348 meat samples, of which 1,422 were found to be contaminated with at least one multidrug-resistant organism. The rate of contamination was 4 percent in the conventionally produced meat samples and just under 1 percent in those that were produced organically.

The study was published May 12 in Environmental Health Perspectives.

"The presence of pathogenic bacteria is worrisome in and of itself, considering the possible increased risk of contracting foodborne illness," says senior author Meghan Davis, DVM, PhD, associate professor in the Department of Environmental Health and Engineering at the Bloomberg School. "If infections turn out to be multidrug resistant, they can be more deadly and more costly to treat."

The analysis also suggested that the type of processing facility may influence the likelihood of meat contamination. Meat processors fall into three categories: exclusively organic, exclusively conventional, or those that handle both organic and conventional meats--so-called "split" processors. The study found that among conventional meats, those processed at facilities that exclusively handled conventional meats were contaminated with bacteria one-third of the time, while those handled at facilities that processed both conventional and organic meats were contaminated one-quarter of the time. The prevalence of multidrug-resistant bacteria was roughly the same in these two meat processor categories.

"The required disinfection of equipment between processing batches of organic and conventional meats may explain our findings of reduced bacterial contamination on products from facilities that process both types of meats," says Davis.

The authors believe their findings have relevance for regulatory agencies and consumers. "How we raise animals matters," says Davis. "As a veterinarian, I recognize that we sometimes need to use antibiotics to treat sick animals, but taking advantage of opportunities to reduce antibiotics use could benefit everyone. Consumer choice and regulatory oversight are two strategies to do this."