Pseudoislet system expected to advance pancreas and diabetes research

The multicellular, 3-D structure of human pancreatic islets—the areas of the pancreas containing hormone-producing or endocrine cells—has presented challenges to researchers as they study and manipulate these cells’ function, but Vanderbilt University Medical Center researchers have now developed a pseudoislet system that allows for much easier study of islet function.

A pancreatic islet is composed primarily of beta cells, alpha cells and delta cells, but also includes many supporting cells, such as endothelial cells, nerve fibers and immune cells, which act in concert as a mini organ to control blood glucose through hormone secretion. Insulin, secreted from beta islet cells, lowers blood glucose by stimulating glucose uptake in peripheral tissues, while glucagon, secreted from alpha islet cells, raises blood glucose through its actions in the liver.

Dysfunction of these islet cells is a primary component of all forms of diabetes, and a better understanding of this dysfunction can lead to improved treatment and management of the disease. Vanderbilt scientists and others around the world have identified potential targets for diabetes using both mouse models and human tissue, however the lack of a system to manipulate these pathways in human islet cells has limited the field.

The VUMC team led by Marcela Brissova, Ph.D., research professor of Medicine and director of the Islet Procurement and Analysis Core of the Diabetes Research and Training Center, began attempting a protocol for the pseudoislet system in 2016, performing countless trials. In late 2017, Rachana Haliyur, then a Vanderbilt MD/Ph.D. student, combined media containing factors that support vascular cells and endocrine cells into what the group named the Vanderbilt Pseudoislet Media. The team watched as the cells began reaggregating, or organizing themselves in a way that resembled native islets.

“A lot of things in science happen serendipitously, and this was one of those,” said Brissova. “We tried and failed many times, and basically it came down to the media we used for our cells. In our recent publication, we have provided all experimental details and our protocol so others can make the media and create pseudoislets in their own laboratories.”

Because of the complex structure of the human islet, it is difficult to introduce and manipulate cells past the first cell-layer of the islet sphere. The pseudoislet system allows investigators to separate the pancreatic islet into single cells, introduce a virus into the cells which allows genetic manipulation and then combine the cells back together again into a pseudoislet. This allows researchers to target certain cell types or replicate changes happening in disease and study them in the 3-D environment of the islet.

John “Jack” Walker, an MD/Ph.D. student in the Powers & Brissova Research Group, continued to refine the pseudoislet system protocol and was co-first author on a recent study based on the system published in JCI Insight, an open access journal published by the American Society for Clinical Investigation (ASCI).

The pseudoislet system allowed the VUMC investigators to more clearly examine intracellular signaling pathways, allowing genetic manipulation of those pathways to change their function and better understand how insulin and glucagon secretion are altered with that manipulation. They determined that activation of Gi protein signaling reduced insulin and glucagon secretion while activation of Gq protein signaling stimulated glucagon secretion but had both stimulatory and inhibitory effects on insulin secretion.

In addition, this approach allowed the scientists to introduce biosensors into the islet cells to measure intercellular signaling events within the cells and better understand how those are linked to hormone secretion.

Another advance was the combination of the pseudoislet system with a unique microfluidic device, developed by co-authors Matthew Ishahak and Ashutosh Agarwal, Ph.D., from the University of Miami, that allowed the investigators to simultaneously document the changes in both calcium ions and hormone secretion.

“The exciting thing about this approach is that we both deconstruct the islet for our manipulation and reconstruct it to understand functional consequences at a larger level,” Walker said. “Since we put the islet cells back together, we can look at both insulin and glucagon secretion, but in a coordinated manner. Both of the secretion profiles measured are reflective of intra-islet interactions that are happening as well.”

This work greatly benefited from the research environment and infrastructure at Vanderbilt, particularly the National Institutes of Health (NIH)-funded Diabetes Research and Training Center (DRTC) and the Vanderbilt Cell Imaging Shared Resource.

“Another research direction will be creating pseudoislets that replicate a specific disease state, such as pseudo-islets that look like native islets from an individual with type 1 diabetes,” Haliyur said.

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The good, the bad, and the ugly of coming off antidepressants

The world has changed a lot in the three and a half years since I started taking antidepressants. I’ve changed a lot, too.

Like most people who are prescribed medication to manage their mood, taking selective serotonin reuptake inhibitors (SSRIs) — a type of antidepressant — was never really my Plan A. Nor was it my plan B, or even C. it was more like a Plan Z — after all other options had been exhausted.

And I was exhausted, too. Crippled by acute anxiety, sleeplessness, intense panic attacks, and unable to cope with even the most basic of my day-to-day responsibilities, SSRIs looked like a raft to safety. 

But like many other people I feared that once I began taking them I’d never be able to stop – that I’d become dependent. That I wouldn’t be able to function without them. It is only now that I feel ready to confront that fear head on – so this month I decided to finish my prescription for the last time. 

My life has changed so dramatically and in such a positive way since I began taking them that I had started to wonder. Had I really changed all that much? What was down to me and what was down to the drugs? 

What started as a small curiosity soon felt much more like a burning question. Added to that was the side effects of the drugs, which though not life-altering, I’d prefer not to experience if I don’t need to. These included lethargy, weight gain, jaw grinding and issues reaching orgasm. 

They were tolerable, and small sacrifices for being able to live a full and healthy life — but I wanted to feel energised again.

While SSRIs protected me from the intensity of the shocks and blows of life, they also had the same blunting effect on the highs. After meeting someone during lockdown (I know) and suddenly being in the throes of a new romance, I felt ready to be more present with my feelings. I wanted to make sure I experienced them in all of their colour, depth and intensity.

When I began taking antidepressants, there was no doubt that I needed help. After being sent home from work after a particularly dramatic panic attack that caused me to collapse in the middle of my office — I was no longer able to pretend. 

‘You can continue battling this yourself and be patient,’ my GP said to me, ‘and you will feel better eventually…. or you can take these pills and within six weeks things are likely to feel much, much more manageable.’

I was under pressure to return to work and in my desperation, lacking the requisite confidence to even believe I could get better alone — this felt like a glimmer of hope, some relative certainty onto which I could cling. 

And so I took the drugs. I surrendered to the help offered, went back to work alongside regular therapy, and quietly waited to feel the effects.

Things really did get better — not because the pills somehow removed my sadness or anxiety, but because I was finally strong enough to be able to do the work

A lot of people assume that taking antidepressants will make you happy. That you’ll wake up one day and everything will be great without you having had to work for it. It would be nice, wouldn’t it? I didn’t know what to expect, but reasoned that anything would be better than the tortuous panic that had taken over my life.

I can’t speak for everyone, but for me the road to recovery was much, much messier. One of the side-effects that’s less well known to those without personal experience is that in the first six weeks or so of beginning treatment, your symptoms can actually get worse. 

Eventually though, things did get easier. The weight of panic began to lift a little from my chest — although it never truly disappeared. I was able to laugh for the first time in months, to concentrate for long enough that I could begin to vaguely follow the plot of TV shows (although only ones I’d seen before).

I could engage in conversation and hear about other people and challenging things that were going on with them, without then fearing that the same thing would happen to me. But my brain was still alert – like fly paper where new ideas of things to worry about could get stuck and cause me to overthink.

Eventually, CBT – a therapeutic process that helps you to challenge negative thinking patterns and therefore change your emotional responses and behaviour – helped me to get to a place where I could recognise that what was going on with me was more than just a spell of difficult mental health.

This allowed me to feel comfortable enough to get a formal psychiatric assessment, where I was diagnosed with post-traumatic stress disorder (PTSD) and obsessive compulsive disorder (OCD) — the latter of which had become a coping mechanism to deal with the former.

My meds were increased and things really did start getting better — but not because the pills somehow removed my sadness or anxiety. It’s because I was finally strong and stable enough to be able to do the work involved to feel better.

They cushioned the blows, but didn’t eliminate them altogether. And staying healthy was – and still is – a lot of work.

I’m being explicit here because – despite progress in our general understanding of mental health as a society – there is still so much misinformation, particularly when it comes to medical intervention and prescription drugs.

Popular culture and mass media have done a lot of damage to the common perception of antidepressants as ‘happy pills’ – and I therefore bear a large amount of responsibility for correcting this, one column at a time.

There’s never a good time to come off antidepressants, but there definitely is a bad time. Many mental health professionals would advise you not to come off them in the winter (particularly in the northern hemisphere), because Vitamin D plays such a huge part in boosting your mood.

You will also be advised to titrate as you come off – which means to slowly reduce your dose over a long period of time to avoid any extreme fluctuations in mood.

There have been three times over the past three years when my plans to come off the meds have been interrupted by stressful life events, either in my personal life  or, most recently, by  the Covid-19 pandemic. 

It’s not that I needed to come off them – many people stay on them forever, and that is up to them and their own needs. It’s an incredibly personal thing and everyone feels different. There’s no ‘one size fits all’.

But there was one morning about a month or so ago, after numerous conversations with my best mate, my doctor and my therapist about whether or not it was the right time, when I suddenly felt ready. And so instead of taking the full dose with my breakfast as usual, I snapped the pill in two and only took half.

I made sure to tell those closest to me so that they could keep an eye on me over the next few weeks as things were likely to get pretty bumpy emotionally.

A month has passed and I feel OK. I don’t feel catatonic, nor jubilant. Just OK.

I’ve felt the return of some intense feelings, for better or worse. I’ve had moments when my emotions feel a lot like looking out the window of an accelerating car as the outside world starts to blur into a mess of indistinguishable colours and shapes. I’ve had moments of crying where I can’t imagine ever feeling less sad. 

I’ve felt the return of some obsessive thinking and been crippled by indecision on a number of occasions. But in each and every such moment, I have used the tools and experience learned over the past few years to steady myself until things begin to feel more solid again.

I don’t know what the future holds, but I do know I’d never rule out going back on antidepressants.

And while I’m excited to close the door on what was an incredibly challenging period of my life and move forward with more awareness and healthier habits – there’s comfort in knowing those little pills would be there if ever I needed a helping hand again. 

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In nation’s 2 largest metros, Blacks and Latinos are more likely to die from COVID-19

A study published today by the UCLA Latino Policy and Politics Initiative found that Latino and Black residents of Los Angeles County and New York City are roughly twice as likely as white residents to die from COVID-19. The research also revealed that high-poverty neighborhoods in both regions have the highest rates of COVID-19 cases and COVID-19–related deaths.

Sonja Diaz, founding director of the policy initiative, said two significant reasons for those trends are that low-income Black and Latino people in both regions tend to have a greater need to work outside of the home and a greater reliance on public transportation, both of which put them at a greater risk for exposure to the coronavirus.

“We are now seven months into the pandemic, and we are starting to have clear information about the disproportionate health and economic impacts that communities of color are facing,” Diaz said. “It’s time to address the specific ways that COVID-19 hurts Latino and Black families and to protect our most vulnerable communities as the virus surges across the nation.”

In Los Angeles County, the age-adjusted death rate was 54 per 100,000 for Latino residents and 46 per 100,000 for Black residents, compared to 23 per 100,000 for white residents; in New York City, the age-adjusted death rates were 247 per 100,000 for Latino residents, 237 per 100,000 for Black residents and 120 per 100,000 for white residents.

The authors recommend that six measures be implemented immediately in cities with large populations of vulnerable communities:

  • Increase testing for low-income communities of color.
  • Provide access to health services and healthy food in low-income communities.
  • Add protections on public transportation, including providing hand sanitizing stations and free masks.
  • Expand access to health care and paid sick leave for essential workers.
  • Increase access to telehealth for low-income residents and the uninsured to bridge the lack of medical care.
  • Ensure that accurate race and ethnicity information is being collected so that elected officials and public health experts can understand the impact of COVID-19 in communities of color.

The researchers analyzed data from Los Angeles County and New York City, two areas that have been hard-hit during the pandemic and are home to large Latino and Black populations. They found that residents who didn’t have health insurance, lived in overcrowded housing conditions and had limited access to the Internet will encounter inequitable access to health care during the pandemic.

In addition, the authors found that people between the ages of 18 and 40 have the highest rate of infection in Los Angeles County; in New York, people over age 45 are most affected. Men in both regions have higher rates of infection than women.

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Teenagers: Less alcohol and cigarettes, more Cannabis

New data on the addictive behaviour of young people show positive developments, especially in the case of cigarettes: The Smoking rate of 12 – to 25-Year-old is on the lowest level in nearly 50 years. The number of young people who use Cannabis is on the rise.

Since the year 1973, the Federal centre for health education (BzgA) every year surveys on the Smoking behaviour, alcohol and cannabis use in the 12 – to 25-Year-olds in Germany. "The Figures in the smoke are more than erfreulich", Daniela Ludwig says, drug Commissioner of the Federal government. The proportion of young people between 12 and 17 years who smoke, with 5.6 percent to a new historic low. In the age group of 18 – to 25-Year-old Smoking with 21.2 percent as few as never before since the beginning of the BZgA-survey series. "To list just watch, we need to pipe the development of the consumption of E-products and water, even if currently there is no further consumption increases sind", Prof. Dr. med says. Heidrun Thaiss, Director of the BZgA.

Binge drinking is still on Trend

Even with alcohol, there are positive developments: at Least once a week alcohol 9.5 per cent of the surveyed 12 – to 17-Year-olds (2004: 21.2 percent) and 32.9 percent of 18 – to 25-Year-olds (2004: 43.6%) drink. Of concern, however, is that overall, too many young people drinking to alcohol intoxication. "This is in particular in the youth age dangerous. Here are increased common prevention is commitment erforderlich", so Thaiss. Over the years, the Trend of the noise is considered a drink, however, also declined.

Young people Smoking weed and more

Only the consumption of Cannabis, an increase is observed. "We see with concern. Cannabis is by far the most consumed illegal substance. This is of particular concern, since the consumption in adolescence linked with specific risks for growing organism ist", Thaiss says. Young people to educate about the health consequences of Cannabis, the government has a new prevention campaign "Drugcom" launched. "The launch of the social media, followed by new national prevention, with a focus on school. This prevention comes at just the right Zeitpunkt", so Ludwig.

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Long and light colored clothing protects you from ticks

In warm weather, ticks are active and waiting in nature to a blood meal. They are not covered by trees, as many erroneously believe, but from the look of the Grass and undergrowth to a host, including humans. Infectious ticks can transmit diseases, it makes sense to protect yourself from bites.

Tick bites by long clothing. Especially suitable bright clothing, because ticks are easy to discover. Repellents will keep ticks and other stinging insects away from your body, can additionally be applied. You can, however, provide no reliable protection. Who was in the nature of on-the-go, should change clothes and, especially in the knees, the groin, the inside of the Elbows and on the scalp are on the lookout for ticks. Measures can be found in spite of all precautions a tick on your body, so you can be with a pair of tweezers, forceps or a tick card removes ticks. It should grab the tick at the Stechapparat and your abdomen do not squeeze it, so that no pathogens from the tick to be pressed in the human bloodstream.

Lyme disease and TBE by ticks

Of ticks before the two diseases can also be transferred to The Lyme disease and tick-borne encephalitis (TBE). In the case of Lyme disease, a wall redness occurs with the engraving around often, a circular, sharply demarcated redness, spreading ring-shaped. More fatigue, head and muscle pain as well as fever may occur. Later on, nerve pain and joint inflammation can be added. The infection can be treated with antibiotics, which should be done soon after the bite. About 30 percent of ticks are Carriers of this disease.

Against TBE is vaccination. This is especially useful if you live in high-risk areas, such as Bavaria and Baden-Wuerttemberg or vacation want to make. Also people who have professionally a lot to do in the woods or go hunting, should be vaccinated, because the virus disease can cause severe inflammation of the nerves and meninges forth.

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What is numerology and how does it work?

You already believe, at least a little bit, in numerology, if you have a lucky number and think there’s truth to expressions like, “bad things happen in threes.” Numerology is the mystical study of numbers, and similar to astrology, believers say it can offer insights on everything from personality traits to what the future holds (via Allure). If you’re intrigued by numerology, you’re in good company; celebrities ranging from Cardi B to Taylor Swift to Jay Z and Beyoncé have embraced this ancient practice (via Fader), which was founded by ancient Greek mathematician Pythagoras (of the famed Pythagorean theorem.) 

Pythagoras’ ah-ha moment that (a² + b² = c²) was something we all had to learn in high school math, but most of us did not learn the more “New Age” theory that this grandfather of mathematics posited: that certain numbers have specific personal, spiritual and predictive meaning to us. Explained numerologist Felicia Bender: “Numbers carry with them not only a quantitative value, like one apples, two apples, three apples, but also a vibration and a frequency,” she told Women’s Health.

So how can you apply the principles of numerology to better understand your life?

Numerology can give you insight into your life

Your life path number is similar to a horoscope birth chart and will be the basis of all of the numerology insights about your life. You can calculate yours by adding up the numbers in your birthdate. If you end up with double digits, you keep adding together those digits until you reach a single number. So if your birthday is June 5, 1995, you start with your birth year, and add 1+9+9+5, getting the sum of 24. Then you add 2+4 to get 6. You would add to 6 the 6 for June and 5 for the fifth, resulting in 17, or 1+7. That gives you a life path number of 8. Oh, 8. We see you, you overachiever, you (via Numerology.com).

Not sure if you’re doing the math right? There are a number of free numerology calculators online. Once you know your life path number, you will have pre-ordained suggestions for your optimal career paths, what to look for in a romantic partner, and yes, what your lucky number actually is for when you’ve got a lottery ticket or a roulette wheel to spin (via How Stuff Works.

But note that this number is just the tip of the iceberg when it comes to numerology; your name also tells a story, as each letter in the alphabet has a numerical value (A=1, B=2, etc.) A psychic advisor can combine these insights with a tarot deck, birth chart and other tools in a more formal reading. If you believe in that stuff, that is. 

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Ability to eliminate spent proteins influences brain aging and individual life span

Aging is the main risk factor for dementia and Parkinson’s disease. As age progresses, toxic protein aggregates pile up in the brain and impair neuronal function. But why does that happen? An international team of scientists coordinated by the Leibniz Institute on Aging—Fritz Lipmann Institute (FLI) (Jena, Germany) and the Scuola Normale Superiore (Pisa, Italy) found answers by studying the brain of the turquoise killifish (Nothobranchius furzeri) brains. They delineate a timeline of molecular events during aging that is triggered by the early reduction of proteasome activity and culminates in aggregates formation. Remarkably, fish that preserve proteasome levels during aging live longer.

Protein homeostasis refers to the processes involved in the synthesis, folding, trafficking, location, and degradation of the entire set of proteins in the cell—the proteome. This complex network regulation is essential for all living organisms and its disturbance contributes to age-related diseases and influence life span.

Neurodegenerative diseases such as Alzheimer’s, ALS, and Parkinson’s are devastating conditions characterized by deterioration of neurons (nervous system cells) and/or spinal cord. These diseases have common features: they usually strike in mid to late-life and are accompanied by an accumulation of protein aggregates inside neurons. As a consequence of the increased age of our population, the percentage of people affected by these diseases increases steadily. Therefore, finding treatments to limit the damage of neurodegeneration is a pressing medical and societal need, and it critically depends on the understanding of how and why protein aggregates form during brain aging.

An international team led by researchers from the Leibniz Institute on Aging—Fritz Lipmann Institute (FLI) in Jena, Germany and the Scuola Normale Superiore in Pisa, Italy, together with the Centre for Misfolding Diseases in Cambridge, UK and the National Hellenic Research Foundation in Athen, Greece, has now used state-of-the-art transcriptomic and proteomic methods to investigate the chain of molecular events that lead to loss of protein homeostasis during brain aging. The researchers used Nothobranchius furzeri (killifish) as a model of aging to study mechanisms triggering protein homeostasis dysfunction. This fish species is the shortest-lived vertebrate bred under laboratory conditions—they have a life span of only 3—12 months! Age-dependent processes are exacerbated in this species, making it easier to detect changes in the concentration of RNAs and proteins, as compared to other model organisms. Also, aging induces in this fish pathological changes that mimic those typical of human aging, making it a practical vertebrate system for studying age-related neurodegenerative disorders.

During aging, proteins and RNAs become uncorrelated

“In order to identify the molecular events in the aging process that are responsible for the loss of protein homeostasis during brain aging, we used mass spectrometry-based proteomics in combination with RNA sequencing and analyzed protein aggregates in the brains of killifish of different ages,” says Dr. Alessandro Ori. The researchers analyzed brains of killifish from three different age groups: young sexually mature fish (5 weeks after hatching, wph), adult fish without aging characteristics (12 wph) and old fish that already showed signs of neurodegeneration (39 wph).

Messenger RNAs are used by the ribosome in the cell to synthetize proteins, which are biologically active molecules. “Measuring RNAs levels is easier that measuring protein levels and scientists very often measure changes in RNA levels under the assumption that the abundance of the corresponding proteins will change in a similar direction. The first result of our study is that during aging almost half of the proteins are regulated in opposite direction with respect to their corresponding RNA. This was a real surprise!” said Prof. Alessandro Cellerino from the Scuola Normale Superiore in Pisa, Italy. The study has now been published in the journal Molecular Systems Biology.

Age-related loss of the stoichiometry of essential protein complexes

“When comparing the data for the different age groups, we found that almost half of the approximately 9000 proteins that we managed to quantify are affected by aging,” says Dr. Alessandro Ori, group leader at FLI. These age-related changes result in abnormal regulation of proteins (subunits) that compose macromolecular protein complexes, the types of machinery responsible for all cellular activities. Protein complexes are built by different proteins that need to be assembled in specific ratios. Our cells have mechanisms to guarantee the proper building of these complexes by regulating the precise (stoichiometric) number of specific subunits. This tightly regulated process, however, is impaired in aging.

As Dr. Ori further explains, “there is a progressive loss of stoichiometry of protein complexes during aging, mainly affecting the ribosomes, which is one of the most important protein complexes in the cell, responsible for producing all other proteins.” The researchers demonstrated that ribosomes do not get adequately formed in old brains and aggregate, potentially influencing vital functions in the cell. Aggregation of ribosomes is not exclusive to killifish but also happens in mice, suggesting it is a conserved feature of brain aging.

Decrease in proteasome activity as an early sign of brain aging

“Ribosome aggregation is something devastating for cell survival. We wanted to understand what is causing it. More than that, we tried to find an early event during aging that triggers aggregates formation”, explains Dr. Erika Kelmer Sacramento, one of the first authors of the study that focused on the proteasome. Proteasomes are complexes of protein molecules that digest and recycle old or defective proteins and are an essential part of the protein homeostasis network (“garbage chipper” of the cell). The authors were able to show that proteasome activity is reduced early and progressively during the course of adult life and causes loss of protein complexes stoichiometry. They induced a reduction of proteasome activity during early adult life of the killifish using a specific drug for just four days and observed a premature aging signature including disrupted ratios of several protein complexes.

Low proteasome activity—short life span?

“As aging is the result of a chain of interconnected progressive events, it has been difficult to identify its early drivers. Decrease of proteasome activity is an early sign of brain aging, but is it relevant for aging of the entire organism? To answer this question, we correlated individual variations in proteasome activity with individual variations in lifespan,” explains Prof. Cellerino. So the team also compared the gene expression data of more than 150 killifish with their lifespan. The analysis showed that the individuals’ lifespan could be predicted based on changes in the expression of genes encoding for proteasomal proteins: fish that showed a greater decrease in proteasome transcripts at the beginning of life lived considerably shorter than fish able to maintain or increase proteasome expression. This finding supports the hypothesis that the reduction of proteasome activity is an early driver of aging in vertebrates.

“The FLI has made large investments in developing the killifish as a biological model. Our results show that this investment was well placed. The killifish revealed novel molecular aspects of aging: we were able to show for the first time that the maintenance of proteasome activity is an important factor for the correct stoichiometry of protein complexes involved in key biological functions such as protein synthesis, degradation, and energy production and ultimately for lifespan determination. These comprehensive results on RNA and protein regulation represent also a public resource that can be mined by scientific community, as it was the case for the genomic, transcriptomic and epigenetic resources previously generated at the FLI,” says Prof. Cellerino summarizing the most important results.

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UK modelling study finds case isolation and contact tracing vital to COVID-19 epidemic control

In the absence of a vaccine or highly effective treatments for COVID-19, combining isolation and intensive contact tracing with physical distancing measures—such as limits on daily social or workplace contacts—might be the most effective and efficient way to achieve and maintain epidemic control, according to new modelling research published in The Lancet Infectious Diseases journal.

Using social-contact data on more than 40,000 individuals from the BBC Pandemic database to simulate SARS-CoV-2 transmission in different settings and under different combinations of control measures, the researchers estimate that a high incidence of COVID-19 would require a considerable number of individuals to be quarantined to control infection. For example, a scenario in which 5,000 new symptomatic cases were diagnosed each day would likely require 150,000-200,000 contacts to be quarantined every day if no physical distancing was in place.

The study is the first time researchers have used social contact data to quantify the potential impact of control measures on reducing individual-level transmission of SARS-CoV-2 in specific settings. They aimed to identify not only what would theoretically control transmission, but what the practical implications of these measures would be in terms of numbers quarantined.

However, the authors note that the model is based on a series of assumptions about the effectiveness of testing, tracing, isolation, and quarantine—for example about the amount of time it takes to isolate cases with symptoms (average 2.6 days) and the likelihood that their contacts adhere to quarantine (90%)—which, although plausible, are optimistic.

“Our findings reinforce the growing body of evidence which suggests that we can’t rely on one single public health measure to achieve epidemic control”, says Dr. Adam Kucharski from the London School of Hygiene & Tropical Medicine, UK. “Successful strategies will likely include intensive testing and contact tracing supplemented with moderate forms of physical distancing, such as limiting the size of social gatherings and remote working, which can both reduce transmission and the number of contacts that need to be traced.”

He adds: “The huge scale of testing and contact tracing that is needed to reduce COVID-19 from spreading is resource intensive, and new app-based tracing, if adopted widely alongside traditional contact tracing, could enhance the effectiveness of identifying contacts, particularly those that would otherwise be missed.”

In the study, researchers analysed data on how 40,162 people moved about the UK and interacted with others prior to COVID-19 to simulate how combinations of different testing, isolation, tracing, and physical distancing scenarios—such as app-based tracing, remote working, limits on different sized gatherings, and mass population-based testing—might contribute to reducing secondary cases. They also modelled the rate at which the virus is transmitted—known as the reproductive number (R), or the average number of people each individual with the virus is likely to infect at a given moment—under different strategies. To keep the COVID-19 epidemic declining, R needs to be less than 1.

In the model, the secondary attack rate (the probability that a close contact of a confirmed case will be infected) was assumed to be 20% among household contacts and 6% among other contacts. The researchers calculated that, had no control measures been implemented, R would be 2.6—meaning that one infected person would infect, on average, 2-3 more people.

The model suggested that mass testing alone, with 5% of the population undergoing random testing each week (i.e. 460,000 tests per day in UK), would lower R to just 2.5, because so many infections would either be missed or detected too late.

Compared with no control measures, self-isolation of symptomatic cases (at home) alone reduced transmission by an estimated 29% (lowering R to 1.8); whilst combining self-isolation, household quarantine, and tracing strategies could potentially lower transmission by as much as 47% (R 1.4) when using app-based contact tracing (assuming the app is adopted by 53% of the population), and by 64% with manual tracing of all contacts (R 0.94).

Achieving such a thorough level of contact tracing may be impractical, but the new study suggests that a large reduction in transmission could also be achieved by supplementing with moderate physical distancing measures. For example, they estimate that, limiting daily contacts outside home, school, and work to four people (e.g. by restricting mass gatherings) along with manual tracing of acquaintances only (i.e. people they have met before) and app-based tracing, would have the greatest impact, reducing disease spread by 66%, and lowering R to 0.87. However, they note that the effectiveness of manual contact tracing strategies is highly dependent on how many contacts are successfully traced, with a high level of tracing required to ensure R is lower than 1, especially if it takes time to isolate symptomatic cases.

The researchers also modelled the number of contacts that might need to be quarantined under different contact tracing strategies. They estimate that a scenario in which 1,000 new symptomatic cases were reported daily would likely require a minimum of 15,000 contacts quarantined every day (isolation plus app-based testing) and a maximum of 41,000 (isolation plus manual tracing all contacts). This could increase to an average of 150,000-200,000 contacts quarantined daily in a scenario where 5,000 new symptomatic cases were diagnosed each day.

“Our results highlight several characteristics of SARS-CoV-2 which make effective isolation and contact tracing challenging. The high rate of transmission, the short time between one person becoming infected and infecting another, and transmission that occurs without symptoms all make things difficult”, says co-author Dr. Hannah Fry from University College London, UK. “If there are a lot of symptomatic COVID-19 cases, then tracing, testing, and trying to quarantine a huge number of contacts will be a big challenge. How well we manage it will affect how and when it is possible to reduce transmission predominantly through targeted isolation and tracing measures or whether ongoing physical distancing measures will be required to control the epidemic.”

According to co-author Professor Julia Gog from the University of Cambridge, UK, “Planning for control based on isolation and contact tracing should consider the likely need for large numbers of cases to be tested and also a large number contacts rapidly quarantined. Crucially, this work is able to quantify the scales of what is needed for a successful control strategy involving tracing and isolation by making use of the dataset from the BBC pandemic project. The BBC data gives a uniquely detailed picture of how people in the UK mix and thus the extent of contact tracing necessary if we return to social mixing patterns as they were before the pandemic.”

The authors highlight several limitations to their study, including that it did not consider more detailed settings beyond home, school, work, or ‘other’ categories, or explicitly include imported infections, which may be detected at a different rate to local infections.

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Blood sample can be used to assess the severity and prognosis of frontotemporal lobar degeneration in the future

Biomarkers to support the diagnosis of frontotemporal lobar degeneration (FTLD) and to assess the severity and expected prognosis of the disease are needed. Neurofilament light chain (NfL) measured from a blood sample strongly correlates with the duration of the disease in FTLD patients and the rate of brain atrophy, according to a new study published by the University of Eastern Finland in the Annals of Clinical and Translational Neurology.

FTLD is the second most common cause of degenerative and progressive dementing diseases in the working-age population after Alzheimer’s disease. FTLD is divided into two subgroups based on the primary symptoms. Early symptoms of the most common form of FTLD, behavioral variant frontotemporal dementia (bvFTD), include changes in behavior, personality, and executive functions. In the second subgroup, primary progressive aphasia (PPA), the primary symptoms are linguistic, including naming problems and problems in speech production. FTLD patients often have also concomitant motor neuron disease (FTD-MND), and there is some overlap in the neuropathology and genetic alterations between these diseases. Several predisposing genetic mutations have been recognized for FTLD, of which the C9orf72 repeat expansion is exceptionally prevalent in Finnish patients.

NfL is an intracellular structural protein that maintains the shape of the nerve cells and the axons. Upon neuronal damage, NfL is released into the intercellular space, from where it eventually ends up in the blood. Indeed, elevated blood NfL levels are observed in a variety of neurodegenerative diseases and after brain trauma. Previously, NfL levels have been measured in cerebrospinal fluid, where it has a higher concentration than in the blood. However, new ultra-sensitive methods allow measuring NfL also in the blood, making blood NfL a minimally invasive biomarker for neurodegeneration.

The new study found that patients with high levels of blood NfL had a shorter duration of the disease and a faster rate of brain atrophy. High levels of blood NfL were detected particularly in the FTD-MND and PPA groups. Also, carriers of the C9orf72 repeat expansion had elevated blood NfL levels. These results provide valuable information on the course of the disease in FTLD patients showing different clinical symptoms or harboring diverse genetic backgrounds.

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Scientists reveal relationship between Dek and Intron retention during muscle stem cells quiescence

Muscle stem cells, the reserve stem cell in the skeletal muscles, are responsible for muscle repair after damage. They are the ‘regenerative medicine’ to cure muscle diseases and muscle damage. In a healthy uninjured condition, muscle stem cells are in quiescence, a dormant state, to preserve them. Whenever there is muscle damage, they will wake up instantly and contribute themselves to building new muscles.

If this dormant state is loosely controlled, muscle stem cells will be wasted when there is no need for repair. If this dormant state is kept too tight, the muscle stem cells will not wake up when they are needed to contribute to muscle repair.

How muscle stem cells control this balance of quiescence remains a topic of heightened interest. Recently, a team of scientists at the Hong Kong University of Science and Technology revealed that intron detention (IR) is a key to the mechanism—when stem cells enter quiescence exit, Dek releases conserved introns, which allow the cell to be activated.

“Using skeletal muscle stem cells, also called satellite cells (SCs), we demonstrated prevalent intron retention (IR) in the transcriptome of quiescent SCs (QSCs),” said Prof. Tom Cheung, lead researcher of the team and SH Ho Associate Professor of Life Science at HKUST. “Intron-retained transcripts found in QSCs are essential for fundamental functions including RNA splicing, protein translation, cell-cycle entry, and lineage specification. Our analysis reveals that phosphorylated Dek protein modulates IR during SC quiescence exit.”

While Dek protein is not present in QSCs, Dek overexpression in vivo results in a global decrease of IR, quiescence dysregulation, premature differentiation of QSCs, and undermined muscle regeneration. The researchers also found in their IR analysis on hundreds of public RNA-seq data that IR is conserved among quiescent adult stem cells, which suggests that IR functions as a conserved post-transcriptional regulation mechanism that plays an important role during stem cell quiescence exit.

Their findings were published online in the journal Developmental Cell on June 4, 2020.

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