Annelies Wouters, Jan-Pieter Ploem, Sabine A. S. Langie, Tom Artois, Aziz Aboobaker, and Karen Smeets

Pluripotent stem cells hold great potential for regenerative medicine. Increased replication and division, such is the case during regeneration, concomitantly increases the risk of adverse outcomes through the acquisition of mutations. Seeking for driving mechanisms of such outcomes, we challenged a pluripotent stem cell system during the tightly controlled regeneration process in the planarian Schmidtea mediterranea. Exposure to the genotoxic compound methyl methanesulfonate (MMS) revealed that despite a similar DNA-damaging effect along the anteroposterior axis of intact animals, responses differed between anterior and posterior fragments after amputation. Stem cell proliferation and differentiation proceeded successfully in the amputated heads, leading to regeneration of missing tissues. Stem cells in the amputated tails showed decreased proliferation and differentiation capacity. As a result, tails could not regenerate. Interference with the body-axis-associated component β-catenin-1 increased regenerative success in tail fragments by stimulating proliferation at an early time point. Our results suggest that differences in the Wnt signalling gradient along the body axis modulate stem cell responses to MMS.

Molecular radiotherapy using ¹⁷⁷Lu-DOTATATE is a most effective treatment for somatostatin receptor–expressing neuroendocrine tumors. Despite its frequent and successful use in the clinic, little or no radiobiologic considerations are made at the time of treatment planning or delivery. On positive uptake on octreotide-based PET/SPECT imaging, treatment is usually administered as a standard dose and number of cycles without adjustment for peptide uptake, dosimetry, or radiobiologic and DNA damage effects in the tumor. Here, we visualized and quantified the extent of DNA damage response after ¹⁷⁷Lu-DOTATATE therapy using SPECT imaging with ¹¹¹In-anti-H2AX-TAT. This work was a proof-of-principle study of this in vivo noninvasive biodosimeter with β-emitting therapeutic radiopharmaceuticals. Methods: Six cell lines were exposed to external-beam radiotherapy (EBRT) or ¹⁷⁷Lu-DOTATATE, after which the number of H2AX foci and the clonogenic survival were measured. Mice bearing CA20948 somatostatin receptor–positive tumor xenografts were treated with ¹⁷⁷Lu-DOTATATE or sham-treated and coinjected with ¹¹¹In-anti-H2AX-TAT, ¹¹¹In-IgG-TAT control, or vehicle. Results: Clonogenic survival after external-beam radiotherapy was cell-line–specific, indicating varying levels of intrinsic radiosensitivity. Regarding in vitro cell lines treated with ¹⁷⁷Lu-DOTATATE, clonogenic survival decreased and H2AX foci increased for cells expressing high levels of somatostatin receptor subtype 2. Ex vivo measurements revealed a partial correlation between ¹⁷⁷Lu-DOTATATE uptake and H2AX focus induction between different regions of CA20948 xenograft tumors, suggesting that different parts of the tumor may react differentially to ¹⁷⁷Lu-DOTATATE irradiation. Conclusion: ¹¹¹In-anti-H2AX-TAT allows monitoring of DNA damage after ¹⁷⁷Lu-DOTATATE therapy and reveals heterogeneous damage responses.

Prostate-specific membrane antigen (PSMA)–targeting α-radiation therapy (TAT) is an emerging treatment modality for metastatic castration-resistant prostate cancer. There is a subgroup of patients with poor response despite sufficient expression of PSMA in their tumors. The aim of this work was to characterize PSMA-TAT–nonresponding lesions by targeted next-generation sequencing. Methods: Of 60 patients treated with ²²⁵Ac-PSMA-617, we identified 10 patients who presented with a poor response despite sufficient tumor uptake in PSMA PET/CT. We were able to perform CT-guided biopsies with histologic validation of the nonresponding lesions in 7 of these nonresponding patients. Specimens were analyzed by targeted next-generation sequencing interrogating 37 DNA damage-repair–associated genes. Results: In the 7 tumor samples analyzed, we found a total of 15 whole-gene deletions, deleterious or presumably deleterious mutations affecting TP53 (n = 3), CHEK2 (n = 2), ATM (n = 2), and BRCA1, BRCA2, PALB2, MSH2, MSH6, NBN, FANCB, and PMS1 (n = 1 each). The average number of deleterious or presumably deleterious mutations was 2.2 (range, 0–6) per patient. In addition, several variants of unknown significance in ATM, BRCA1, MSH2, SLX4, ERCC, and various FANC genes were detected. Conclusion: Patients with resistance to PSMA-TAT despite PSMA positivity frequently harbor mutations in DNA damage-repair and checkpoint genes. Although the causal role of these alterations in the patient outcome remains to be determined, our findings encourage future studies combining PSMA-TAT and DNA damage-repair–targeting agents such as poly(ADP-ribose)-polymerase inhibitors.

Chronic cough is a common complaint in the general population but there are no precise data on the incidence of, and prospectively examined risk factors for chronic cough in a population-based setting. Therefore, we investigated the period prevalence, incidence and risk factors for chronic cough in adult subjects.

In a prospective population-based cohort study among subjects aged ≥45 years, data on chronic cough were collected on two separate occasions using a standardised questionnaire. Chronic cough was defined as daily coughing for at least 3 months duration during the preceding 2 years. Potential risk factors were gathered by interview, physical examination and several investigations.

Of the 9824 participants in this study, 1073 (10.9%) subjects had chronic cough at baseline. The prevalence of chronic cough increased with age and peaked in the eighth decade. In subjects aged <70 years, chronic cough was more common in women. During an average follow-up of 6 years, 439 incident cases of chronic cough occurred with an overall incidence rate of 11.6 per 1000 person-years (95% CI 10.6–12.8). In current smokers, the incidence of chronic cough was higher in men. In the multivariable analysis, current smoking, gastro-oesophageal reflux disease (GORD), asthma and COPD were identified as risk factors for chronic cough.

Chronic cough is common among adults and highly prevalent in the older population. Current smoking, GORD, asthma and COPD are independent risk factors for chronic cough. Individuals at risk of developing chronic cough may benefit from smoking cessation and control of the underlying disease.

The type VI secretion system (T6SS) is a weapon for delivering effectors into target cells that is widespread in Gram-negative bacteria. The T6SS is a highly versatile machine, as it can target both eukaryotic and prokaryotic cells, and it has been proposed that T6SSs are adapted to the specific needs of each bacterium. The expression of T6SS gene clusters and the activation of the secretion apparatus are therefore tightly controlled. In enteroaggregative Escherichia coli (EAEC), the sci1 T6SS gene cluster is subject to a complex regulation involving both the ferric uptake regulator (Fur) and DNA adenine methylase (Dam)-dependent DNA methylation. In this study, an additional, internal, promoter was identified within the sci1 gene cluster using +1 transcriptional mapping. Further analyses demonstrated that this internal promoter is controlled by a mechanism strictly identical to that of the main promoter. The Fur binding box overlaps the –10 transcriptional element and a Dam methylation site, GATC-32. Hence, the expression of the distal sci1 genes is repressed and the GATC-32 site is protected from methylation in iron-rich conditions. The Fur-dependent protection of GATC-32 was confirmed by an in vitro methylation assay. In addition, the methylation of GATC-32 negatively impacted Fur binding. The expression of the sci1 internal promoter is therefore controlled by iron availability through Fur regulation, whereas Dam-dependent methylation maintains a stable ON expression in iron-limited conditions.

IMPORTANCE Bacteria use weapons to deliver effectors into target cells. One of these weapons, the type VI secretion system (T6SS), assembles a contractile tail acting as a spring to propel a toxin-loaded needle. Its expression and activation therefore need to be tightly regulated. Here, we identified an internal promoter within the sci1 T6SS gene cluster in enteroaggregative E. coli. We show that this internal promoter is controlled by Fur and Dam-dependent methylation. We further demonstrate that Fur and Dam compete at the –10 transcriptional element to finely tune the expression of T6SS genes. We propose that this elegant regulatory mechanism allows the optimum production of the T6SS in conditions where enteroaggregative E. coli encounters competing species.

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City of Windsor payouts on personal injury and property damage claims totaled $2.1 million in 2019, the lowest number in eight years. The total — for settlements as well as court decisions — was well below the $3 million budgeted for the hundreds of claims made each year against the city for everything from trip-and-falls, […]

The covid-19 pandemic has many of us stuck at home. The result could completely reshape how we use the internet, writes Annalee Newitz

THE CORONAVIRUS lockdown is now causing serious damage to the UK's economy, Tory MP Steve Baker has warned - stressing he was now "gravely concerned" at the situation

From haute gardening hats, to nettles dresses and sexy necklines, here are the trends that are coming for you for this spring/summer

• Read more from the spring/summer 2020 edition of The Fashion, our biannual style supplement

Afraid of looking like a dunce when it comes to your fashion knowledge? We’ve created a cheat sheet for the new season.

SBS On Demand is streaming more than 10 hours of his features. Our isolated film critic took the bait and watched them all

Many terrible things are discussed in the maelstrom of mayhem and misery I call my inbox – terrible, terrible things, such as requests involving me needing to go somewhere, or speak to someone or do something.

But last Thursday afternoon a lovely email broke through like a ray of sunshine piercing grey clouds on a stormy day. It was an email from a publicist at SBS. The subject line read: “Binge 627 minutes of ADAM DRIVER for free.”

The 61-year-old singer recently revealed she has antibodies for the respiratory condition and sparked confusion when she was then seen

Follow our live coronavirus updates HERE Coronavirus: the symptoms

'Notre Dame is an old, injured lady'

Donate at virginmoneygiving.com/fund/FoodforLondonNOW Download Damien Hirst's Butterfly Heart 2020 image here to print out and display in your window

A new artwork from Damien Hirst supporting the Evening Standard's Food For London Now appeal has been displayed in windows across the capital.

Follow our live coronavirus updates here Coronavirus: the symptoms

Nearly half of NHS doctors have been forced to buy their own personal protective equipment (PPE) for coronavirus treatment or rely on donations, a new survey has found.

The ONS total is 34% higher than the Department of Health total.

A new portrait of Dame Vera Lynn has been unveiled ahead of the 75th anniversary of VE Day

The author of The Miniaturist on the beguiling blend of tradition and modernity (and pancakes) in a city that provided the inspiration for her 17th-century-set debut novel and Waterstones Book of the Year 2014

• Top 10 free things to do in Amsterdam
  
• A new Amsterdam – and a new Rijksmuseum

Amsterdam is classically romantic but is also funky, forward-thinking and citizen-friendly. In the old centre, around the southern canal belt, there are these beautiful 17th-century merchants’ houses that 21st-century Amsterdammers still live in. I’ve always thought it wears its historical cloak quite casually and doesn’t just dwell in the past.

The Rijksmuseum is stunning and I love it as a fascinating, cool, accessible museum, as well as for the part it played in inspiring The Miniaturist. I came across Petronella Oortman’s doll’s house there by chance. It’s an exact scale replica of her real home, and Oortman spent a fortune having it created. I thought at the time it was an interesting story, but I didn’t think I was going to write a novel about it. I’m in its debt, really.

Jan-Werner Müller

The post One Damn Thing After Another appeared first on The Nation.

Like most of us, Adam Tooze is stuck at home. The British-born economic historian and Columbia University professor of history had been on leave this school year to write a book about climate change. But now he’s studying a different global problem. There are more than 700,000 cases of COVID-19 in the United States and over 2 million infections worldwide. It’s also caused an economic meltdown. More than 18 million Americans have filed for unemployment in recent weeks, and Goldman Sachs analysts predict that U.S. gross domestic product will decline at an annual rate of 34 percent in the second quarter.

Tooze is an expert on economic catastrophes. He wrote the book Crashed: How a Decade of Financial Crises Changed the World, about the 2008 economic crisis and its aftermath. But even he didn’t see this one coming. He hadn’t thought much about how pandemics could impact the economy—few economists had. Then he watched as China locked down the city of Wuhan, in a province known for auto manufacturing, on January 23; as northern Italy shut down on February 23; and as the U.S. stock market imploded on March 9. By then, he knew he had another financial crisis to think about. He’s been busy writing ever since. Tooze spoke with Nautilus from his home in New York City.

What do you make of the fact that, in three weeks, more than 16 million people in the U.S. have filed for unemployment?

The structural element here—and this is quite striking, when you compare Europe, for instance, to the U.S.—is that America has and normally celebrates the flexibility and dynamism of its labor market: The fact that people move between jobs. The fact that employers have the right to hire and fire if they need to. The downside is that in a shock like this, the appropriate response for an employer is simply to let people go. What America wasn’t able to do was to improvise the short-time working systems that the Europeans are trying to use to prevent the immediate loss of employment to so many people.

The disadvantage of the American system that reveals itself in a crisis like this is that hiring and firing is not easily reversible. People who lose jobs don’t necessarily easily get them back. There is a fantasy of a V-shaped recovery. We literally have never done this before, so we don’t know one way or another how this could happen. But it seems likely that many people who have lost employment will not immediately find reemployment over the summer or the fall when business activity resumes something like its previous state. In a situation with a lot of people with low qualifications in precarious jobs at low income, the damage from that kind of interruption of employment in sectors notably which are already teetering on the edge—the chain stores, which are quite likely closing anyway, and fragile malls, which were on the edge of dying—it’s quite likely that this shock will also induce disproportionately large amounts of scarring.

What role has wealth and income inequality played during this crisis?

The U.S. economic system is bad enough in a regular crisis. In one like this, where you shut the entire economy down in a matter of weeks, the damage is barely conceivable. There are huge disparities, all of which ultimately are rooted in social structures of race and class, and in the different types of jobs that people have. The profound inequality in American society has been brought home for us in everyone’s families, where there is a radical disparity between the ability of some households to sustain the education of their children and themselves living comfortably at home. Twenty-five percent of kids in the United States appear not to have a stable WiFi connection. They have smartphones. That seems practically universal. But you can’t teach school on a smartphone. At least, that technology is not there.

Presumably by next year something like normality returns. But forever after we’ll live under the shadow of this having happened.

President Trump wants the economy to reopen by May. Would that stop the economic crisis?

Certainly that is presumably what drives that haste to restart the economy and to lift intense social distancing provisions. There is a sense that we can’t stand this. And that has a lot to do with deep fragilities in the American social system. If all Americans live comfortably in their own homes, with the safety of a regular paycheck, with substantial savings, with health insurance that wasn’t conditional on precarious employment, and with unemployment benefits that were adequate and that were rolled out to most people in this society if they needed them, then there wouldn’t be such a rush. But that isn’t America as we know it. America is a society in which half of families have virtually no financial cushion; in which small businesses, which are so often hailed as the drivers of job creation, the vast majority of owners of them live hand-to-mouth; in which the unemployment insurance system really is a mockery; and with health insurance directly tied to employment for the vast majority of the people. A society like that really faces huge pressures if the economy is shut down.

How is the pandemic-induced economic collapse we’re facing now different from what we faced in 2008?

This is so much faster. Early this year, America had record-low unemployment numbers. And last week or so already we probably broke the record for unemployment in the United States in the period since World War II. This story is moving so fast that our statistical systems of registration can’t keep up. So we think probably de facto unemployment in the U.S. right now is 13, 14, 15 percent. That’s never happened before. 2007 to 2008 was a classic global crisis in the sense that it came out of one particular over-expanded sector, a sector which is very well known for its volatility, which is real estate and construction. It was driven by a credit boom.

What we’re seeing this time around is deliberately, government-ordered, cliff edge, sudden shutdown of the entire economy, hitting specifically the face-to-face human services—retail, entertainment, restaurants—sector, which are, generally speaking, lagging in cyclical terms and are not the kind of sectors that generate boom-bust cycles.

Are we better prepared this time than in 2008?

You’d find it very hard to point to anyone in the policymaking community at the beginning of 2020 who was thinking of pandemic risk. Some people were. Former Treasury Secretary and former Director of the National Economic Council Larry Summers, for example, wrote a paper about pandemic flu several years ago, because of MERS and SARS, previous respiratory illnesses caused by coronaviruses. But it wasn’t top of stack at the beginning of this year. So we weren’t prepared in that sense. But do we know what to do now if we see the convulsions in the credit markets that we saw at the beginning of March? Yes. Have the central banks done it? Yes. Did they use some of the techniques they employed in ’08? Yes. Did they know that you had to go in big and you had to go in heavy and hard and quickly? Yes. And they have done so on an even more gigantic scale than in ’08, which is a lesson learned in ’08, too: There’s no such a thing as too big. And furthermore, the banks, which were the fragile bit in ’08, have basically been sidelined.

You’ve written that the response to the 2008 crisis worked to “undermine democracy.” How so, and could we see that again with this crisis?

The urgency that any financial crisis produces forces governments’ hands—it strips the legislature, the ordinary processes of democratic deliberation. When you’re forced to make very dramatic, very rapid decisions—particularly in a country as chronically divided as the U.S. is on so many issues—the risk that you create opportunities for demagogues of various types to take advantage of is huge. We know what the response of the Tea Party was to the ’08, ’09 economic crisis. They created an extraordinarily distorted vision of what had happened and then rode that to see extraordinary influence over the Republican party in the years that followed. And there is every reason to think that we might be faced with similar stresses in the American political system in months to come.

The U.S. economic system is bad enough in a regular crisis. In one like this, where you shut the entire economy down in a matter of weeks, the damage is barely conceivable.

How should we be rethinking the economy to buffer against meltdowns like this in the future?

We clearly need to have a far more adequate and substantial medical capacity. There’s no alternative to a comprehensive publicly backstopped or funded health insurance system. Insofar as you haven’t got that, your capacity to guarantee the security in the most basic and elementary sense of your population is not there. When you have a system in which one of the immediate side effects, in a crisis like this, is that large parts of your hospital system go bankrupt—one of the threats to the American medical system right now—that points to something extraordinarily wrong, especially if you’re spending close to 18 percent of GDP on health, more than any other society on the planet.

What about the unemployment insurance system?

America needs to have a comprehensive unemployment insurance system. It can be graded by local wage rates and everything else. But the idea that you have the extraordinary disparities that we have between a Florida and a Georgia at one end, with recipiency rates in the 11, 12, 13, 14, 15 percent, and then states which actually operate an insurance system, which deserve the name—this shouldn’t be accepted in a country like the U.S. We would need to look at how short-time working models might be a far better way of dealing with shocks of this kind, essentially saying that there is a public interest in the continuity of employment relationships. The employer should be investing in their staff and should not be indifferent as to who shows up for work on any given day.

What does this pandemic teach us about living in a global economy?

There are a series of very hard lessons in the recent history of globalization into which the corona shock fits—about the peculiar inability of American society, American politics, and the American labor market to cushion shocks that come from the outside in a way which moderates the risk and the damage to the most vulnerable people. If you look at the impact of globalization on manufacturing, industry, inequality, the urban fabric in the U.S., it’s far more severe than in other societies, which have basically been subject to the same shock. That really needs to raise questions about how the American labor market and welfare system work, because they are failing tens of millions of people in this society.

You write in Crashed not just about the 2008 crisis, but also about the decade afterward. What is the next decade going to look like, given this meltdown?

I have never felt less certain in even thinking about that kind of question. At this point, can either you or I confidently predict what we’re going to be doing this summer or this autumn? I don’t know whether my university is resuming normal service in the fall. I don’t know whether my daughter goes back to school. I don’t know when my wife’s business in travel and tourism resumes. That is unprecedented. It’s very difficult against that backdrop to think out over a 10-year time horizon. Presumably by next year something like normality returns. But forever after we’ll live under the shadow of this having happened. Every year we’re going to be anxiously worrying about whether flu season is going to be flu season like normal or flu season like this. That is itself something to be reckoned with.

How will anxiety and uncertainty about a future pandemic-like crisis affect the economy?

When we do not know what the future holds to this extent, it makes it very difficult for people to make bold, long-term financial decisions. This previously wasn’t part of the repertoire of what the financial analysts call tail risk. Not seriously. My sister works in the U.K. government, and they compile a list every quarter of the top five things that could blow your departmental business up. Every year pandemics are in the top three. But no one ever acted on it. It’s not like terrorism. In Britain, you have a state apparatus which is geared to address the terrorism risk because it’s very real—it’s struck many times. Now all of a sudden we have to take the possibility of pandemics that seriously. And their consequences are far more drastic. How do we know what our incomes are going to be? A very large part of American society is not going to be able to answer that question for some time to come. And that will shake consumer confidence. It will likely increase the savings rate. It’s quite likely to reduce the desire to invest in a large part of the U.S. economy.

Max Kutner is a journalist in New York City. He has written for Newsweek, The Boston Globe, and Smithsonian. Follow him on Twitter @maxkutner.

Lead image: Straight 8 Photography / Shutterstock

Five top pediatric heart, infectious disease or critical care specialists told Yahoo News they are tracking a serious new syndrome they believe is related to Kawasaki disease, affecting children infected with the coronavirus.

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On Monday, Australia's Prime Minister Malcolm Turnbull announced he had removed the titles of "knights" and "dames" from the Order of Australia, a formal award system that honours those who provide a great service to Australia.

The two archaic titles were only brought back last year in a controversial move by former prime minister Tony Abbott. In a decision that made many question Abbott's leadership, the first knighthood was awarded to Prince Philip, the Duke of Edinburgh — a man who has only been to Australia a handful of times.

Neco Williams has revealed how Adam Lallana has played a major role in helping him adapt to the demands of training regularly with Liverpool's first team.

Former Tottenham and Liverpool director Damien Comolli has raised fears over the safety of players if football returns behind closed doors during the coronavirus pandemic, asking: 'What happens if someone dies?'

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Arsenal legend Tony Adams has told of how the club's transfer market ambition in the 1990s helped convince him to turn down Manchester United – and revealed his frustration at the difference in attitude today.

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Liverpool are benefiting from an analytics-led transfer policy that helps them find value even at the top end of the market, the club's former director of football Damien Comolli has declared.

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The former Bulls star saw himself as a basketball player. The current Lakers star sees himself as something more. “I have a responsibility to lead,” James says.

The oil on canvas painting is entitled The Enduring Sweetheart.

MORE than 50 firefighters on the ground and in the air were needed to tackle a huge factory fire in Melbourne’s west overnight.