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Laboratory-generated mini-kidneys help understand the link between diabetes and COVID-19 disease

• In an international collaboration, researchers led by Nuria Montserrat, ICREA Research Professor at IBEC, have generated human mini-kidneys that simulate…

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• In an international collaboration, researchers led by Nuria Montserrat, ICREA Research Professor at IBEC, have generated human mini-kidneys that simulate the kidney of a person with diabetes in the early stages of the disease. These diabetic mini-kidneys open the door to studying, among others, the relationship between diabetes and COVID-19. 

Credit: Institute for Bioengineering of Catalonia

• In an international collaboration, researchers led by Nuria Montserrat, ICREA Research Professor at IBEC, have generated human mini-kidneys that simulate the kidney of a person with diabetes in the early stages of the disease. These diabetic mini-kidneys open the door to studying, among others, the relationship between diabetes and COVID-19. 

• The researchers demonstrated that diabetic mini-kidneys have a higher susceptibility to SARS-CoV-2 infection, as well as genetic evidence for the essential role of the ACE2 receptor in COVID-19. These observations have been confirmed in kidney cells from diabetic patients. 

• In addition, they have identified that the metabolic programming caused by diabetes is critical and increases susceptibility to SARS-CoV-2 infection in the kidney. These results may lead to the identification of new interventions in the pathogenesis of COVID-19 targeting energy metabolism.

Barcelona, May 9th, 2022.

For two years, thousands of scientists and doctors around the world have been working to understand how COVID-19 develops and what relationship it has with other types of diseases. Various studies indicate that people with diabetes are more likely to develop severe COVID-19, as well as that more than 20% of patients hospitalized for COVID-19 suffer acute kidney damage. However, to date, it was unknown what was the factor that caused this to happen.

Now, an international team led by Nuria Montserrat, ICREA research professor at the Institute of Bioengineering of Catalonia (IBEC) and principal investigator of the “Pluripotency for organ regeneration” group, in collaboration with, among others, researchers from the University of Florida, the Life Sciences Institute of the University of British Columbia in Canada, Karolinska Institutet and Karolinska University Hospital in Sweden have used bioengineering to develop mini-kidneys that simulate the kidney of a person in the early stages of diabetes.

In this international collaboration the researchers have provided, for the first time, the use of kidney organoids to understand the early stages of diabetes in this organ. In order to demonstrate that the ACE2 receptor plays an essential role in SARS-CoV-2 infection in the kidney, the team has also used genetic engineering to generate defective organoids for other receptors described to date as gateways for the virus. Using patient kidney cells, this study also reveals the role of energy metabolism in SARS-CoV-2 infection, opening the door to the identification of new therapeutic interventions to treat COVID-19. This groundbreaking study has just been published in the prestigious journal Cell Metabolism.

 

Diabetic mini-kidneys have more portals of entry for SARS-CoV-2

Mini-kidneys have been developed in the laboratory from pluripotent human stem cells. To reproduce the diabetic environment, the researchers have subjected the mini-kidneys to culture conditions that result in the generation of mini-kidneys with the same cellular characteristics and metabolic alterations as those found in the kidneys of a person with early-stage diabetes.

Using different molecular biology techniques, such as gene editing, the researchers have observed that, in diabetic mini-kidneys, it is the abundance of the ACE2 receptor that determines susceptibility to viral infection, establishing a causal relationship between diabetes and the presence of one of the receptors described so far as determinant in SARS-CoV-2 infection.

 “Our diabetic renal organoid model has allowed us to observe that diabetic mini-kidneys, with a greater number of ACE2 receptors, have a greater susceptibility to viral infection.”

Elena Garreta, Institute for Bioengineering of Catalonia and first co-author of the study

“It is absolutely imperative to understand the molecular mechanisms that underlie more severe COVID-19 in patients with diabetes and other metabolic comorbidities. The development of a diabetic kidney organoid is a great step towards experimentally dissecting how metabolic changes can impact SARS-CoV-2 infections. The data again demonstrate that ACE2 is the essential receptor for SARS-CoV-2 even under conditions of comorbidity.”

Josef Penninger, Institute of Molecular Biotechnology

Furthermore, using state-of-the-art techniques such as RNA sequencing, the researchers identified that diabetic mini-kidneys have a metabolic signature that could explain why diabetic mini-kidneys become more infected.

 

Diabetes increases susceptibility to SARS-CoV-2 infection in patient cells.

To verify whether the results obtained with the mini-kidneys are also observed in the native organ, the researchers analyzed kidney cells from patients with diabetes and individuals without diabetes. The data show that kidney cells from diabetic patients, in the same way as what happens in mini-kidneys, have more ACE2 receptors and suffer a higher rate of SARS-CoV-2 infection. To delve into the mechanisms that may explain such observations, the researchers used a compound that modulates the metabolic state of cells and found that the treatment reduced viral infection.

“This finding sheds a light on a potential mechanism behind more severe cases of diabetic patients. This technology will improve our capability to investigate how the virus interacts with different organs in the human body.”

Ali Mirazimi, adjunct professor at Karolinska Institutet and one of the study’s corresponding authors.

We have shown that the SARS-CoV-2 virus is capable of directly infecting proximal tubule cells isolated from the human kidney and that diabetes makes these cells more prone to infection.”

Megan Stanifer, first co-author of the study (University of Florida)

This research was supported in part by the Institute of Health Carlos III and the Foundation Banco Bilbao Vizcaya through emergency funding focused on accelerating the development, testing, and implementation of measures to deal with the COVID-19 outbreak.

 

Reference article:

Elena Garreta, Patricia Prado, Megan Stanifer, Vanessa Monteil, Andrés Marco, Asier Ullate-Agote, Daniel Moya-Rull, Amaia Vilas-Zornoza, Carolina Tarantino, Juan Pablo Romero, Gustav Jonsson, Roger Oria, Alexandra Leopoldi, Astrid Hagelkruys, Maria Gallo, Federico González, Pere Domingo-Pedrol, Aleix Gavaldà, Carmen Hurtado del Pozo, Omar Hasan Ali, Pedro Ventura-Aguiar, Josep María Campistol, Felipe Prosper, Ali Mirazimi, Steeve Boulant, Josef M. Penninger, Nuria Montserrat. A diabetic milieu increases ACE2 expression and cellular susceptibility to SARS-CoV-2 infections in human kidney organoids and patient cells. Cell Metabolism.

About the Institute for Bioengineering of Catalonia

The Institute for Bioengineering of Catalonia (IBEC) is a leading-edge multidisciplinary research centre based in Barcelona that conducts research at the frontiers of basic and life sciences linked with engineering to generate new knowledge and applications that helps to enhance health and quality of life. IBEC create wealth by putting together biophysics, cell engineering, nanomedicine, biomaterials, tissue engineering and the applications of information technology to health. IBEC is a non-profit-making foundation set up in 2005 by the Departments of Health and Innovation, Universities and Enterprise of the Government of Catalonia, the University of Barcelona and the Technical University of Catalonia. http://www.ibecbarcelona.eu/

About LSI

The Life Sciences Institute (LSI) at the University of British Columbia conducts basic research aimed at improving human and planetary health. Home to 17 prestigious Canada Research Chairs, the LSI hosts multidisciplinary teams working to develop a comprehensive understanding of living organisms and systems. Members of our nine research groups conduct world-class research in diabetes, cardiovascular disease, immune response, infectious disease, cancer biology, developmental disorders, bacterial regulation, neuroscience, structural biology, environmental microbiology and molecular epigenetics.

Launched in 2005 in association with the UBC Faculties of Science and Medicine, LSI houses the vibrant research labs of 87 investigators drawn from 15 departments across five faculties. We collaborate in the 270,000 s.f. Life Sciences Centre, where seven state-of-the-art core facilities – ranging from flow cytometry to cryo-electron microscopy and bioformatics – support discoveries that hold promise of direct health benefits for Canadians and Canada.

About University of British Columbia (UBC)

The University of British Columbia is a global centre for research and teaching, consistently ranked among the top 20 public universities in the world. Since 1915, UBC’s entrepreneurial spirit has embraced innovation and challenged the status quo. UBC encourages its students, staff and faculty to challenge convention, lead discovery and explore new ways of learning. At UBC, bold thinking is given a place to develop into ideas that can change the world. 

About Karolinska Institutet

Karolinska Institutet is one of the world’s leading medical universities. Our vision is to advance knowledge about life and strive towards better health for all. Karolinska Institutet accounts for the single largest share of all academic medical research conducted in Sweden and offers the country’s broadest range of education in medicine and health sciences. The Nobel Assembly at Karolinska Institutet selects the Nobel laureates in Physiology or Medicine.

 


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World-first study reveals why people with COPD are more susceptible to COVID-19

Researchers from the Centenary Institute and the University of Technology Sydney have published the first study showing why people with chronic obstructive…

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Researchers from the Centenary Institute and the University of Technology Sydney have published the first study showing why people with chronic obstructive pulmonary disease (COPD) are at higher risk of developing severe COVID-19.

Credit: Centenary Institute

Researchers from the Centenary Institute and the University of Technology Sydney have published the first study showing why people with chronic obstructive pulmonary disease (COPD) are at higher risk of developing severe COVID-19.

The findings, reported in the American Journal of Respiratory and Critical Care Medicine, could lead to the development of new therapeutic interventions that reduce COVID-19 infection in COPD patients.

An inflammatory lung condition, COPD causes airway blockage and makes it difficult to breathe. It affects around 400 million people globally. The increased susceptibility to COVID-19 of COPD patients is still to be fully understood.

In the study, the researchers infected differentiated airway cells from COPD patients and healthy people with SARS-CoV-2 (the virus that causes COVID-19).

The researchers found that the COPD airway cells had 24-fold greater infection with SARS-CoV-2 than the healthy cells.

“We examined the genetic information of infected cells through advanced single cell RNA-sequencing analysis,” said lead author of the study, Dr Matt Johansen, from the Centenary UTS Centre for Inflammation.

“Seven days after SARS-CoV-2 infection, there was a 24-fold increase of viral load in the COPD patient airway cells compared to the cells taken from healthy individuals.”

Significantly, the team found that the infected COPD cells had increased levels of transmembrane protease serine 2 (TMPRSS2) and cathepsin B (CTSB). Both are enzymes that SARS-CoV-2 uses to enter into the host cell.

“These two enzymes are increased in COPD patients and favour greater SARS-CoV-2 infection compared to healthy people. Simply put, easier and increased cell infection makes it far more likely that individuals with COPD will have more severe disease outcomes,” said Dr Johansen.

Other results from the study showed additional reasons for COPD patient susceptibility to severe COVID-19.

Key anti-viral proteins (interferons) that protect against infection were largely blunted in the COPD patient airway cells. This was a likely trigger in causing increased viral production in COPD patients.

Dr Johansen said that infected COPD patient airway cells also had higher levels of pro-inflammatory cytokines, which are linked to more severe COVID-19 and COPD outcomes.

“COPD is an inflammatory disease with patients having increased inflammation at baseline compared to healthy people. It’s highly likely that SARS-CoV-2 exacerbates this existing high inflammation level which leads to even poorer outcomes,” he said.

Initial laboratory drug testing by the researchers, to inhibit the enzymes TMPRSS2 and CTSB, and to target the high inflammation levels, successfully and substantially reduced SARS-CoV-2 viral levels in COPD patient cells, ultimately confirming the study’s results.

“Collectively, these findings have allowed us to understand the mechanisms of increased COVID-19 susceptibility in COPD patients,” said Professor Phil Hansbro, the study’s senior author and Director of the Centenary UTS Centre for Inflammation.

“We believe that new drug treatments targeting relevant enzymes and pro-inflammatory responses in SARS-CoV-2 infection could have excellent therapeutic potential in reducing the severity of COVID-19 in patients with COPD.”

Professor Hansbro said the research was critical with hundreds of millions of people affected by COPD globally and with COVID-19 likely to be around for many years to come.

[ENDS]

Publication:

Increased SARS-CoV-2 Infection, Protease and Inflammatory Responses in COPD Primary Bronchial Epithelial Cells Defined with Single Cell RNA-Sequencing.

https://www.atsjournals.org/doi/10.1164/rccm.202108-1901OC

Images:

Dr Matt Johansen: https://drive.google.com/file/d/1Wc5WxHcS1fSWE68Q7xu8jT53Dki2ZBo4/

 

Professor Phil Hansbro:

https://drive.google.com/file/d/1GaHOyCjXfSb3hsE_bS-g2Cxs81dEhL4G/

 

For all media and interview enquiries, please contact

Tony Crawshaw, Media and Communications Manager, Centenary Institute on 0402 770 403 or email: t.crawshaw@centenary.org.au

 

About the Centenary Institute

The Centenary Institute is a world-leading independent medical research institute, closely affiliated to the University of Sydney and the Royal Prince Alfred Hospital. Our research focuses on three key areas: cancer, inflammation and cardiovascular disease. Our strength lies in uncovering disease mechanisms and applying this knowledge to improve diagnostics and treatments for patients.

For more information about the Centenary Institute, visit centenary.org.au

 

About the University of Technology Sydney (UTS)

The University of Technology Sydney (UTS), located in central Sydney, is one of

Australia’s leading universities of technology. It is known for fusing innovation, creativity

and technology in its teaching and research and for being an industry-focused university.

For more information go to uts.edu.au


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The New Rift Between WHO And China

The New Rift Between WHO And China

Authored by Jeffrey Tucker via The Brownstone Institute,

From the beginning of the pandemic, the World…

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The New Rift Between WHO And China

Authored by Jeffrey Tucker via The Brownstone Institute,

From the beginning of the pandemic, the World Health Organization and China’s CCP have worked and spoken hand-in-glove, culminating in the Potemkin Village junket of mid-February 2020. The WHO-sponsored travel report—how wonderfully China had performed!—was written and signed by American public health officials who recommended Wuhan-style lockdowns, a disastrous policy that further inspired most governments in the world to do the same.

Twenty-six months later, it turns out that China in fact had not “eliminated the virus fully within its borders,” contrary to the over-the-top claims of TV pundit Devi Sridhar in her new book “Preventable.” They only pushed cases into the future, as the CCP discovered when positive tests appeared all over Shanghai, leading to 7 weeks of brutal lockdowns.

This move on China’s part has been a disaster for the country and the world economy, and presently endangers the financial and technological future of the entire country.

For Xi Jinping, lockdowns and zero-covid were his greatest achievement, one which was celebrated the world over, causing his political pride to swell beyond all bounds. Now, he cannot back off lest he face possible losses in upcoming party elections.

Just this past weekend, he made it clear to the entire government that there would be no backing off the zero-covid policy: the CCP will “unswervingly adhere to the general policy of ‘dynamic zero-Covid,’ and resolutely fight against any words and deeds that distort, doubt or deny our country’s epidemic prevention policies.”

The problem is acute: vast numbers in China likely need to acquire natural immunity via exposure. The lockdown policy likely puts a damper on the achievement of endemicity. That means long-term damage to China’s future.

Sensing this problem, the head of the WHO, Tedros Adhanom Ghebreyesus, offered a mild criticism:

“Considering the behavior of the virus, I think a shift will be very important,” adding that he had discussed this point with Chinese scientists.

What happened next is truly fascinating: Tedros’s comments were censored all over China and searches for the name Tedros were immediately blocked within the country.

Implausibly, merely by stating the incredibly obvious point, Tedros has made himself an enemy of the state.

Meanwhile, another WHO/China partisan, Bill Gates, has been sheepishly saying something very similar in interviews, namely that the virus cannot be eradicated.

It’s not just Tedros and Gates who are trying to flee their advocacy of lockdowns. Anthony Fauci himself denied that the United States ever had “complete lockdowns”—which is technically correct but not because he didn’t demand them.

On March 16, 2020, Fauci faced the national press and read from a CDC directive: “In states with evidence of community transmission, bars, restaurants, food courts, gyms and other indoor and outdoor venues where groups of people congregate should be closed.”

In fact, one gets the strong sense that governments around the world are pretending as if the whole pathetic and terrible affair never happened, even as they are attempting to reserve the power to do it all over again should the need arise.

On May 12, 2022, many governments around the world gathered for a video call and agreed to pour many billions more into covid work, and reaffirm their dedication to an “all-of-society” and “whole-of-government” approach to infectious disease. The U.S. government under the administration readily agreed to this idea.

Leaders reinforced the value of whole-of-government and whole-of-society approaches to bring the acute phase of COVID-19 to an end, and the importance of being prepared for future pandemic threats. The Summit was focused on preventing complacency, recognizing the pandemic is not over; protecting the most vulnerable, including the elderly, immunocompromised people, and frontline and health workers; and preventing future health crises, recognizing now is the time to secure political and financial commitment for pandemic preparedness.

The Summit catalyzed bold commitments. Financially, leaders committed to provide nearly $2 billion in new funding—additional to pledges made earlier in 2022. These funds will accelerate access to vaccinations, testing, and treatments, and they will contribute to a new pandemic preparedness and global health security fund housed at the World Bank.

Is it progress to see these people throwing around language from the much-criticized but now wholly vindicated Great Barrington Declaration? Doubtful. You can’t make a bad policy better by tossing around words. There is every indication from this statement that there will be no apologies, no regrets, and no changes in the default position that governments must always and everywhere have maximum power to control any pathogen of their choosing.

Despite Tedros’s censored words, it’s no wonder that Xi Jinping continues to feel vindicated and affirmed, and sees no real political danger in choosing his own power over the health and well-being of his people. Governments around the world still cannot muster the courage to make a full-throated and solid attack on zero-covid, for fear of the implications of such a concession. Nudges and hints, even from the WHO, will not do it.

Tyler Durden Mon, 05/16/2022 - 19:45

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100,000 More Recalls And Even More Shanghai Delays Sting Tesla To Start The Week

100,000 More Recalls And Even More Shanghai Delays Sting Tesla To Start The Week

Just as it started to look like everything had finally been…

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100,000 More Recalls And Even More Shanghai Delays Sting Tesla To Start The Week

Just as it started to look like everything had finally been sorted out for Tesla in Shanghai, we reported last week that the company once again had to halt its production due to "issues with supplies". 

Starting off this week, it doesn't look like things are getting any better. First, Bloomberg reported that "no vehicles were sold in Shanghai last month" as a result of the lockdown, according to an auto-seller association in the city. 

Meanwhile, Tesla's plans to restart Shanghai to its pre-pandemic production levels have been pushed back another week, Reuters reported this weekend. Citing an internal memo, Reuters wrote that Tesla is still planning on just one shift for its plant this week and a daily output of about 1,200 units.

Tesla is aiming for 2,600 units per day by May 23. 

Additionally, it was reported Monday that Tesla would be recalling over 100,000 vehicles in China. 107,293 vehicles in China will be recalled "due to safety risks", according to the China People's Daily

The recall, which relates to a defect in the central touchscreen during fast charging, "involves Model 3 and Model Y vehicles produced in the country between Oct 19, 2021, and April 26, 2022," the report says. 

Recall, Tesla's most recent Shanghai shutdown came just three weeks after the plant resumed production. The plant was closed for a total of 22 days, Reuters noted. Shanghai is now in its seventh week of lockdowns, and we noted last week that it was "unclear when the supply issues can be resolved and when Tesla can resume production".

Wire harness maker Aptiv is one supplier who is currently facing issues due to "infections found among its employees", we reported last week. Meanwhile, Tesla had just started to eye resuming double shifts at its plant, we noted two weeks ago. The plant was making plans to "resume double shifts" at its Shanghai factory as soon as mid-May after starting back up in mid April. 

Tyler Durden Mon, 05/16/2022 - 19:25

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