Thousands died needlessly in Fauci, Birx 'irrational' lockdow: Trump adviser Atlas in new book

 

• Controversial adviser Scott Atlas says 'Birx-Fauci lockdowns' failed America
• In a new book, he blasts the two scientists for 'nonsensical' policies and thinking that the virus could be eradicated after millions of people already infected
• And he says they contributed to mixed messaging by contradicting Trump
• 'A Plague Upon Our House' is published by Bombardier on November 23

Strict lockdowns pushed by White House advisers Drs. Anthony Fauci and Deborah Birx failed to stop the vulnerable dying from COVID-19, while families suffered and children lost out on their education, according to a forthcoming book by Trump adviser Dr. Scott Atlas.

His is the latest contribution to unpicking how the Trump administration responded to the pandemic.

And the former Stanford radiologist offers an unsparing account of dysfunction and political paralysis that allowed Trump's two most high-profile scientific advisers to publicly contradict the president and hijack the response.

'People were dying from the virus, and the lockdown policies were not preventing the deaths,' he writes in a copy obtained by DailyMail.com

'The simple logic of assuming you could stop the spread of, and some said eliminate, a highly contagious virus by shutting down society after millions had been infected was worse than nonsensical. 

'The idea of stopping all businesses and closing schools while quarantining healthy young people at little risk from a disease in order to protect those aged seventy and over - that is simply irrational.'

His account will reignite some of the most contentious debates of the past year over how to handle COVID-19, and attract fresh accusations that he is peddling misinformation.

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In a new book, Dr Scott Atlas accuses coronavirus advisers Drs Anthony Fauci and Deborah Birx of sticking to 'irrational' lockdown policies that failed to protect vulnerable Americans

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Atlas accuses the scientists around Trump - specifically Fauci and Birx - of implementing policies that harmed children and families by closing schools and families

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Atlas's book, 'A Plague Upon Our House: My Fight at the Trump White House to Stop COVID from Destroying America,' is published by Bombardier Books on Nov 23

Although the U.S. has made progress with vaccinations, the death toll is still ticking up and currently stands at more than three quarters of a million people. 

Atlas was a divisive and controversial figure as soon as he was brought into the White House in August last year, apparently as a bulwark to the influence of Fauci and Birx.

Critics said he was appointed more for his appearances on Fox News than any infectious disease expertise he would have picked up as a radiologist.

He had already published essays arguing that lockdowns were harming public health through their impacts on missed medical appointments, the harm of school closures, mental health effects and other negative outcomes. 

And his book describes how he repeatedly clashed with Birx and Fauci - the public face of the White House response.

Not only were their lockdowns harming the economy, he says, but they failed to protect America's most vulnerable people. 

'By the time I arrived, lockdowns had already been implemented throughout the country for months—including strict business restrictions and school closures as well as quarantines of healthy, asymptomatic people,' he writes.

'Those lockdowns were continually pushed, successfully, by Drs. Fauci and Birx to nearly all governors and throughout the media. 

'Those policies - the Birx-Fauci lockdowns - were widely implemented, and they were destroying America’s children and families. 

'Meanwhile, hundreds of thousands of deaths kept piling up, including tens of thousands of elderly Americans - their policies were in place and were failing.'

Throughout, he portrays his role as critical thinker, asking awkward questions of the conventional wisdom while his opponents sought to block the president's wishes.

Why, he asks, were scientists developing and promoting White House policy when their role should have been to offer advice and expertise to the nation's elected leaders. 

Instead, Atlas says he pushed for reopening coupled with shielding of those at risk. 

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Trump announced that Atlas would join his administration as an adviser on COVID-19 on August 10, 2020. Atlas resigned at the end of November just before his 130-day term expired

Trump introduces new coronavirus task force member Dr. Scott Atlas

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Testing and isolating healthy people, he said, was a waste of time and resources, and compounded a culture of fear.

Leaks quickly suggested he was pushing for a policy of 'herd immunity,' essentially by letting the virus spread until the level of natural immunity meant the coronavirus had nowhere left to go. 

He denies that is what he was proposing, instead describing how he once described the principle of 'herd immunity' in a meeting. 

'Not once did I advocate allowing infections to spread - not in that meeting nor in any other meeting, and never to the president,' he says.

Throughout, he expresses frustration that the White House coronavirus task force was dominated by the views of Fauci and Birx - even as they advocated policies that contradicted Trump's stated desire to reopen schools and businesses. 

Trump's inner circle, he writes, seemed reluctant to rock the boat and reduce the power of two advisers that were popular with the public ahead of the election.

'They had let Birx and Fauci tell governors to prolong the lockdowns and school closures and continue the severe restrictions on businesses - strategies that failed to stop the elderly from dying, failed to stop the cases, and destroyed families and sacrificed children,' he writes.

'The closest advisers to the president, including the VP, seemed more concerned with politics, even though the task force was putting out the wrong advice, contrary to the president’s desire to reopen schools and businesses.'

The result, he says, was dangerous and confusing mixed messaging from the White House. 

Atlas resigned in November, shortly before his term was due to end.  

Since then Fauci has been a target of Republicans, who accuse him of flip-flopping in his recommendations and of misleading the public over 'gain-of-function' research that they say may have triggered the pandemic.

Both have been unstinting in their criticism of Atlas. 

In recent closed-door testimony to the House Select Subcommittee on the Coronavirus Crisis, Birx accused Atlas of using incomplete information to draw dangerous conclusions. 

'I was constantly raising the alert in the doctors’ meetings of the depth of my concern about Dr. Atlas’ position, Dr. Atlas’ access, Dr. Atlas’ theories and hypothesis, and the depths and breadths of my concern,' she said. 

She also confirmed that she refused to attend meetings where he would be present.

'I felt like by my presence and my discussions with him, by even legitimizing my responses to him, that I was giving his theories credibility,' she said.

https://www.dailymail.co.uk/news/article-10193133/People-died-COVID-19-Fauci-Birx-stuck-irrational-lockdown-policies-says-Atlas.html

US COVID-19 deaths in 2021 outpace last year's toll

 The United States passed yet another sobering milestone in the COVID-19 pandemic as the number of 2021 coronavirus deaths outpaced the 2020 total.

According to the latest available data from Johns Hopkins University, the U.S. has reached at least 770,691 COVID-19 deaths over the full course fo the pandemic.

Data from the Centers for Disease Control and Prevention (CDC) indicate that the total number of deaths involving COVID-19 in 2020 was 385,343.

That means that at least 385,348 COVID-19 deaths — 15 more than the 2020 total —have so far been recorded in 2021, and that number will only rise in the days and weeks to come. 

In June, a Wall Street Journal analysis found that global COVID-19 deaths in 2021 had already outpaced 2020 numbers. The newspaper reported at the time that 1.883 people had died in connection with COVID-19 at that point in 2021, surpassing the global death toll of 1.88 million from 2020.

The grim U.S. milestone comes despite the fact that three COVID-19 vaccines have been authorized in the country, most recently for children as young as 5 years old. 

About 69 percent of the U.S. population are at least partially vaccinated, while 59 percent are fully vaccinated, according to CDC data. 

Among that group, Americans aged 65 years and older boast impressively high vaccination rates. Nearly 100 percent of people in that age range are at least partially vaccinated, while 86 percent are fully vaccinated, per CDC data.

While the U.S. started to celebrate a decline of COVID-19 cases in September, those numbers have steadily started trending upward again. Last week, 29 states saw higher COVID-19 counts than the week prior.

https://thehill.com/policy/healthcare/582502-us-covid-19-deaths-in-2021-outpace-last-years-toll

Roche, Blueprint’s RET cancer drug Gavreto cleared in EU

 Roche and Blueprint Medicines have opened a second front in their rivalry with Eli Lilly in RET-mutated cancers, after getting approval for Gavreto from the European Commission.

Gavreto (pralsetinib) has been cleared as a first-line treatment of people with RET fusion-positive advanced non-small cell lung cancer (NSCLC), a disease that is diagnosed in around 37,000 people worldwide every year. Roughly 2% of NSCLC patients have tumours with a RET mutation.

Lilly’s first-to-market Retevmo (selpercatinib) is currently approved as a second-line therapy for RET-positive NSCLC, so Gavreto can be used earlier in the treatment pathway.

Lilly still has the EU market to itself for second-line treatment of RET-positive thyroid cancers, although Gavreto has been approved for thyroid cancers in the US.

Sales of both drugs are still pretty modest, with Roche and Blueprint reporting $5.5 million in revenues from Gavreto in the US in the third quarter, while Lilly booked just under $34 million from Retevmo.

The EU approval is based on results from the phase 1/2 ARROW study, which showed that Gavreto had a 72% overall response rate (ORR) in previously-untreated people with RET-positive advanced NSCLC, and a 58.8% ORR in patients previously treated with chemotherapy.

The median duration of response still hasn’t been reached for the treatment-naïve group in the ongoing trial, with a 22.3 month duration seen when Gavreto was used as a second-line therapy.

Blueprint and Roche are co-developing Gavreto globally, with the exception of certain Asian territories, including China, under the terms of a deal signed last year. Roche paid Blueprint $775 million upfront for rights to the drug, with another $927 million in potential milestones.

The Swiss drugmaker’s Genentech subsidiary is commercialising Gavreto alongside Blueprint in the US, while Roche has exclusive rights in other markets covered by the deal.

EvaluatePharma has previously predicted $1.2 billion in 2026 sales for Retevmo and $723 million for Gavreto, although that was before Roche lent its marketing muscle to the Blueprint drug.

https://pharmaphorum.com/news/roche-blueprints-ret-cancer-drug-gavreto-cleared-in-eu/

Arterial stiffness in adolescence tied to hypertension and obesity in young adulthood

 Arterial stiffness is a novel risk factor to be targeted for preventing and treating hypertension and obesity from a young age, a new study published in Hypertension suggests.

Researchers from the University of Eastern Finland, the University of Exeter, and the University of Bristol carried out the study using data from one of the world's most extensive ongoing prospective birth cohort studies -- the Avon Longitudinal Study of Parents and Children (ALSPAC).

Globally, hypertension and obesity are major preventable risk factors for atherosclerotic cardiovascular diseases and death. However, several efforts to decrease the incidence and prevalence of hypertension and obesity have yielded minimal effects. Hence, understanding the natural development and pathogenesis of hypertension and obesity is important to decreasing these risks. In the newly published study, the researchers examined whether atherosclerotic traits such as arterial stiffness temporally precede the development of hypertension and obesity. This is the first time over 3800 adolescents, aged 17 years were followed up for seven years. The researchers employed several statistical approaches to untangle potential causal associations.

The researchers found that higher arterial stiffness during adolescence increased the risk of systolic hypertension by 20 percent and diastolic hypertension by two-fold, seven years later. Moreover, participants were categorised into four equal groups according to their level of arterial stiffness. Adolescents whose arterial stiffness levels were in the highest quartile both at 17 years of age and 24 years of age had a systolic blood pressure increase of 4 mmHg, and their diastolic blood pressure increased by 3 mmHg during the seven-year observation period. Of note, mild elevations in systolic and diastolic blood pressure were also observed in adolescents with mildly increased arterial stiffness but within normal limits. However, the change in blood pressure in the "mild" group was half that of the change in the "high" group. These results were similar in both males and females, despite controlling for important risk factors such as smoking, physical activity, lipid and glucose, body fat, heart rate, family history of cardiovascular diseases, etc.

Previous studies have focused on the adverse effect of obesity on the heart and blood vessels. However, the present study found that higher arterial stiffness at age 17 years increased the risk of abdominal obesity and whole body obesity by 20 percent at age 24 years. The findings reveal a possible two-way direction between unhealthy arteries and obesity, although the evidence was stronger for obesity leading to unhealthy arteries, and not vice versa.

A recent American Heart Association scientific statement notes that "lifestyle modification, including diet, reduced sedentariness, and increased physical activity, is usually recommended for patients with obesity; however, the long-term success of these strategies for reducing adiposity, maintaining weight loss, and reducing blood pressure has been limited." It has also been established that a 5 mmHg rise in blood pressure over five years increases the risk of death in the adult population by 16 percent.

"Therefore, our novel findings are significant clinically and for population health, in that future hypertension and obesity prevention and treatment strategies may now consider reducing arterial stiffness, particularly from adolescence," says Andrew Agbaje, a physician and clinical epidemiologist at the University of Eastern Finland.

This research was supported in part by research grants from Jenny and Antti Wihuri Foundation, the Finnish Cultural Foundation Central Fund, the Finnish Cultural Foundation North Savo Regional Fund, and the Doctoral Programme of Clinical Research, Faculty of Health Sciences, University of Eastern Finland. The UK Medical Research Council, Wellcome Trust, and the University of Bristol provided core support for theALSPAC study. 

Story Source:

Materials provided by University of Eastern Finland. Note: Content may be edited for style and length.

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Journal Reference:

1. Andrew O. Agbaje, Alan R. Barker, Tomi-Pekka Tuomainen. Effects of Arterial Stiffness and Carotid Intima-Media Thickness Progression on the Risk of Overweight/Obesity and Elevated Blood Pressure/Hypertension: a Cross-Lagged Cohort Study. Hypertension, 2021; DOI: 10.1161/HYPERTENSIONAHA.121.18449

https://www.sciencedaily.com/releases/2021/11/211117100058.htm

How herpes checks into the nervous system for life

 Herpes type 1 is for a lifetime. More than half of U.S. adults are carriers of HSV1 (herpes simplex virus type 1) which hibernates in the peripheral nervous system and can never be eradicated.

A new Northwestern Medicine study has uncovered the virus's sneaky strategy for infecting the nervous system, opening a path to long-needed vaccine development for both HSV1 and its close sibling HSV2.

Some carriers will never even experience so much as a cold sore from HSV1. But for others, it can cause blindness or life-threatening encephalitis. There is increasing evidence it contributes to dementia.

And HSV2, which is more commonly transmitted via sexual contact, can be passed from a mother to newborn during the birthing process asneonatal herpes, appearing as lesions all over the body of the infant. Most babies recover, but in the worst cases, it can cause brain damage or disseminate through all the organs and be lethal.

"We desperately need a vaccine to prevent herpes from invading the nervous system," said Greg Smith, professor of microbiology and immunology at Northwestern University Feinberg School of Medicine.

The new Northwestern Medicine study from Smith's lab has uncovered a route to that. The study discovered how herpes kidnaps a protein from epithelial cells and turns it into a defector to help it travel into the peripheral nervous system. They have termed the process "assimilation." It's a discovery that may have wide-ranging implications for many viruses, including HIV and SARS-CoV-2, Smith said.

The study will be published in Nature Nov. 17.

Riding the rails

"The virus needs to inject its genetic code into the nucleus, so it can start making more herpes viruses," Smith said. "It reprograms the cell to become a virus factory. The big question is how does it get to the nucleus of a neuron?"

Like many viruses, herpes hops on train tracks in the cell called microtubules and uses protein engines called dynein and kinesin to move along the tracks. Smith's team discovered herpes uses a kinesin engine that it brings with it from other cells to ferry it to the nucleus in the neuron. That kinesin protein becomes a defector to serve the virus's purpose.

"By learning how the virus is achieving this incredible feat to get into our nervous system, we can now think about how to take away that ability," Smith said. "If you can stop it from assimilating kinesin, you would have a virus that couldn't infect the nervous system. And then you have a candidate for a preventive vaccine."

Herpes takes a 'cross-country' trip

Picture the cell as a rail yard. All tracks lead to the hub called the centrosome. There are two types of train engines: proteins dynein and kinesin. One travels toward the hub -- say downtown -- and the other leads away from it to the suburbs.

When a more typical virus, such as influenza, infects mucosal epithelial cells (cells that line your nose and mouth), it grabs onto both engines and moves back and forth on the microtubule tracts until it eventually arrives at the nucleus more or less by chance. Overall, going from the suburbs to the nucleus, via the centrosome, is a short commute.

But traveling down nerves is the equivalent of a cross-country journey. Herpes jumps on the dynein engine for this trip, but it also makes sure kinesin engines do not take it back the way it came.

"It's a long way to go," Smith said. "It probably takes eight hours for it to travel from the end of the neuron to the hub."

But the dynein engine can't take it any further than the hub. And herpes needs to reach the nucleus. That's when it reaches into its 'pocket' and pulls out a kinesin engine that it kidnapped from the mucosal epithelial cells and convinced to become part of its team. And in an act of betrayal, that assimilated kinesin ferries it right to the nucleus.

"This is the first discovery of any virus repurposing a cellular protein and using it to drive subsequent rounds of infection," said first author Caitlin Pegg, a graduate student in Smith's lab. "We are excited to further uncover the molecular mechanisms that these viruses have evolved that make them arguably the most successful pathogens known to science," Smith said.

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Story Source:

Materials provided by Northwestern University. Original written by Marla Paul. Note: Content may be edited for style and length.

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Journal Reference:

1. Caitlin E. Pegg, Sofia V. Zaichick, Ewa Bomba-Warczak, Vladimir Jovasevic, DongHo Kim, Himanshu Kharkwal, Duncan W. Wilson, Derek Walsh, Patricia J. Sollars, Gary E. Pickard, Jeffrey N. Savas, Gregory A. Smith. Herpesviruses assimilate kinesin to produce motorized viral particles. Nature, 2021; DOI: 10.1038/s41586-021-04106-w

https://www.sciencedaily.com/releases/2021/11/211117115131.htm

In the brain’s cerebellum, a new target for suppressing hunger

 People with Prader Willi syndrome, a genetic disorder, have an insatiable appetite. They never feel full, even after a hearty meal. The result can be life-threatening overeating and obesity.

According to a new study, their constant hunger results in part to disordered signaling in the brain's cerebellum, a region of the brain also responsible for motor control and learning. An international research team spanning 12 institutions, led by J. Nicholas Betley, an assistant professor of biology in the School of Arts & Sciences, and Albert I. Chen, an associate professor at the Scintillion Institute, in San Diego, used clues from Prader Willi patients to guide investigations in mice that uncovered a subset of cerebellar neurons that signals satiation after eating.

When the researchers activated these neurons, the magnitude of the effect "was enormous," accordingly to Betley. The animals ate just as often as typical mice, but each of their meals was 50-75% smaller.

"This was mind-blowing," he says. "In fact, it was so mind-blowing I thought it had to be wrong." Betley encouraged Aloysius Low, a postdoctoral researcher in his lab and first author on the study, to conduct a number of other experiments to ensure the effect was real. Over nearly a year, they became convinced.

"It's amazing that you can still find areas of the brain that are important for basic survival behaviors that we had never before implicated," Betley says. "And these brain regions are important in robust ways."

The work, shared in the journal Nature, suggests that neurons in the cerebellum's anterior deep cerebellar nuclei (aDCN) are involved in helping animals regulate their meal size.

A new region

Since its start, Betley's lab has unraveled a variety of neural circuits related to how the brain regulates food intake. That work as well as other research has implicated areas of the hindbrain and hypothalmus in this control. "But we also know that drugs that target the hypothalmus and the hindbrain aren't really good obesity therapeutics," Betley says.

With collaborators who study the human cerebellum, Roscoe Brady of Beth Israel Deaconess Medical Center in Boston and Mark Halko of McLean Hospital in Belmont, Massachusetts, Betley and Chen discussed the possibility that the cerebellum could play a role in hunger suppression. The two reached out to Laura Holsen of Boston's Brigham and Women's Hospital, who had a rare set of data containing functional MRI scans -- a way to track blood flow in the brain -- from Prader Willi patients. Holsen had used the data to pursue other questions related to the neural circuitry of the disorder, but the researchers took a fresh look at the data, looking for differences in how these patients' brains responded to food compared to an unaffected group.

"The cerebellum pops out," Betley says, "and we were all looking at this, saying, 'Is this real?'"

Turning to the mice, single-cell transcriptomic analysis confirmed that a small subset of glutamatergic neurons in the aDCN were the ones being activated upon eating. Activating only these aDCN neurons led the animals to dramatically constrain their meal size, whether they had been deprived of food or given as much food as they wanted previously. When the researchers did the reverse, inhibiting these same neurons, the mice ate larger-than-normal meals. While reducing food intake can often lead people and animals to compensate by eating more food later, the aDCN-stimulated animals did not do so, and measures of metabolic activity remained steady.

The findings were remarkable but didn't reveal what exactly the neurons were doing. Were they simply causing the animals to eat less, or were they involved in helping them predict how much to eat or regulate eating based on other feedback?

One hint came from the fact that when mice with activated aDCN neurons were given a food that was less calorie dense than their normal diet, they ate more than normal to obtain an equal number of calories. "That told us that this animal is calculating the number of calories it is taking in and stopping when it thinks it's had enough," Betley says.

Zeroing in on a subset of aDCN neurons shown to be activated by feeding, the research team dug deeper into the neurons' role in regulating hunger and satiety. In hungry animals, these neurons turned on quickly and strongly upon being given food; in fed animals, the neurons remained quiet.

A piece in the puzzle

In a final set of investigations, the researchers sought to understand how aDCN activity fit into what was already known about hunger and satiation circuits in the brain. Betley's lab had previously studied a group of neurons in the hypothalmus, called AgRP neurons, that are activated when animals are in a caloric deficit and are responsible for driving increased feeding. When the team activated these neurons at the same time as the aDCN neurons, the mice still had a dramatic reduction in food intake, suggesting that the cerebellum is signaling in a hypothalamic-independent pathway.

Feeding behaviors can also be driven by the reward and pleasure of eating, and thus Betley, Low, and colleagues next looked to see if dopamine signaling in the brain's ventral striatrum -- associated with neural "reward" pathways -- was affected by aDCN activation. They found that when the aDCN neurons associated with reduced feeding were activated dopamine flooded the ventral striatum. This was perplexing, as increased dopamine signaling generally drives animals to seek more reward.

To better understand the relationship between dopamine signaling and aDCN activity, the researchers activated the mice's aDSC neurons for an hour prior to feeding them. While mice normally have a spike in dopamine levels upon being given food, the aDCN-activated mice had a severely hindered dopamine increase.

"Other people have seen that when you activate dopaminergic neurons with dopamine, or take away dopamine, the animal will eat less," says Betley. "There may be a Goldilocks principle, making sure you eat just enough." Too much dopamine blocks the subsequent dopamine spike to rewards, ultimately changing behavior, he says.

"We think this is why the animal stops eating," Betley says. "It's no longer rewarding enough to continue."

These findings may guide therapeutic strategies to blunt the "reward" that Prader Willi syndrome patients get from eating, helping manage their uncontrollable hunger. "We are excited to translate these results into humans using non-invasive brain stimulation with Holsen, Halko, and Brady," Betley says. Such an approach could offer a way to treat obesity as well.

In ongoing work, Betley and colleagues aim to continue filling in the details about the regulatory control of hunger, contributing to a more complete overall picture of how hunger and satiety are regulated in the brain.

In addition to Betley, Low, Chen, Brady, Halko, and Holsen, coauthors on the paper were Penn's Nitsan Goldstein, Jamie R.E. Carty, Ju Y. Choi, Alekso M. Miller, and Clara Lenherr; Nanyan Technological University's Jessica R. Gaunt, Norliyana Zainolabidin, Helen S. T. Ho, Alaric K.K. Yip, and Toh Hean Ch'ng; the Monell Chemical Senses Center's Kuei-Pin Huang and Amber L. Alhadeff; the Salk Institute's Nicholas Baltar and Eiman Azim; the National University of Singapore's October M. Sessions; and the University of Kansas Medical Center's Amanda S. Bruce and Laura E. Martin. Low is first author, and Chen and Betley are co-corresponding authors.

The study was supported in part by the National Science Foundation (Grant 1845298), National Institutes of Health (grants NS105555, NS111479, NS112959, MH111868, MH125995, MH116170, DK104772, DK119574, DK114104, and DK124801), Searle Scholars Program, Pew Charitable Trusts, McKnight Foundation, Klingenstein Simons Fellowship Award, American Heart Association (grants 857082 and 17SDG33400158), American Diabetes Association (118IBS116), Whitehall Foundation, Warwick-NTU Neuroscience Programme, and Singapore Ministry of Education (MOE2018-T2-1-065 and MOE2017-T3-1-002).

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Story Source:

Materials provided by University of Pennsylvania. Note: Content may be edited for style and length.

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Journal Reference:

1. Aloysius Y. T. Low, Nitsan Goldstein, Jessica R. Gaunt, Kuei-Pin Huang, Norliyana Zainolabidin, Alaric K. K. Yip, Jamie R. E. Carty, Ju Y. Choi, Alekso M. Miller, Helen S. T. Ho, Clara Lenherr, Nicholas Baltar, Eiman Azim, October M. Sessions, Toh Hean Ch’ng, Amanda S. Bruce, Laura E. Martin, Mark A. Halko, Roscoe O. Brady, Laura M. Holsen, Amber L. Alhadeff, Albert I. Chen, J. Nicholas Betley. Reverse-translational identification of a cerebellar satiation network. Nature, 2021; DOI: 10.1038/s41586-021-04143-5

https://www.sciencedaily.com/releases/2021/11/211117211610.htm

Chronic stress, depression boost brain receptor; study maps how to block it

 Scientists at Scripps Research, Florida have determined the near-atomic-scale structure of an unusual brain-cell receptor called GPR158, which has been linked to depression and anxiety. The structural study reveals both the receptor and its regulating complex, advancing understanding of basic cell receptor biology. It also enables work on potential therapeutics designed to block GPR158 as a strategy for treating depression, anxiety and possibly other mood disorders.

In the study, published Nov. 18 in the journal Science, the researchers used ultracold, single-particle electron microscopy, or cryo-EM, to map, at a resolution of about a third of a billionth of a meter, the atomic structure of GPR158, both on its own and when bound to a group of proteins that mediate its activity.

"We've been studying this receptor for more than 10 years, and have done a lot of biology on it, so it's really gratifying to see for the first time how it's organized," says lead author Kirill Martemyanov, PhD, Professor and Chair of the Department of Neuroscience at the Scripps Research.

Clinical depression, also called major depressive disorder, is estimated to affect roughly 20 million people in the United States in any given year. Current treatments work on other known receptors, including monoamine, but don't always work well for all people and alternative options are needed.

Martemyanov and his team found in a 2018 study that GPR158 is present at unusually high levels in the prefrontal cortex of people diagnosed with major depressive disorder at the time of their death. They also found that exposing mice to chronic stress increased levels of this receptor in the mouse prefrontal cortex, leading to depression-like behavior -- whereas eliminating GPR158 activity in chronically stressed mice made them resistant to depression and the effects of stress. Additionally, the activity of GPR158 receptor has been also linked to prostate cancer.

Historically, GPR158 hasn't been easy to study. It is called an "orphan receptor" because scientists haven't yet identified the molecule responsible for turning its signaling function "on" in a manner similar to flipping a switch. The receptor is also considered unusual because, in the brain, unlike most receptors in its family, it exists in close association with a protein complex called the RGS signaling complex. RGS is short for "regulator of G protein signaling" and it acts as a powerful brake on cellular signaling. However, it has been unclear why GPR158 engages it.

In the new study, solving the receptor's structure offered many insights into how GPR158 works. First, scientists found that it binds RGS complex in the same way that many receptors typically engage their conventional transducers, leading to the idea that it employs RGS proteins as means of transducing its signal. Second, the structure revealed that the receptor exists as two interconnected copies of the GPR158 proteins stabilized by phospholipids.

"These are fat-related molecules that effectively staple the two halves of the receptor together" Martemyanov explains.

Finally, on the other side of the receptor that faces outside of the cell, an unusual module called the cache domain was revealed. The authors believe the cache domain serves as a trap for the molecules that activate GPR158. Cache domains have never been observed in these types of receptors before, demonstrating the unique biology of this orphan receptor.

First author Dipak Patil, PhD, a staff scientist in the Martemyanov laboratory, says solving the structure provides many new insights.

"I am thrilled to see the structure of this unique GPCR. It is first of its kind, showing many new features and offering a path for drug development," Patil says.

The challenge is now to use the information gleaned from the structure to inform the design of small molecule therapeutics to combat depression, Martemyanov adds.

He is now exploring several possible approaches, including disrupting the two-part arrangement, interfering with engagement of RGS complex, or by specifically targeting the cache domain with small, drug-like molecular binders. Regardless of the road taken, availability of structural information should greatly facilitate drug development efforts to treat depression, Martemyanov says.

This study was made possible by the latest technological advances in microscopy, including freezing proteins at ultra-cold temperatures and examining their organization through the lens of powerful microscopes, a technique called cryogenic electron microscopy, or Cryo-EM.

"The microscope uses a beam of electrons instead of light to image protein assemblies. The shorter wavelength of electrons compared to light allowed us to visualize our sample at near-atomic resolution," says structural biologist Professor Tina Izard, PhD. Patrick Griffin, PhD, Scripps Research, Florida scientific director, co-authored the study, applying a structural proteomic platform technology.

"The promise of Cryo-EM for achieving significant breakthroughs in solving structures of biomolecules is enormous. Our Institute is firmly committed to expanding Cryo-EM microscopy, which is made possible through the recent acquisition and installation of a new microscope on campus."

The study was a collaboration including researchers from Columbia University and Appu Singh, PhD, a structural biologist at the Indian Institute of Technology in Kanpur.

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Story Source:

Materials provided by Scripps Research Institute. Note: Content may be edited for style and length.

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Journal Reference:

1. Dipak N. Patil et al. Cryo-EM structure of human GPR158 receptor coupled to the RGS7-Gβ5 signaling complex. Science, 2021 DOI: 10.1126/science.abl4732

https://www.sciencedaily.com/releases/2021/11/211118203432.htm