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Column One: How Does COVID-19 Change the Brain? This Scientist Is Finding Out

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NEW YORK — 

In a room as cold as a refrigerator, Dr. Maura Boldrini bends over a plastic box filled with pale slices of human brain, each piece nestled in its own tiny, fluid-filled compartment.

She gestures with purple-gloved fingers: Here are the folds of the cortex, where higher cognition takes place. There is the putamen, which helps our limbs move. Here is the emotion-processing amygdala, with its telltale bumps.

Each piece in this box came from a single brain — one whose owner died of COVID-19.

There are dozens more containers just like it stacked in freezers in Boldrini’s lab at the New York State Psychiatric Institute.

“Each of these boxes is one person,” she says in a lilting Italian accent. Each will play a crucial role in helping to unravel COVID-19’s impacts on the brain.

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The disease may be best known for its ability to rob people of their breath, but as the pandemic spread, patients began reporting a disconcerting array of cognitive and psychiatric issues — memory lapses, fatigue and a mental fuzziness that became known as brain fog. There were also more acute problems, including paranoia, hallucinations, thoughts of suicide and psychosis.

This strange constellation of symptoms has led researchers to suspect that the disease is mounting a direct attack on the brain. Researchers want to figure out how — and what the assault’s long-term effects may be.

Boldrini, a neuroscientist at Columbia University, studies the biology of suicide and the physiological markers of resilience in brain tissue. She is also a practicing psychiatrist.

That combination makes her uniquely suited to investigate the underpinnings of “long COVID.” She has gathered more than 40 brains from COVID-19 victims to guide her in her quest.

Dr. Maura Boldrini catalogs brain tissue from COVID-19 victims. “We have a lot of work to do,” she says.

(Kirk McKoy / Los Angeles Times)

What Boldrini and her colleagues learn could have implications far beyond COVID-19, shedding light on mental illness, the origins of dementia and on the myriad ways viral infections affect the brain.

To unlock the disease’s secrets, they’ll have to carefully take each brain apart, count its cells, track its gene expression and document its proteins.

“We have a lot of work to do,” Boldrini says.

::

New York City was one of the coronavirus’ early targets, and it didn’t take long for Boldrini to notice surprising issues among COVID-19 patients, including serious mood and psychiatric symptoms.

“Very strange symptoms,” she recalls — made even stranger because they were cropping up in people with no personal or family history of such problems. Adding to the mystery was the appearance of these conditions relatively late in a patient’s life rather than in adolescence and early adulthood.

I feel like this dread that I’m feeling is something organic in my brain, one patient told her. Psychologically, I’m not anxious about anything.

“It’s a very different kind of symptomatology compared to people that have normal anxiety,” Boldrini says.

Boldrini explains her research on the psychiatric symptoms seen in COVID-19 patients. The disease may be best known for its ability to rob people of their breath, but many patients report an array of cognitive and psychiatric issues — memory lapses, fatigue and a mental fuzziness that became known as brain fog.

(Kirk McKoy / Los Angeles Times)

Then there were the rarer, but more disturbing, cases of suicidal ideation.

Boldrini has not encountered a COVID-19 patient who died of suicide. But one case did hit her university close to home: Dr. Lorna Breen, an emergency department physician at Columbia who worked on the front lines before becoming ill herself during the pandemic’s brutal first wave.

Breen was a talented and dedicated doctor who took up snowboarding and salsa dancing in her spare time. Shortly after returning to work, her mental health deteriorated and she died by suicide within weeks.

“She had COVID, and I believe that it altered her brain,” her sister Jennifer Feist said on NBC’s “Today” last year.

If so, how?

Researchers have found signs that the virus can establish a foothold of sorts on the periphery of the brain, where the protective blood-brain barrier opens up to allow key molecules to slip through. One of those places is the olfactory bulb, which can be reached through the nose — a fact that could explain why so many COVID-19 patients lose their sense of smell.

Yet scientists have so far found little evidence that the virus penetrates any deeper than that. Instead, they’ve seen the type of damage caused by strokes, as well as the blood clots that may have precipitated them.

That’s part of why Boldrini and many others suspect that inflammation — the immune system’s all-hands-on-deck response to an invader — may play an essential role in the brain damage experienced by COVID-19 patients.

Inflammation can trigger blood clots, and once a clot forms, inflammation increases around it. It’s similar to what’s seen in people who experience traumatic brain injury, including football players, military veterans and victims of car accidents.

“People that have this kind of trauma in the brain have presented with sudden changes in behavior and personality and suicide and other brain symptoms,” Boldrini says. It’s eerily similar to what many COVID-19 patients face — and she doesn’t think that’s a coincidence.

::

To gain a deeper understanding of what’s happening on a cellular and molecular level, scientists need to study the brains of people who died of COVID-19. But Boldrini prefers not to work with brains collected by others — she has to know everything about how the tissue was collected and preserved so she can understand the results of her experiments.

“Depending how you freeze, store and fix the brain, you can get very different results,” she says.

At Columbia, she and her colleagues examine tissue from autopsies, so they have complete control over how the precious tissue is handled.

Boldrini wants to know which genes were being expressed; to track molecular markers of inflammation; to see how microglia — the brain’s immune cells — were behaving; and to document the state of the neurons and their connections with one another.

Suzuka Nitta prepares brain tissue from a COVID-19 victim to be thinly sliced for examination.

(Kirk McKoy / Los Angeles Times)

Mapping the multifaceted effects of one disease is an ambitious endeavor, and it requires painstaking work. One of the students working in the lab starts by taking a scallop-edged sample of the amygdala and mounting it on a bed of dry ice. Drop by drop, she coats the tissue in sugar water, which eventually freezes and holds the sample in place.

Next, she slices off pieces that are a mere 50 microns thick — just wide enough to contain a single layer of brain cells. Each fragile cut is then submerged in water and centered on a glass slide with fine-tipped paint brushes.

A sample of brain tissue is mounted on a glass slide.

(Kirk McKoy / Los Angeles Times)

The slides are stained with dyes that allow the researchers to see different types of cells in the tissue. Those cells are counted under a microscope, partly by human eye and partly with the help of a computer algorithm.

Boldrini looks over the student’s shoulder at one of the slides magnified on a computer screen. This slice of brain tissue resembles a galactic crush of stars stretched across a darkened sky: The scattered blue stars are glia, the brain’s protective cells. The green ones are neurons, densely packed together. The red stars are young, immature neurons.

“It’s beautiful,” Boldrini says. “Anatomy is very beautiful.”

Boldrini examines an image of brain cells.

(Kirk McKoy / Los Angeles Times)

The red stars are the rarest of the three, and they’re even more sparse in many patients who had COVID-19 — about 10 times less abundant. That’s a problem because these young neurons are necessary for learning and memory, for coping with stress, and for integrating memories with emotions.

Boldrini suspects these immature cells are done in by stress hormones and inflammation.

“This would explain the brain fog,” she says.

A few days earlier, the researchers went through the same steps with the hippocampus, a tiny, delicate brain structure involved in mood and memory.

Other scientists have found that COVID-19 damages the hippocampus. That could help explain why some patients have lingering issues with depression and anxiety.

If this damage is caused by inflammation, it probably wreaks havoc in several ways. Scientists suspect it disrupts the flow of serotonin, a hormone that’s implicated in depression, and prompts the body to make kynurenine instead, even though it’s toxic to neurons.

Inflammation also triggers coagulation, creating clots that can block blood flow to cells and kill them. And it activates the microglia, which may attempt to remove more neurons than they normally would.

Boldrini’s work will help scientists disentangle the factors driving that damage.

“She’s an expert at that,” says Dr. James Goldman, a neuropathologist at Columbia University. “We’re looking forward to seeing what she comes up with.”

::

In a nearby room, research assistant Cheick Sissoko checks to see whether the DNA fragments obtained from the tissue are too big or too small for proper analysis. If they’re the right size, Sissoko will use them to better understand the gene expression in these brain cells — particularly in the young neurons that seem to be taking a hit in COVID-19 patients.

“Ideally, we can look at every single gene expressed by a single cell,” he says.

Boldrini and research assistant Cheick Sissoko confer on the progress of their work.

(Kirk McKoy / Los Angeles Times)

On other days, Sissoko focuses on RNA, the molecule that helps turn DNA’s instructions into actual proteins. The RNA contained in brain tissue may provide clues about the alarms that were set off in the body in response to the coronavirus, and how the body reacted to a perceived threat.

Sissoko uses a sophisticated new technique to sequence the RNA on a slide-by-slide basis. That allows him to see how RNA expression changes in different parts of the brain.

Ultimately, the researchers aim to combine the data on RNA, the microglia, the new and mature neurons, and the connections they make to create a portrait of a brain ravaged by COVID-19.

By comparing the brains of COVID-19 patients with and without neurological symptoms, Boldrini hopes to shed light on the role of inflammation in a wide swath of neurodegenerative diseases, from depression to dementia.

“This pandemic is almost like a natural experiment where you have a lot of inflammation like in a very unusual way,” she says. “We hope that this is going to clarify some mechanisms of brain damage independently of COVID itself.”

That, in turn, may help people understand that mental health is a crucial part of physical health.

“I think this could be very useful to fight the stigma against psychiatric illness,” Boldrini says. “The brain is an organ, like any other one.”

Dr. Christian Hicks Puig, a psychiatrist at Columbia Medical Center who works at the long COVID clinic, agreed. Many mental health issues are rooted in biological processes. “It’s all extremely interconnected,” he says.

As researchers like Boldrini map COVID-19’s assault on the brain, they may help doctors more deeply understand the relationship between mental health, cognitive health and disease. They may also gain insight into the long-term needs of COVID-19 survivors.

That progress would not be possible without the contributions of those who didn’t make it, Goldman says.

“We are very, very grateful to families who have allowed us to do these autopsies,” he says.

Boldrini agrees, adding that she and others feel immense pressure to handle these organs with care.

“These are people,” she says. What they reveal about COVID-19 is crucial. What they represent is irreplaceable.

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Article: latimes.com

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Why Mexico’s President Is Promoting a Recall Against Himself

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MEXICO CITY — 

Standing before hundreds of thousands of cheering supporters in downtown Mexico City’s central square, President Andrés Manuel López Obrador saved his most striking comment for the end of his speech.

He urged the Mexicans packed into the Zócalo to participate in an April referendum to decide whether they want to boot him from office more than two years early.

“None of, ‘They chose me for six years and I can do whatever I want,’” López Obrador said at the rally Wednesday to mark his midterm. “If one who governs is not up to the task and obeying the people, revoke their mandate and out!”

The president, 68, likely believes he has nothing to worry about.

Recent polls show that about two-thirds of the public approve of his performance since taking office in 2018 on a platform that promised a radical transformation of Mexican society to combat corruption and inequality and to roll back free-market economic policies.

Families and marching bands making their way to the Zócalo passed vendors hawking gray-haired López Obrador dolls and posters with the hashtag #QueSigaAMLO, or “may AMLO continue,” referring to the president by his initials. Many said they view a referendum, authorized by a 2019 constitutional reform spearheaded by the president, as proof of his honest character when compared to decades of presidents accused of corruption.

“AMLO is the first president that dares to put himself to the test before the people,” said Debanhi Andrea Garcia, 22, who drove 14 hours from the state of Nuevo León with her boyfriend. “Because he’s like that, we support him.”

Supporters of López Obrador hold banners in support of the president at Mexico City’s Zócalo.

(Manuel Velasquez / Getty Images)

Mexicans have until Dec. 25 to sign a petition supporting the referendum, which can move forward only with the signatures of at least 3% of eligible voters, among other caveats.

So far, the initiative has received more than 703,000 signatures from Mexicans who have valid voting credentials, or 25% of the required total, according to the National Electoral Institute, an independent agency overseeing the process. (That tally includes signatures that will be discarded because they are duplicates or have other irregularities.)

Officially called the “revocation of mandate,” the measure follows other efforts by the president to increase citizen engagement in public policy. López Obrador has also backed referendums to decide whether former Mexican presidents should be prosecuted for alleged crimes, on the construction of a new airport near Mexico City and on the development of a tourism train line that would run through the Yucatan Peninsula.

“He does conceive his power as being a function of people reiterating their support actively,” said Francisco González, a professor of Latin American politics at Johns Hopkins University. “He wants it officially confirmed to give him that comfort of being the popular leader who is doing the right thing for Mexico.”

Since taking office, López Obrador has also expanded social welfare programs while introducing sharp austerity measures. He has halted renewable energy projects, promoted a constitutional reform to increase the country’s control of the electricity market, and given more power to the military — putting it in charge of projects such as the tourism train.

President López Obrador gives an address to mark the midpoint of his term.

(Manuel Velasquez / Getty Images)

His critics say that he hasn’t done enough to reduce high levels of homicides, including many killings of women and attacks against journalists and public officials. Dozens of candidates across the country were assassinated ahead of last spring’s midterm elections for governorships and legislative and mayoral seats.

Critics also are concerned about López Obrador’s attacks against democratic agencies that could check his power, notably the National Electoral Institute. He has repeatedly disparaged the independent agency, which last May sanctioned him for making statements in at least 29 news conferences that it said could be considered government propaganda that could influence the midterm elections. In Mexico, such statements by public officials are generally barred during the election season.

But the president’s vision of transformational change continues to resonate among many voters who view him as a paternal figure. López Obrador is in constant dialogue with his electorate, holding press conferences every morning that last hours.

“The figure he has constructed of an honest man, an honorable man, an incorruptible man — that helps him in a society that is used to seeing terribly corrupt politicians,” said René Torres-Ruiz, a political scientist at the Universidad Iberoamericana in Mexico City.

Even if enough signatures are gathered, hurdles to a referendum remain. The National Electoral Institute’s members have said that the agency doesn’t have the budget to carry out the vote and at least 40% of eligible voters must participate for the referendum to be binding. The referendum on former presidents last August fell far short of the 40% voting figure.

Ariadna Gomez, left, and another volunteer collect signatures for a referendum on whether Mexico’s president should continue.

(Leila Miller / Los Angeles Times)

Stephanie Brewer, the director for Mexico and migrant rights at the D.C.-based Washington Office on Latin America, said that winning a referendum would increase López Obrador’s perception that he could move forward freely with his agenda.

“What he wants is to come out of the vote, supposing there is one, politically strengthened with this renewed and amplified popular mandate,” she said.

Opposition parties have accused the president’s supporters of twisting the stated purpose of the referendum into a tool to promote López Obrador’s agenda. The 2019 reform called for a referendum to “revoke” a president’s mandate rather than “ratify” it and a complaint before the National Electoral Institute by the National Action Party referenced how volunteers have registered voters next to posters that advertise the referendum as a means of promoting the president rather than recalling him from office.

Luis Cházaro, a congressman from the Party of the Democratic Revolution, told The Times that the referendum “has been transformed into a promotional tool for the party.” He does not plan to participate.

In Coyoacán, a cobblestoned neighborhood in Mexico City known for Frida Kahlo’s home, volunteers last Sunday gathered signatures at a plaza in front of posters of the president that said “may AMLO continue.”

Ariana Garcia, a 24-year-old volunteer, said she uses the term “ratification” for people she senses like the president and “revocation” for those she thinks oppose him.

“People tell you, ‘But I don’t want my president to leave,’ so we tell them, ‘OK, then in this case you can ratify your support for the president,’” she said.

A supporter of López Obrador listens to his speech at a rally to commemorate the president’s midterm.

(Marco Ugarte/Associated Press)

Roberto Garcia, a systems engineer in Mexico City, said that he would vote against the president, uncomfortable that the federal government recently issued a decree that requires federal agencies to automatically approve infrastructure projects that are deemed to be of interest to the public or national security. He also sees the referendum as “a type of manipulation,” suspicious of why the president has contradicted the National Electoral Institute, saying it has enough funding to hold a vote he himself has fought for.

María de los Angeles Resendiz, a grandmother of 10 from the state of Mexico, will support López Obrador without hesitation.

Resendiz, 62, watches the president’s 7 a.m. news conferences each day with her husband while preparing breakfast and washing dishes. If she needs to skip one, she’ll track it down later on YouTube. She also listens to summaries in case she’s missed something.

Before López Obrador took power, Resendiz tried to stay as far away from politics as she could. She became disillusioned when she was a little girl after the 1968 Tlatelolco massacre, in which soldiers killed as many as 300 people at a student protest in Mexico City.

She called López Obrador a “simple” man who has won her confidence with his anti-corruption platform. She eagerly described how his government has set money aside for youth job training and expanded welfare payments to the elderly.

“He’s given us back our dignity,” she said. “I am proud to say that I am Mexican and that he is my president.”

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Original Post: latimes.com

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Op-Ed: the U.S. Shouldn’t Ignore Mexico’s Ongoing Human Rights Catastrophe

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On Dec. 1, Mexican President Andrés Manuel López Obrador reached the halfway point of his six-year term. Since his election in 2018, López Obrador has not only failed to improve the country’s disastrous human rights record, he has worked to undo many of the hard-fought gains in transparency and the rule of law that rights groups, activists and campaigners have achieved since the end of one-party rule in Mexico in 2000.

The United States has been noticeably silent regarding the Mexican president’s accelerating attacks on democracy. President Biden has instead chosen to focus on enlisting López Obrador to prevent migrants from reaching the U.S. border.

López Obrador, a prominent anti-establishment figure in Mexican politics for decades, is the kind of populist leader that has become increasingly common in Latin America. He was democratically elected in a landslide on a promise to “transform” Mexico by taking back control of the country from the elites whose policies he blamed for economic inequality, social breakdown and growing violence.

López Obrador inherited a human rights catastrophe. When he came to office in 2018, 12 years of a military-led drug war had led to horrific abuses. Homicides hit staggering numbers. Thousands of people disappeared every year. But he has not addressed these problems. Soldiers continue to kill civilians. Homicides remain at historically high rates. And according to the government’s figures, more than 25,000 people have gone missing on his watch.

Even so, López Obrador has remained immensely popular with his base. He appears to believe that his continued popular support gives him the moral authority to concentrate as much power as possible in his own hands and to attempt to control every part of the state to bring about his promised transformation.

He labels anyone who criticizes him or stands in his way as a “neoliberal” or “conservative,” nebulous groups of supposed adversaries whom he describes as corrupt and morally bankrupt. Leveling this charge allows him to avoid responding to genuine concerns raised by journalists who question him, women’s rights campaigners upset at his lack of action on gender-based violence, Indigenous communities who oppose his megaprojects, environmentalists who disagree with his coal and oil-focused energy policy, and press freedom campaigners concerned about his government’s harassment of journalists, among others.

He has eliminated or proposed eliminating many government agencies not under his direct control, including the independent energy and telecommunications regulators, funds for protecting journalists and responding to climate change and natural disasters, the independent transparency agency and the independent electoral authority. He recently decreed that his government’s construction and infrastructure projects would be automatically granted permits without any review and that as matters of “national security,” would be exempted from transparency rules.

He has also gone after the judicial system, which has delayed or blocked a number of his projects and proposals as abusive or unconstitutional. His efforts to intimidate the judiciary have grown brazen. López Obrador has publicly singled out those whose rulings he dislikes and called for a judge who ruled against him to be investigated.

In April, his coalition in Congress passed a law — since overturned — to extend the term of the Supreme Court chief justice who has ruled in favor of the president. And in August, López Obrador held a referendum on whether the government should put five previous presidents on trial for alleged crimes such as “neoliberalism” and the “privatization of public goods.”

The U.S. policy of ignoring López Obrador’s attacks on the rule of law came into stark relief in June, when Vice President Kamala Harris visited Mexico and met with him. At the end of the trip, a journalist asked the vice president if the United States was concerned about López Obrador’s hostile attitude toward the media and civil society.

Harris initially responded that she had urged the Mexican president to respect the independence of the judicial system, the press and civil society. However, hours later, her spokesperson issued a correction to the Spanish wire service EFE, saying the vice president had been confused; she and the Mexican president had only discussed immigration and the economy, nothing else.

López Obrador will be in office for another three years. His coalition still controls both houses of Congress and he has made it clear that he is willing to amend the constitution if necessary to remove obstacles to achieving his goals. Unless the circumstances change, there are no signs he intends to alter his course.

José Miguel Vivanco is Americas director at Human Rights Watch. Tyler Mattiace is a researcher at Human Rights Watch.

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Source: latimes.com

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Photos: As Roe Vs. Wade Challenged, Demonstrators Gather Outside Supreme Court

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Juanito Estevez, of Freeport, N.Y., holds a cross as he and abortion rights advocates and anti-abortion protesters demonstrate in front of the Supreme Court in Washington, D.C.

(Kent Nishimura/Los Angeles Times)

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Article: latimes.com

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