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Gene Expression Pattern Predicts Which Neurons Will Regenerate after Injury

Researchers used single-cell RNA sequencing (scRNA-seq) to identify a pattern of gene expression that can predict whether or not neurons will regenerate…

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Researchers from University of California San Diego School of Medicine have used single-cell RNA sequencing (scRNA-seq) to identify a pattern of gene expression that can be used to predict whether or not neurons will regenerate after an injury. Tests in mice showed that this “Regeneration Classifier” was consistently reliable in predicting the regeneration potential of neurons across the nervous system and at different developmental stages. Conditional gene deletion then validated a role for NFE2L2 (or NRF2), a master regulator of antioxidant response, in corticospinal tract regeneration.

“Single-cell sequencing technology is helping us look at the biology of neurons in much more detail than has ever been possible, and this study really demonstrates that capability,” said senior author Binhai Zheng, PhD, professor in the Department of Neurosciences at UC San Diego School of Medicine. “What we’ve discovered here could be just the beginning of a new generation of sophisticated biomarkers based on single-cell data.” Zheng and colleagues reported on their findings in Neuron, in a paper titled “Deep scRNA sequencing reveals a broadly applicable Regeneration Classifier and implicates antioxidant response in corticospinal axon regeneration.” In their paper the team concluded, “Our data demonstrate a universal transcriptomic signature underlying the regenerative potential of vastly different neuronalpopulations and illustrate that deep sequencing of only hundreds of phenotypically identified neurons has the power to advance regenerative biology.”

 

Neurons, shown here in red and yellow, are some of the slowest cells to regenerate after injury. In this section of a mouse brain, yellow neurons are regenerating while red neurons are non-regenerating. [UC San Diego Health Sciences]
Neurons are among the slowest cells to regenerate after an injury. While scientists have made progress in understanding neuronal regeneration, it remains unknown why some neurons regenerate and others do not.

For their study the researchers focused on neurons of the corticospinal tract, which is a critical part of the central nervous system that helps control movement. After injury, these neurons are among the least likely to regenerate axons—the long, thin structures that neurons use to communicate with one another. This is why injuries to the brain and spinal cord are so devastating. As the authors noted, “Despite substantial progress in understanding the biology of axon regeneration in the CNS, our ability to promote regeneration of the clinically important corticospinal tract (CST) after spinal cord injury remains limited.”

First author Hugo Kim, PhD, a postdoctoral fellow in the Zheng lab, added, “If you get an injury in your arm or your leg, those nerves can regenerate and it’s often possible to make a full functional recovery, but this isn’t the case for the central nervous system. It’s extremely difficult to recover from most brain and spinal cord injuries because those cells have very limited regenerative capacity. Once they’re gone, they’re gone.”

To carry out their investigations the researchers used Patch-based single-cell RNA sequencing to analyze gene expression in neurons from mice with spinal cord injuries. They encouraged these neurons to regenerate using established molecular techniques, but ultimately, this only worked for a portion of the cells. This experimental setup allowed the researchers to compare sequencing data from regenerating and non-regenerating neurons.

Further, by focusing on a relatively small number of cells—just over 300—the researchers were able to look extremely closely at each individual cell. “Just like how every person is different, every cell has its own unique biology,” said Zheng. “Exploring minute differences between cells can tell us a lot about how those cells work.”

Using a computer algorithm to analyze their sequencing data the researchers identified a unique pattern of gene expression that can predict whether or not an individual neuron will ultimately regenerate after an injury. The pattern also included some genes that had never been previously implicated in neuronal regeneration. “It’s like a molecular fingerprint for regenerating neurons,” commented Zheng.

Hugo Kim, PhD (left) designed and executed the single-cell RNA sequencing experiments under the supervision of Binhai Zheng, PhD (right). [UC San Diego Health Sciences]
Hugo Kim, PhD (left) designed and executed the single-cell RNA sequencing experiments under the supervision of Binhai Zheng, PhD (right).
To validate their findings the researchers tested this molecular fingerprint, which they named the Regeneration Classifier, on 26 published single-cell RNA sequencing datasets. These datasets included neurons from various parts of the nervous system and at different developmental stages.

The team found that with few exceptions, the Regeneration Classifier successfully predicted the regeneration potential of individual neurons and was able to reproduce known trends from previous research, such as a sharp decrease in neuronal regeneration just after birth.  “We found that our Regeneration Classifier can be applied in an unbiased manner to characterize any published scRNA-seq dataset,” the team commented. “This generated a pattern of regeneration classification for various neuronal populations that remarkably reflects prior knowledge on their regenerative potential based on the neuronal type and developmental stage.”

Zheng added, “Validating the results against many sets of data from completely different lines of research tells us that we’ve uncovered something fundamental about the underlying biology of neuronal regeneration,” said Zheng. “We need to do more work to refine our approach, but I think we’ve come across a pattern that could be universal to all regenerating neurons.” In their paper the investigators stated, “It has been extensively shown in the literature that neurons undergo a developmental stage-dependent decline in regenerative abilities. However, our data provide, for the first time to our knowledge, a transcriptomic basis for this phenomenon across vastly different neuronal types.”

A closer evaluation of differentially expressed genes, and gene network analyses, highlighted a gene called NFE2L2 (nuclear-factor-erythroid-derived-2-like 2) also known as NRF2 (nuclear-factor erythroid-2-related factor 2), as a potential regulator of differentially expressed genes in regenerating, compared with non-regenerating CST neurons. NFE2L2 encodes a transcription factor that activates antioxidant genes that are under oxidative stress in response to injury and inflammation. Tests in engineered mice indicated that NFE2L2 acted as a positive regulator of CST regeneration. The team said the findings “… validate our Patch-seq approach in discovering new regeneration regulators.”

Another top candidate PPARGC1A (or PGC-1α), encodes a master regulator of mitochondrial biogenesis, but the role of PGC-1α in CST regeneration has yet to be validated in vivo, the authors noted. Nevertheless, they stated, “… our observation that these two genes (NFE2L2 and PPARGC1A) sit at the top of the regulatory network in regenerating neurons highlights the importance of both antioxidative response and mitochondrial biogenesis.”

While the results in mice are promising, the researchers caution that at present, the Regeneration Classifier is a tool to help neuroscience researchers in the lab rather than a diagnostic test for patients in the clinic. “For preclinical studies, a Regeneration Classifier may serve as a biomarker to predict the likelihood of success for candidate regenerative therapies. In this regard, our approach will likely have broad applicability in studying many other neurological conditions,” the scientists stated.

“There are still a lot of barriers to using single-cell sequencing in clinical contexts, such as high cost, difficulty analyzing large amounts of data and, most importantly, accessibility to tissues of interest,” said Zheng. “For now, we’re interested in exploring how we can use the Regeneration Classifier in preclinical contexts to predict the effectiveness of new regenerative therapies and help move those treatments closer to clinical trials.”

The post Gene Expression Pattern Predicts Which Neurons Will Regenerate after Injury appeared first on GEN - Genetic Engineering and Biotechnology News.

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Women’s basketball is gaining ground, but is March Madness ready to rival the men’s game?

The hype around Caitlin Clark, NCAA Women’s Basketball is unprecedented — but can its March Madness finally rival the Men’s?

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In March 2021, the world was struggling to find its legs amid the ongoing Covid-19 pandemic. Sports leagues were trying their best to keep going.

It started with the NBA creating a bubble in Orlando in late 2020, playing a full postseason in the confines of Disney World in arenas that were converted into gyms devoid of fans. Other leagues eventually allowed for limited capacity seating in stadiums, including the NCAA for its Men’s and Women’s Basketball tournaments.

The two tournaments were confined to two cities that year — instead of games normally played in different regions around the country: Indianapolis for the men and San Antonio for the women.

But a glaring difference between the men’s and women’s facilities was exposed by Oregon’s Sedona Prince on social media. The workout and practice area for the men was significantly larger than the women, whose weight room was just a single stack of dumbbells.

The video drew significant attention to the equity gaps between the Men’s and Women’s divisions, leading to a 114-page report by a civil rights law firm that detailed the inequities between the two and suggested ways to improve the NCAA’s efforts for the Women’s side. One of these suggestions was simply to give the Women’s Tournament the same March Madness moniker as the men, which it finally got in 2022.

But underneath the surface of these institutional changes, women’s basketball’s single-biggest success driver was already emerging out of the shadows.

During the same COVID-marred season, a rookie from Iowa led the league in scoring with 26.6 points per game.

Her name: Caitlin Clark.

Caitlin Clark has scored the most points and made the most threes in college basketball.

Matthew Holst/Getty Images

As it stands today, Clark is the leading scorer in the history of college basketball — Men’s or Women’s. Her jaw-dropping shooting ability has fueled record viewership and ticket sales for Women’s collegiate games, carrying momentum to the March Madness tournament that has NBA legends like Kevin Garnett and Paul Pierce more excited for the Women’s March Madness than the Men’s this year.

Related: Ticket prices for Caitlin Clark's final college home game are insanely high

But as the NCAA tries to bridge the opportunities given to the two sides, can the hype around Clark be enough for the Women’s March Madness to bring in the same fandom as the Men for the 2024 tournaments?

TheStreet spoke with Jon Lewis of Sports Media Watch, who has been following sports viewership trends for the last two decades; Melissa Isaacson, a veteran sports journalist and longtime advocate of women’s basketball; and Pete Giorgio, Deloitte’s leader for Global and US Sports to dissect the rise Caitlin Clark and women’s collegiate hoops ahead of March Madness.

“Nobody is moving the needle like Caitlin Clark,” Lewis told TheStreet. “Nobody else in sports, period, right now, is fueling record numbers on all these different networks, driving viewership beyond what the norm has been for 20 years."

The Caitlin Clark Effect is real — but there are other reasons for the success of women's basketball

The game in which Clark broke the all-time college scoring record against Ohio State on Sunday, Mar. 3 was seen by an average of 3.4 million viewers on Fox, marking the first time a women’s game broke the two million viewership barrier since 2010. Viewership for that game came in just behind the men’s game between Michigan State vs Arizona game on Thanksgiving, which Lewis said was driven by NFL viewership on the same day.

A week later, Iowa’s Big Ten Championship win over Nebraska breached the three million viewers mark as well, and the team has also seen viewership numbers crack over 1.5 million viewers multiple times throughout the regular season.

The success on television has also translated to higher ticket prices, as tickets to watch Clark at home and on the road have breached hundreds of dollars and drawn long lines outside stadiums. Isaacson, who is a professor at Northwestern, said she went to the game between the Hawkeyes and Northwestern Wildcats — which was the first sellout in school history for the team — and witnessed the effect of Clark in person.

“Standing in line interviewing people at the Northwestern game, seeing men who've never been to a women's game with their little girls watching and so excited, and seeing Caitlin and her engaging with little girls, it’s just been really fun,” Isaacson said.

But while Clark is certainly the biggest success driver, her game isn’t the only thing pulling up the women’s side. The three-point revolution, which started in the NBA with the introduction of deeper analytics as well as the rise of stars like Steph Curry, has been a positive for the Women’s game.

“They backed up to the three-point line and it’s opening up the game,” Isaacson said.

One of the major criticisms from a lot of women’s hoops detractors has been how the game does not compare in terms of quality to the men. However, shooting has become a great equalizer, displayed recently during the 2024 NBA All-Star Weekend last month when the WNBA’s Sabrina Ionescu nearly defeated Curry — who is widely considered the greatest shooter ever — in a three-point contest.

Clark has become the embodiment of the three-point revolution for the women. Her shooting displays have demanded the respect of anyone who has doubted women’s basketball in the past because being a man simply doesn’t grant someone the ability to shoot long-distance bombs the way she can.

Basketball pundit Bill Simmons admitted on a Feb. 28 episode of “The Bill Simmons Podcast” that he used to not want to watch women’s basketball because he didn’t enjoy watching the product, but finds himself following the women’s game this year more than the men’s side in large part due to Clark.

“I think she has the chance to be the most fun basketball player, male or female, when she gets to the pros,” Simmons said. “If she’s going to make the same 30-footers, routinely. It’s basically all the same Curry stuff just with a female … I would like watching her play in any format.”

But while Clark is driving up the numbers at the top, she’s not the only one carrying the greatness of the product. Lewis, Isaacson, Giorgio — and even Simmons, on his podcast — agreed that there are several other names and collegiate programs pulling in fans.

“It’s not just Iowa, it’s not just Caitlin Clark, it’s all of these teams,” Giorgio said. “Part of it is Angel Reese … coaches like Dawn Staley in South Carolina … You’ve got great stories left and right.”

LSU's Angel Reese (right) and her head coach Kim Mulkey are two of the biggest names in Women's college hoops. 

Eakin Howard/Getty Images

The viewership showed that as well because the SEC Championship game between the LSU Tigers and University of South Carolina Gamecocks on Sunday, Mar. 10 averaged two million viewers.

Bridging the gap between the Men’s and Women’s March Madness viewership

The first reason women are catching up to the men is really star power. While the Women’s division has names like Clark and Reese, there just aren’t any names on the Men’s side this year that carry the same weight.

Garnett said on his show that he can’t name any men’s college basketball players, while on the women’s side, he could easily throw out the likes of Clark, Reese, UConn’s Paige Bueckers, and USC’s JuJu Watkins. Lewis felt the same.

“The stars in the men's game, with one and done, I genuinely couldn't give you a single name of a single men’s player,” Lewis said.

A major reason for this is that the Women’s side has the continuity that the Men’s side does not. The rules of the NBA allow for players to play just one year in college — or even play a year professionally elsewhere — before entering the draft, while the WNBA requires players to be 22-years-old during the year of the draft to be eligible.

“You know the stars in the women's game because they stay longer,” Lewis said. “[In the men’s game], the programs are the stars … In the women's game, it's a lot more like the NBA where the players are the stars.”

Parity is also a massive factor on both sides. The women’s game used to be dominated by a few schools like UConn and Notre Dame. Nowadays, between LSU, Iowa, University of South Carolina, Stanford, and UConn, there are a handful of schools that have a shot to win the entire tournament. While this is more exciting for fans, the talent in the women's game isn’t deep enough, so too many upsets are unlikely. Many of the biggest draws are still expected to make deep runs.

But on the men’s side, there is a bigger shot that the smaller programs make it to the end — which is what was seen last year. UConn eventually won the whole thing, but schools without as big of a national fanbase in San Diego State, Florida Atlantic University, and the University Miami rounded out the Final Four.

“People want to see one Cinderella,” Lewis said. “They don't want to see two and three, they want one team that isn't supposed to be there.”

Is Women's March Madness ready to overtake the Men?

Social media might feel like it’s giving more traction to the Women’s game, but experts don’t necessarily expect that to show up in the viewership numbers just yet.

“There’s certainly a lot more buzz than there used to be,” Giorgio said. “It’s been growing every year for not just the past few years but for 10 years, but it’s hard to compare it versus Men’s.”

But the gap continues to get smaller and smaller between the two sides, and this year's tournament could bridge that gap even further.

One indicator is ticket prices. For the NCAA Tournament Final Four in April, “get-in” ticket prices are currently more expensive for the Women’s game than the Men’s game, according to TickPick. The ticketing site also projects that the Women’s Final Four and Championship game ticket prices will smash any previous records for the Women’s side should Clark and the Hawkeyes make a run to the end.

NCAA "get-in" price comparison.

Getty Images/TheStreet

The caveat is that the Women’s Final Four is played in a stadium that has less than a third of the seating capacity of the Men’s Final Four. That’s why the average ticket prices are still more expensive for the men, although the gap is a lot smaller this year than in previous years.

The gap between the average ticket prices of the Final Four tournaments is getting smaller.

But that caveat pretty much sums up where the women’s game currently stands versus the men’s: There is still a significant gap between the distribution and availability of the former.

While Iowa’s regular season games have garnered millions of viewers, the majority of the most-viewed games are still Men’s contests.

To illustrate the gap between the men’s and women’s game — last year’s Women’s Championship game that saw the LSU Tigers defeat the Hawkeyes was a record-breaking one for the women, drawing an average of 9.9 million viewers, more than double the viewership from the previous year.

One of the main reasons for that increase, as Lewis pointed out, is that last year’s Championship game was on ABC, which was the first time since 1995 that the Women’s Championship game was on broadcast television. The 1995 contest between UConn and Tennessee drew 7.4 million viewers.

The Men’s Championship actually had a record low in viewership last year garnering only 14.7 million viewers, driven in-part due to a lack of hype surrounding the schools that made it to the Final Four and Championship game. Viewership for the Men’s title game has been trending down in recent years — partly due to the effect the pandemic had on collective sports viewership — but the Men’s side had been easily breaching 20 million viewers for the game as recently as 2017.

The 2023 Women's National Championship was the most-viewed game ever, while the Men's Championship was the division's least watched. 

Iowa's Big Ten Championship win on Sunday actually only averaged 6,000 fewer viewers than the iconic rivalry game between Duke and University of North Carolina Men’s Basketball the day prior. However, there is also the case that the Iowa game was played on broadcast TV (CBS) versus the Duke-UNC game airing on cable channel (ESPN).

So historical precedence makes it unlikely that we’ll see the women’s game match the men’s in terms of viewership as early as this year barring another massive viewership jump for the women and a lack of recovery for the Men’s side.

But ultimately, this shouldn’t be looked at as a down point for Women’s Basketball, according to Lewis. The Men’s side has built its viewership base for years, and the Women’s side is still growing. Even keeping pace with the Men’s viewership is already a great sign.

“The fact that these games have Caitlin Clark are even in the conversation with men's games, in terms of viewership is a huge deal,” Lewis said.

Related: Angel Reese makes bold statement for avoiding late game scuffle in championship game

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One city held a mass passport-getting event

A New Orleans congressman organized a way for people to apply for their passports en masse.

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While the number of Americans who do not have a passport has dropped steadily from more than 80% in 1990 to just over 50% now, a lack of knowledge around passport requirements still keeps a significant portion of the population away from international travel.

Over the four years that passed since the start of covid-19, passport offices have also been dealing with significant backlog due to the high numbers of people who were looking to get a passport post-pandemic. 

Related: Here is why it is (still) taking forever to get a passport

To deal with these concurrent issues, the U.S. State Department recently held a mass passport-getting event in the city of New Orleans. Called the "Passport Acceptance Event," the gathering was held at a local auditorium and invited residents of Louisiana’s 2nd Congressional District to complete a passport application on-site with the help of staff and government workers.

A passport case shows the seal featured on American passports.

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'Come apply for your passport, no appointment is required'

"Hey #LA02," Rep. Troy A. Carter Sr. (D-LA), whose office co-hosted the event alongside the city of New Orleans, wrote to his followers on Instagram  (META) . "My office is providing passport services at our #PassportAcceptance event. Come apply for your passport, no appointment is required."

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The event was held on March 14 from 10 a.m. to 1 p.m. While it was designed for those who are already eligible for U.S. citizenship rather than as a way to help non-citizens with immigration questions, it helped those completing the application for the first time fill out forms and make sure they have the photographs and identity documents they need. The passport offices in New Orleans where one would normally have to bring already-completed forms have also been dealing with lines and would require one to book spots weeks in advance.

These are the countries with the highest-ranking passports in 2024

According to Carter Sr.'s communications team, those who submitted their passport application at the event also received expedited processing of two to three weeks (according to the State Department's website, times for regular processing are currently six to eight weeks).

While Carter Sr.'s office has not released the numbers of people who applied for a passport on March 14, photos from the event show that many took advantage of the opportunity to apply for a passport in a group setting and get expedited processing.

Every couple of months, a new ranking agency puts together a list of the most and least powerful passports in the world based on factors such as visa-free travel and opportunities for cross-border business.

In January, global citizenship and financial advisory firm Arton Capital identified United Arab Emirates as having the most powerful passport in 2024. While the United States topped the list of one such ranking in 2014, worsening relations with a number of countries as well as stricter immigration rules even as other countries have taken strides to create opportunities for investors and digital nomads caused the American passport to slip in recent years.

A UAE passport grants holders visa-free or visa-on-arrival access to 180 of the world’s 198 countries (this calculation includes disputed territories such as Kosovo and Western Sahara) while Americans currently have the same access to 151 countries.

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Fast-food chain closes restaurants after Chapter 11 bankruptcy

Several major fast-food chains recently have struggled to keep restaurants open.

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Competition in the fast-food space has been brutal as operators deal with inflation, consumers who are worried about the economy and their jobs and, in recent months, the falling cost of eating at home. 

Add in that many fast-food chains took on more debt during the covid pandemic and that labor costs are rising, and you have a perfect storm of problems. 

It's a situation where Restaurant Brands International (QSR) has suffered as much as any company.  

Related: Wendy's menu drops a fan favorite item, adds something new

Three major Burger King franchise operators filed for bankruptcy in 2023, and the chain saw hundreds of stores close. It also saw multiple Popeyes franchisees move into bankruptcy, with dozens of locations closing.

RBI also stepped in and purchased one of its key franchisees.

"Carrols is the largest Burger King franchisee in the United States today, operating 1,022 Burger King restaurants in 23 states that generated approximately $1.8 billion of system sales during the 12 months ended Sept. 30, 2023," RBI said in a news release. Carrols also owns and operates 60 Popeyes restaurants in six states." 

The multichain company made the move after two of its large franchisees, Premier Kings and Meridian, saw multiple locations not purchased when they reached auction after Chapter 11 bankruptcy filings. In that case, RBI bought select locations but allowed others to close.

Burger King lost hundreds of restaurants in 2023.

Image source: Chen Jianli/Xinhua via Getty

Another fast-food chain faces bankruptcy problems

Bojangles may not be as big a name as Burger King or Popeye's, but it's a popular chain with more than 800 restaurants in eight states.

"Bojangles is a Carolina-born restaurant chain specializing in craveable Southern chicken, biscuits and tea made fresh daily from real recipes, and with a friendly smile," the chain says on its website. "Founded in 1977 as a single location in Charlotte, our beloved brand continues to grow nationwide."

Like RBI, Bojangles uses a franchise model, which makes it dependent on the financial health of its operators. The company ultimately saw all its Maryland locations close due to the financial situation of one of its franchisees.

Unlike. RBI, Bojangles is not public — it was taken private by Durational Capital Management LP and Jordan Co. in 2018 — which means the company does not disclose its financial information to the public. 

That makes it hard to know whether overall softness for the brand contributed to the chain seeing its five Maryland locations after a Chapter 11 bankruptcy filing.

Bojangles has a messy bankruptcy situation

Even though the locations still appear on the Bojangles website, they have been shuttered since late 2023. The locations were operated by Salim Kakakhail and Yavir Akbar Durranni. The partners operated under a variety of LLCs, including ABS Network, according to local news channel WUSA9

The station reported that the owners face a state investigation over complaints of wage theft and fraudulent W2s. In November Durranni and ABS Network filed for bankruptcy in New Jersey, WUSA9 reported.

"Not only do former employees say these men owe them money, WUSA9 learned the former owners owe the state, too, and have over $69,000 in back property taxes."

Former employees also say that the restaurant would regularly purchase fried chicken from Popeyes and Safeway when it ran out in their stores, the station reported. 

Bojangles sent the station a comment on the situation.

"The franchisee is no longer in the Bojangles system," the company said. "However, it is important to note in your coverage that franchisees are independent business owners who are licensed to operate a brand but have autonomy over many aspects of their business, including hiring employees and payroll responsibilities."

Kakakhail and Durranni did not respond to multiple requests for comment from WUSA9.

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