Erin Stone
covers climate and environmental issues in Southern California.
Published October 14, 2024 5:00 AM
The Salton Sea from the Santa Rosa Mountains.
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Courtesy Sicco Rood
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Topline:
Southern California farmers are conserving a lot more Colorado River water, but that’s also causing the Salton Sea to dry up faster.
Why it matters: Since Southern California farmers agreed to a major new deal with the federal government to cut water use significantly, the Salton Sea has dropped about 10 inches and the sea has shrunk by some 3,500 acres, exposing more toxic dust from the lakebed.
Keep reading...to learn more about addressing this conservation conundrum.
Southern California farmers are conserving a lot more Colorado River water, but that’s also causing the Salton Sea to dry up faster.
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The flip side to Colorado River conservation? A drying Salton Sea
That’s because the Salton Sea is filled primarily by agricultural runoff from farms in the Imperial Valley in far Southern California. Those farms have a single source of water: the Colorado River.
The Salton Sea is a landlocked, shallow lake in Riverside and Imperial counties. The lakebed has been contaminated for more than 100 years with pesticides and other chemicals that create dangerous air pollution for surrounding communities.
Balancing conservation with the impact on the Salton Sea is a long-running conundrum.
“It feels that we are responsible for conserving the Colorado River for the good of the many,” said Silvia Paz, director of grassroots group Alianza Coachella Valley, which is working to address the impacts of pollution from the Salton Sea.
“And on the flip side, I don't think it's fair that one particular community that's already an environmental justice community has to bear that responsibility — almost alone it feels like,” Paz said.
A brief history of the Salton Sea
The Salton Sea is part of the massive Colorado River delta. For millennia, the area flooded periodically as the river shifted across the sandy delta region spanning across present-day Southern California, southern Arizona and northern Mexico.
Lake Cahuilla is some of the last evidence of that era of flooding before the river was controlled and diverted via dams and canals. Today, the river no longer meets the sea.
The Salton Sea as we now know it is California’s largest lake. And it's man made. It was first created back in 1905, when an irrigation canal gate failed and the river flooded into the historic lakebed of Lake Cahuilla.
Since then, the sea has been fed by agricultural runoff. Once a popular vacation destination in the 1950s, as farmers got more efficient with water use and climate change-driven heat worsened, the lake — and its tourists — has been drying up, and the lakebed has become increasingly exposed.
Though it’s saltier than the ocean, the Salton Sea remains a biodiversity hotspot for fish and migratory birds.
Conservation to save the Colorado River
Imperial Valley farmers in Southern California use more Colorado River water than anyone. They grow primarily hay as well as leafy greens and other produce that feeds much of the country and the world.
In August, the Imperial Irrigation District agreed to a major new deal with the federal government to cut its water use by an amount that’s more than double the amount the entire state of Nevada uses in a year. The cuts will happen through 2026.
A blanket of crops covers the floor of the Imperial Valley in Southern California, a patchwork of vibrant greens given life by the Colorado River.
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Sandy Huffaker
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AFP via Getty Images
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And they're needed: Two wet years have helped, but the risk of Lake Mead reaching deadpool — meaning the water level has dropped so low that it can no longer flow downstream — remains a looming possibility. That could cut off the main water supply for tens of millions of people and farms downstream.
The first phase of this new program started this summer, and included a program where participating forage crop growers didn’t water those crops for 49 days, during the hottest part of the year. The main crop grown in the Imperial Valley is alfalfa.
Lake Mead, the largest reservoir in the nation, had shrunk so low in 2022 there were concerns it'd reach deadpool, cutting off hydropower and water to millions downstream.
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In return, the Imperial Irrigation District got $589 million from the feds to pay those farmers who can then invest in more water-efficient technologies, pay workers, or otherwise invest in their farms.
The program was a success, said Tina Shields, the Imperial Irrigation District’s water manager. She said the district cut water use by about 175,000 acre-feet this summer. For comparison, the entire city of L.A. uses about 500,000 acre-feet of water every year.
The short duration of the program had little impact on the economy. If anything, it helped farmers stay in business because hay markets are bad right now — that’s a reason why so many farmers participated this summer, Shields said.
Plus, water use in the area is down in general because October has been abnormally hot, so watering would just burn crops.
Trevor Tagg, 38, grows alfalfa and other hay crops in the Imperial Valley of Southern California. He participated in the Irrigation District's recent conservation program where he didn't water his crops during the hottest time of year. He said the program helped keep his business going during tough times, while saving water.
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Erin Stone
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The consequences of conservation
Since that program ended at the end of September, the surface elevation of the Salton Sea has dropped about 10 inches and the sea shrunk by some 3,500 acres, exposing more dust from the lakebed, said Paz, whose group along with researchers from UCLA and the Pacific Institute measured the decline.
“Our communities don't have the luxury to escape the dust that is blown into the air,” Paz said. “Siloing this issue as a water-only issue leads to all these other consequences.”
A study by UC Riverside found that the Salton Sea’s rotting odors have become a yearlong nuisance for people living near the lake due to shrinking levels.
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Getty Images
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In its review, the federal government found the new agreement with the Imperial Irrigation District, or IID, would have no significant new environmental impacts to the Salton Sea and surrounding communities. But many people in the area disagree.
“The reality is that, for our communities, it's not a negligible impact,” Paz said. “This is a cumulative impact to the conditions that we're already suffering.”
Research has shown that asthma rates and other respiratory diseases are far higher than average among communities near the Salton Sea.
The Salton Sea at Bombay Beach last year.
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Robyn Beck
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AFP and Getty Images
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Who's responsible for the Salton Sea?
Those impacts are why the Sierra Club recently sued the IID about the conservation deal. The organization says the district did not do a proper environmental review of the impacts to the Salton Sea and nearby communities.
“We believe that they should be paying the bill for some of the impacts,” said Richard Miller, director of the Sierra Club’s San Diego chapter.
The IID argues it's already done it's part to address the issues caused by a drying Salton Sea. Shields said the district only agreed to this recent round of additional conservation efforts because they negotiated that $250 million in federal dollars would go towards accelerating the state’s Salton Sea efforts.
Water from the Colorado River flows through the All American Canal in the Imperial Valley.
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“That funding is conditioned on IID implementing these additional conservation efforts,” Shields said. “So we up front took care of the Salton Sea from our perspective.”
But it’s the state that is primarily responsible for addressing the pollution impacts of a shrinking Salton Sea. They are behind on their 10-year plan, which aims to restore nearly 30,000 acres by 2028 of exposed lakebed to native desert habitat and man-made ponds that support endangered fish, migratory birds and reducing pollution.
In recent years, restoration efforts have accelerated, in large part thanks to that $250 million in funding from the Biden-Harris Administration, said Miguel Hernandez, a spokesperson for the state’s Salton Sea Management project, in a statement to LAist.
He wrote that, so far, the state has completed more than 2,000 acres of habitat restoration and dust control, with some 6,500 acres currently under construction and major construction complete for a 4,100-acre conservation area — additional federal funding is helping to expand that project by 750 acres.
See a map of completed and ongoing Salton Sea restoration projects here.
“IID is doing the right thing conserving water to stabilize the Colorado River, and our federal partners stepped up to provide funding for this water conservation and for California’s ongoing projects at the Sea to reduce dust emissions and restore habitat,” Hernandez wrote.
But Paz said the sea is shrinking faster than projects are being built to cover the exposed lakebed.
“We need to balance this out. They need to move a lot faster,” Paz said.
Dust from the exposed lakebed of the Salton Sea, farm fields and the open desert all contribute to particulate pollution in the community of North Shore, on July 17, 2024.
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Zoë Meyers
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CalMatters
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What’s the solution?
Everyone agrees the ongoing restoration efforts are key to addressing the impacts of a shrinking Salton Sea. But balancing necessary conservation with the impacts of that conservation can seem like an impossible problem to solve.
“It’s the rock and a hard place,” said Shields. “As we get more efficient, the downside is the Salton Sea has less water. It's a tough thing with an inland body of water that has no outlet and the only inlet is receiving drainage water from the adjacent areas. So it's a balancing act to keep everybody happy.”
It’s the rock and a hard place.
— Tina Shields, water manager for Imperial Irrigation District
Shields continued: “But if the Colorado River crashes, that's not something you just fix the next year,” So we're going to do everything we can to ensure that our communities have a reliable and safe water supply. And it may be that there are impacts to the Salton Sea, but without the Colorado River, there would be no Salton Sea.”
Paz said she supports and understands the conservation needs, but that means that policymakers and water managers need to think more holistically about the mitigation efforts.
“If this is the only way, we need to broaden how we think about how we’re protecting and preparing our communities,” Paz said.
She said accelerating the state's restoration projects is essential, plus funding for air filters and weatherizing more homes, particularly mobile homes that house farmworkers, for which funding is lacking, she said.
A dirt road in the Shady Lane Estates mobile home park in unincorporated Thermal, a community within the Coachella Valley in Riverside County on March 23, 2023.
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Pablo Unzueta
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CalMatters
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But Paz said mitigation for conservation impacts to the Salton Sea could go beyond direct impacts, to improving general quality of life, especially as desert communities face some of the quickest accelerating impacts of the climate crisis.
One example? A new plan envisioned by the community and supported by local governments to build a commuter rail line connecting all the Coachella Valley communities, that will also add green space, shade and an emergency shelter to help communities ride out disasters and excessive heat.
“We’re talking about being very mindful of how our built environment is being developed to address the needs that we have, particularly when it comes to climate resilience,” Paz said.
She added that funding from Proposition 4, which is on the November ballot, would help speed up some existing efforts.
“We're very hopeful that Proposition 4 gets support statewide and that that funding will become available,” Paz said. (Update: Voters did indeed pass that proposition).
Cormorants in the Salton Sea.
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Courtesy Sicco Rood
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As for the state’s plan, it’s estimated it will cost more than a billion dollars to complete the necessary habitat restoration and dust mitigation efforts.
Among other things, a large chunk of the $250 million from the Biden Administration’s Inflation Reduction Act will go towards a more than 4,000-acre restoration area to plant habitat that supports migratory birds and reduces dust pollution, said Mike Lynes, public policy director for Audubon California. Other ongoing projects are showing preliminary promise.
“We cannot lose our hope,” said Paz. “Transforming our communities takes a lot of work, but at the end of it, this is a work of hope and that is what allows us to keep envisioning and to keep trying. Because I believe that a different future is possible.”
Climate Emergency Questions
Fires. Mudslides. Heat waves. What questions do you need answered as you prepare for the effects of the climate emergency?
Raz Chowdhury, a 45-year-old unhoused man, died at The Mayfair in July 2026 after being moved to hotel as part of the Inside Safe program.
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Nathan Solis
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The LA Local
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Topline:
45-year-old Raz Chowdhury was moved off the streets into interim housing through an Inside Safe operation. A week later, he was found dead in his hotel room.
The backstory: L.A. Mayor Karen Bass’ office said it does not disclose the locations where an individual is placed following an Inside Safe operation. According to Ktown for All, Chowdhury died at the Mayfair Hotel in Westlake, which is used for interim housing.
A spokesperson for the Los Angeles County Department of Medical Examiner said the case is still under investigation and Chowdhury died at a hotel in the 1200 block of West 7th Street.
A week after 45-year-old Raz Chowdhury was moved off the streets into interim housing through an Inside Safe operation, he was found dead in his hotel room.
Chowdhury had spent years living on the streets of Koreatown, moving between encampments along Sixth Street and Wilshire Boulevard and Manhattan Place.
Sherin Varghese first met him three or four years ago. Chowdhury would reach out to Varghese, a volunteer with Ktown for All, an advocacy group that provides direct aid for people experiencing homelessness in Koreatown. He would ask her for tents, tarps, clothes and other supplies. More often than not, she said, they weren’t for him.
“He would always go above and beyond to take care of the people around him,” Varghese said at a vigil for Chowdhury on Saturday, Aug. 29.
Once, after Chowdhury lost his phone during a sanitation sweep, he searched for Varghese online and found her work number. He called to ask if she could bring tents and tarps for him and other people whose belongings were lost in the sweep.
“He was resourceful, he was reliable, and he was so thoughtful about the way that he talked about how all of this affected him and affected his friends,” Varghese said.
On June 25, Chowdhury was among 31 people moved into housing during an Inside Safe operation at Wilshire Boulevard and Manhattan Place, according to Mayor Karen Bass’ office.
A week later he was dead.
What happened after Inside Safe
According to Ktown for All, Chowdhury died at the Mayfair Hotel in Westlake, which is used for interim housing.
A spokesperson for the Los Angeles County Department of Medical Examiner said the case is still under investigation and Chowdhury died at a hotel in the 1200 block of West 7th Street on July 2. His cause of death is listed as deferred and the case is under investigation by the Los Angeles Police Department’s Rampart Division.
The Los Angeles Homeless Services Authority, which oversees the Mayfair, would not say if Chowdhury was a resident when he died. An agency spokesperson said they cannot confirm an individual’s enrollment in a LAHSA-contracted program without a written release from next of kin.
LAHSA’s latest Inside Safe report shows that 6,406 people had entered interim housing through the program as of July 31. About 1,750 people remained in interim housing, including 289 at the Mayfair. Meanwhile, 1,802 people, or more than one in four who entered the program, had returned to homelessness. Another 126 people, or about 2%, were listed as deceased.
Bass’ office said it does not disclose the locations where an individual is placed following an Inside Safe operation.
Once someone is connected to interim housing, ongoing services and case management are handled by a LAHSA-contracted service provider, mayor spokesperson Jieun Kim said.
Remembering Chowdhury
The people who knew Chowdhury gathered last week to remember him at the site of the encampment where he had lived at Wilshire Boulevard and Manhattan Place.
A little more than two dozen people attended the memorial, where they placed flowers at the base of a small tribute to him.
Planters now line the sidewalk where the tents once were. Several people cried as they shared memories of Chowdhury, who they said spent years looking out for others living on the streets of Koreatown.
Cynthia Zhang, who has volunteered with Ktown for All for about four to five years, remembers visiting an encampment where Chowdhury was staying after the Los Angeles fires. Newly displaced people there told her they felt safer with that community than they did at shelters.
“I think Raz was really instrumental in helping create that kind of space,” Zhang said at the vigil.
The last time Zhang saw Chowdhury, he had moved again and did not have a lot of his stuff. But he had a new puppy named T-Rex and seemed to be in good spirits.
“He had a really lovely smile,” Zhang said. “I just remember him skateboarding around … all these little things, maybe because I didn’t see him every day, it really does feel like I’ll be walking around and I’ll see him in one of our old spots.”
David Strugar, another longtime Ktown for All volunteer, said Chowdhury was often the person volunteers went to when they wanted to know how people in the area were doing.
“I would always point him out and say, ‘That’s the mayor of this area,’ because wherever he was, he was just the center of it, and he took care of people,” Strugar said.
Chowdhury would tell volunteers who needed what and help distribute supplies, Strugar said.
A few weeks before he died, Varghese said, she and Chowdhury were looking for places where he could stay outside a 41.18 zone, where the city restricts sitting, lying, sleeping and storing personal property in certain public rights-of-way under specified circumstances.
Then Inside Safe moved him indoors.
“I hoped that he’d be one of its success stories, but a week later, he was gone,” Varghese said. “The program is called Inside Safe, but for Raz and 125 others, it wasn’t that. And it was never going to be Inside Safe, and it was never going to be easy to be inside alone for someone who had so much to give and always surrounded himself with people to take care of.”
The last time Strugar saw Chowdhury, he had his dog T-Rex with him. Ktown for All volunteers don’t know where T-Rex is now.
Chowdhury believed he had the right to community and companionship, Strugar said.
“And there are so many people who have so much and won’t give anything,” Strugar said. “And Raz kept having everything taken away from him, and he still ended up being the person to give.”
He added, “I just keep expecting to walk around the corner and see him, and I’m angry that I won’t.”
Fiona Ng
is LAist's deputy managing editor and leads a team of reporters who explore food, culture, history, events and more.
Published September 5, 2026 5:00 AM
Hong Pham, aka That Peking Duck Guy, takes a roasted Pipa duck out of his outdoor oven.
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Fiona Ng
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LAist
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Topline:
Radiologist Hong Pham has an unusual side hustle — cooking and selling Peking and roast ducks from his South Pasadena backyard.
The backstory: That Peking Duck Guy started out as a social media account documenting Pham's culinary journey to make the perfect duck. It then became a side hustle when strangers and neighbors offered to buy his birds.
Read on ... to learn about how Pham got started and how he cooks his ducks.
Got a taste for ducks cooked the Chinese way? Your quest may take you to a quiet suburban backyard in South Pasadena.
That's where That Peking Duck Guy cooks and sells his birds. His clients, he said, include Phil Rosenthal and Roy Choi.
The guy behindThat Peking Duck Guy is Hong Pham, who started the social media account in late 2025 as a way to document his latest culinary obsession: making the perfect duck, be itPeking or Pipa (deboned and flattened into the shape of the namesake Chinese string instrument).
The intention was not to sell. "I have a day job," Pham said. A radiologist, to be precise.
"I was actually making so many that neighbors wanted to claim it and offered to buy it," he added. "So I'm like, 'OK, that makes it easier 'cause I don't have to eat it all.'"
Soon came DMs from strangers asking for the same thing.
These days, That Peking Duck Guy caters events and holds takeout pop-ups where people can purchase and pick up a duck (which comes with sides and duck soup) from his South Pasadena backyard — right where he cooks them.
Peking duck from That Peking Duck Guy served with Chinese sweet sauce, chopped spring onions and cucumber slices.
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Duck is the latest obsession
Duck is not his first rodeo. Pham said he and his wife are foodies who've always been curious about delving into Vietnamese and other Asian culinary traditions. For Pham, that also means replicating some of these dishes at home, from scratch.
He'd gone on a tofu bender — making gallons of the stuff, as blocks, drinks and pudding — and also a bánh cuốn spree, or Vietnamese steamed rice rolls. He landed on duck as his latest subject only because he had wanted to make better heo quay, or Vietnamese roasted pork belly.
It's the oven
Pham and one of his special outdoor ovens he uses to roast duck.
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He researched how to get that extra crisp online and landed on an oven people in Asia use to make roast and Peking ducks.
"It was called the Apollo oven 'cause it looks like an Apollo space capsule," he said.
He bought one and then another. In between, he experimented cooking different meats with the new oven to get a feel before turning to the waterfowl.
He even got advice from Top Chef winner Mei Lin, whom he messaged cold: "She's like, 'Keep it simple. Keep it basic. Keep it traditional.'"
Three Pipa ducks inside the oven.
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Fiona Ng
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Hundreds of ducks later, Pham said he still learns something new. That's one reason why his side hustle has stuck around.
"I didn't create like, you know, That Bánh Cuốn Man," he said. "Yeah, duck's gonna last."
How That Peking Duck Guy cooks his ducks
Pham starts 7 to 10 days before cooking. Here's the preparation process:
He usually trims off the legs and the wings, because those parts get burnt in the oven.
He insufflates the duck. He sticks an air pump in between the meat and the skin to separate the two, so the entire duck blows up into a "huge balloon essentially," he said.
He scalds the skin with a combination of vinegar and maltose to make it "aerodynamic and tight" to get that crispiness.
He seasons the inside of the duck.
He then hangs and dries the ducks for about 7 to 10 days.
Then in the Apollo oven they go. Peking ducks take about an hour and 15 minutes to cook. Pipa ducks take about 40 minutes.
When does he know they're done? "Well, you know the color, we're looking for that beautiful mahogany glistening skin, you know?" Pham said.
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Josie Huang
is a reporter and Weekend Edition host who spotlights the people and places at the heart of our region.
Published September 5, 2026 5:00 AM
A MINISO logo is displayed on a sign outside of a store in San Diego.
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Kevin Carter
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Getty Images
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Topline:
SoCal has become a proving ground for some of the country’s fastest-growing Asian and Asian American retailers, giving chains like Miniso and 99 Ranch Market an early test of broader U.S. appeal.
Growing fast: On the National Retail Federation’s 2026 Hot 25 list, Miniso ranks No. 1, Daiso No. 3, Uniqlo parent Fast Retailing No. 6 and 99 Ranch Market No. 15.
Backstory: All four have had a Southern California presence for years, giving them experience in one of the country’s most diverse and competitive retail markets.
Southern Californians who’ve long shopped at Daiso, Miniso, Uniqlo or 99 Ranch Market may not be surprised to see the Asian-rooted chains expand across the country.
But that growth is now showing up in the numbers.
The National Retail Federation’sHot 25 Retailers list ranks retailers by U.S. sales growth from 2024 to 2025. Miniso tops the list, with sales up nearly 53%.
The Chinese chain of gift shops opened its first U.S. store in Pasadena’s Old Town more than nine years ago and is now aiming to grow its American footprint tonearly 500 stores this year.
“If you can make it in Southern California, that's great,” said David Marcotte, senior vice president of global retail and technology at Kantar and an author of the NRF list.
A 99 Ranch market opened in 2023 in Eastvale.
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Gina Ferazzi
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Los Angeles Times via Getty Images
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Marcotte says succeeding in California’s highly competitive retail market can teach chains lessons that translate elsewhere.
“The stone-cold reason is quality. The second one is experience,” he said. “Those are the two things that when shoppers go into any retailer, they’re looking for.”
Daiso ranks third, with growth of nearly 26%, while another Japanese company, Fast Retailing — the parent company of Uniqlo — comes in sixth.
99 Ranch Market, an American supermarket chain founded in Orange County that specializes in Asian groceries, comes in 15th.
Marcotte says Southern California has been a logical landing spot for these companies because of its proximity to Asia. But Marcotte says it can also be an unforgiving place to launch because of the competition, and he often encourages the clients he advises to consider smaller markets.
“I said if you open in Southern California, open one store, get it right,” Marcotte said. “If you get it wrong, you're dead. You'll never recover. You'll have to leave the country and come back in.”
The supermarket industry is particularly tough to break into because customers here, he says, have plenty of alternatives if the quality, selection or experience falls short.
He also emphasizes a retailer in California focused on Asian goods will see more success serving Chinese, Filipino and other Asian customers rather than designing around a particular ethnic group.
“That type of diversity of Asian customers that you have to address in the same store is what really proves to be the difference for an Asian retailer in the California market,” Marcotte said.
That’s part of the business model for 99 Ranch, which was founded by a Taiwanese immigrant who opened the first location in Westminster's Little Saigon in 1984.
Courtesy of the UCSF Quantitative Biosciences Institute
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Topline:
Scientists have now gotten closer to understanding how gene mutations may lead some people to develop profound autism.
Why it matters: A team of researchers from UC San Francisco mapped more than a thousand interactions between many proteins that come from certain autism risk genes.
Why now: This molecular atlas, published in the journal Science, could point researchers toward new and promising treatments.
Scientists have now gotten closer to understanding how gene mutations may lead some people to develop profound autism.
The clues, they say, lie in the murky space between genes and disease — where key proteins come together and interact.
A team of researchers from UC San Francisco mapped more than a thousand interactions between many proteins that come from certain autism risk genes. This molecular atlas, published in the journal Science, could point researchers toward new and promising treatments.
"It's an unprecedented resource for the field," says Dr. Daniel Geschwind, a professor of human genetics, neurology, and psychiatry at UCLA who was not involved with the study. "A lot of people interested in understanding autism and drug development are going to be using this."
For families affected by profound autism, it offers hope for eventual drug therapies. "This is the kind of scientific advance we have been waiting for and praying for," says Alison Singer, president of the nonprofit Autism Science Foundation, who has a daughter with severe cognitive impairment. "There's still a lot of work ahead, [but] this paper makes the path from genetic discovery to treatment much clearer."
The work builds on progress made in recent years to identify single genes that harbor mutations found in a subset of individuals with profound autism.
Getting past the "wall"
People with profound autism often live with severe intellectual disability and require around-the-clock care. They're nonverbal or minimally verbal, and often have serious medical conditions like epilepsy.
Pinning down the biology behind profound autism has always been a complicated endeavor — while both genes and environmental factors play a role, those factors can vary widely from person to person.
In the past decade or so, some genetics researchers have had remarkable success in identifying high-impact genetic differences in a subset of people with profound autism.
"They've discovered several hundred genes and corresponding mutations that are prevalent in [these] individuals," says Nevan Krogan, director of the Quantitative Biosciences Institute at UC San Francisco.
"But they kind of hit a wall," he added — because scientists haven't been able to turn those gene discoveries into many promising drugs and treatments.
"There was this huge missing piece," says Dr. Matthew State, a clinical psychiatrist and geneticist at UCSF: The genes serve as blueprints for making proteins that drive brain development, but researchers lacked visibility into how those proteins do the work.
State has been a pioneer in identifying high-risk genes, and the mutations in those genes, that are associated with profound autism. Krogan has been at the forefront of using new technology to look into protein interactions.
More than a decade ago, the two researchers were introduced by their mutual boss, the chancellor at UCSF, who encouraged them to collaborate. "[State] had the genes and the mutations. I had the technologies to look at the corresponding proteins," Krogan says.
They focused on filling a knowledge gap. "What we've been missing is the mechanistic understanding of how these mutations [on the genes] are seemingly resulting in autism," Krogan says. "In order to understand that, you need to go to the proteins."
Proteins are the complex molecules that come together to build the body, based on instructions encoded in the genes. "What makes an eye cell an eye cell, and a muscle a muscle, are the proteins and how they work together," State says. "They are the machinery of life."
In this case, the researchers wanted to find the molecular machinery of profound autism — to understand which proteins came from those high-risk autism genes, and how those proteins worked together.
The research was slow at first, but more recent advances in technology — including artificial intelligence — have sped things up.
To start, the researchers went on a "fishing expedition" for protein interactions. They chose 100 proteins from these high-risk autism genes, injected them into lab-grown cells, and then pulled them out, along with the additional proteins that attached to them.
Then, they used an AI system called AlphaFold, developed by Google DeepMind, to help determine which proteins in the clumps were directly touching. "Where AI is playing an important role is being predictive about who's talking to who," says Krogan. "Sometimes they take years to figure out. Now, we can get these insights in an hour." While imperfect, the system has worked well enough to save significant time and money, Krogan says.
Then, they wanted to see what happened to the proteins when the genes got tweaked. They introduced mutations that appear in patients with profound autism, and assessed what changed. "We broke the proteins in the way that they're broken in autism," says State. "That allows us ultimately to answer the question of, when they're going wrong in autism, how are they going wrong?"
They conducted this research in frogs and in organoids, which are lab-grown tissues that model the human brain. In one example, the mutations weakened the connection between two proteins related to which genes turn on and off in a cell. Then, one went rogue, turning on other genes that led to neurodevelopmental defects in organoids.
Molecular convergence
There are hundreds of rare, high-risk autism genes, acting in more than a thousand different ways.
But in mapping more than 1,800 protein interactions, the researchers found that many of them moved along shared biological pathways — particularly those related to early brain development, such as how synapses get constructed, and which neurons develop and when.
The convergence found in this study aligns with other recent publications, adding to an emerging understanding in the field, says Dr. Geschwind of UCLA.
"If we look at multiple mutations and they converge on the same process, that's strong evidence that you're dealing with the things that you want to treat," State says.
Identifying this more limited set of protein complexes that likely contribute to the development of profound autism could change the approach to treatments, says Singer with the Autism Science Foundation. "We've been working gene-by-gene to correct mutations," she says.
And if future drugs could target these shared protein pathways, she adds, "we may not need that separate therapeutic strategy for every autism gene."
Setting sights on new drug-development targets
It takes years to go from a biological discovery like this to an approved drug that treats humans. The findings would need to be translated into drug candidates, then tested for safety and effectiveness.
"It takes time and a lot of persistence and focus," State says. "This [paper] is unlikely to lead to therapies tomorrow — but it lays an important foundation for them."
Most human drugs are made to target proteins, Geschwind at UCLA says, so the newly published map of protein interactions offers an accessible entry point for pharmaceutical development.
And researchers hope to combine recent technological advances in ways that accelerate that progress even more. "When you put together the ability to borrow from successes in other fields [such as cancer treatments], and the development of AI, we're at an inflection point that will hopefully shorten the time cycle," State says.
Last week, Krogan's Quantitative Biosciences Institute received a $46 million grant from the Aligning Research to Impact Autism initiative, funded by philanthropist and Google co-founder Sergey Brin. The researchers are already working on next steps.