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  • China warns EV makers to stop price-cutting to protect the economy | Automotive industry

    China warns EV makers to stop price-cutting to protect the economy | Automotive industry

    China is urging its electric vehicle industry to stop cutting prices and rein in production amid fears that persistent deflation is imperilling economic growth.

    In recent months Chinese officials have talked repeatedly of the need to combat “involution” in sectors suffering from overcapacity, such as EVs, referring to the phenomenon of investing more effort and money for diminishing returns.

    Xi Jinping has spoken of the problem directly. In an unusually blunt speech this month, China’s president criticised provincial governments for blindly overinvesting in artificial intelligence, in computing power and in new energy vehicles, industries that Beijing has identified as strategic priorities but which are also at risk of overheating.

    On 23 July, Xi gave another speech in which he stressed the importance of breaking the cycle of “involution” that has gripped parts of the Chinese economy, the world’s second-biggest after the US.

    Some of China’s big car companies, including BYD, the EV maker that is seen as China’s rival to Tesla, were summoned to meetings with regulators last month to receive warnings about overcapacity.

    Hutong Research, an independent advisory firm based in Beijing and Shanghai, said in a recent note: “Government agencies across China have moved swiftly in response to Xi’s recent remarks, pledging to implement supply-side reductions.

    “These developments highlight not only the elevated political attention to excess capacity but also the breadth of the problem across China’s economy.”

    In the hyper-competitive Chinese economy, consumers, unwilling to part with their cash, have come to expect rock-bottom prices. Companies across industries often cut prices to near or below cost levels in a play for market dominance.

    China’s EV companies are no exception, and many bosses have complained about the phenomenon while also being dragged into it.

    BYD has repeatedly cut the price of its low-end Seagull, most recently offering it for 55,800 yuan (£5,862), nearly 20% below the official retail price. In March, it cut prices across the Seagull range by 3,000 yuan. Great Wall Motors, one of BYD’s competitors, released a new version of its Ora 3 car in June for about 20% less than the September retail price.

    In January, He Xiaopeng, the chief executive of XPeng Motors, reportedly told employees that “the market will definitely see fiercer competition in 2025” and that some auto companies would not survive the looming price war.

    Vehicles under production at Great Wall Motors’ factory in the Yongchuan district of Chongqing, south-west China. Photograph: Xinhua/Rex/Shutterstock

    Last month, China revealed a new draft amendment to its law on pricing – the first revision to the law since 1998 – specifically aimed at the price wars.

    The amendment would strengthen rules around the government’s ability to set price limits, identify “unfair pricing behaviour” and curb “involution-style” competition, including using market dominance to influence prices and bulk sales.

    But the responses may not go far enough, some analysts said.

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    Antonia Hmaidi, a senior analyst at Merics, said: “I am not convinced that the Chinese government will do something to curb in any significant way because so far at least no one’s been really punished for investing too much in strategic priorities.”

    Hmaidi said few EV companies were actually profitable in China and many others were inextricably linked to local governments that do not want to see them go under.

    “We are seeing some changes in specific types of action that the government is taking that are pointing towards this,” she said. “But we’ve seen these kinds of actions before, and nothing came of it. And ultimately, you would need to provide an alternative to a lot of these local governments, for instance.”

    Hmaidi said one solution to a glut of products in China could be to sell even more overseas, aggravating foreign companies and regulators. “I think in the short term, there will be more tension with most of its trading partners,” she added.

    The flood of Chinese EVs to the European Union has alarmed EU officials who worry that their own carmakers will not be able to compete.

    Last year, the EU imposed tariffs of up to 45% on Chinese-built battery EVs, angering Beijing. A recent EU-China summit failed to make any progress on the issue, which has been a major sticking point between the two trading partners.

    But Chinese carmakers adapted by pushing plug-in hybrid vehicles instead. In June, Chinese companies reached a 10% share of Europe’s EV market, making a full comeback on their pre-tariff market share.

    Last week the politburo, the group of leading officials in the Chinese Communist party, met to discuss the economic outlook for the year ahead. While they did not mention the anti-involution campaign specifically, they spoke of the need to “regulate disorderly competition” in the economy.

    Additional research by Jason Tzu Kuan Lu

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  • ‘The place I’d never go back to? Hong Kong’

    ‘The place I’d never go back to? Hong Kong’

    Alex Polizzi, 53, is a hotelier, businesswoman and TV personality best known since 2008 as the presenter of The Hotel Inspector on Channel 5. In the show she visits struggling British hotels to try to turn their fortunes around by giving advice and suggestions to their owners or managers, often undertaking renovation projects on their behalf. Her uncle Sir Rocco Forte and her mother Olga Polizzi co-founded the Rocco Forte Hotels group. Polizzi owns the Polizzi Collection of three UK hotels. She lives in London with her two children, Olga, 17, and Rocco, 12.

    I travel all over Britain for The Hotel Inspector, and I always feel I’ve seen it all. On a trip to the Scottish Borders, just before the pandemic, one young couple proved otherwise. They had a pub with rooms that had been donated by a parent, but they had absolutely no interest in it. The husband droned on about hand-churning butter while the place fell apart. I stayed the night and agreed to meet his wife downstairs at 9am with our crew of eight. At 10.30am she finally arrived, dressed in a kangaroo onesie. I was really cross — it had taken us six hours to get there and she couldn’t even be bothered to get out of bed.

    I loved growing up around hotels and always took it for granted. A hotel always stands out for me if it has good service. A not-particularly-beautiful hotel becomes somewhere special if the staff are amazing. I love working in my own hotels, and people are amazed when they see me. They say, “Why are you working?” But I like clearing and cleaning tables, sorting things out.

    Polizzi’s East Sussex hotel, the Star at Alfriston

    There’s the odd unfortunate moment, though. In my East Sussex hotel, the Star at Alfriston, a lady complained recently because the coat she’d hung up had disappeared — it turned out another guest had worn it in the garden because she was cold.

    18 of the best hotels in Venice

    The last time I stayed at a five-star hotel that wasn’t one of my uncle’s was the Ritz in Paris in 2019. I felt it was snobby — we weren’t quite their target clientele, and it was full of extremely rich, soignée ladies with expensive shopping bags, while I was there with my daughter and we were in trainers.

    My favourite hotel, for a luxurious weekend, is the Aman Venice overlooking the Grand Canal. It’s extraordinarily expensive but with a wonderful sitting room, bar and high frescoed ceilings. For a countryside retreat, it has to be Le Mas de Peint in the Camargue. I also love the hotel L’Arlatan in Arles, Provence, where there are so many brilliant food markets.

    Aman Venice hotel on a canal in Venice.

    The Aman Venice overlooks the Grand Canal

    One place I’d never go back to is Hong Kong, where I trained at the Mandarin Oriental for three years in my twenties. I found the region overcrowded, dirty and polluted — it’s a fun place to visit if you’re really rich, but not if you’re not. The hotel was wonderful, though, and the training was dedicated and professional. I think they had three times as many staff as guests and wages were very low. My mother had to send me money every month so I could work there.

    Revealed: 100 Best Places to Stay in the UK for 2025

    I grew up in Bayswater in west London. My mother was widowed when I was nine, and we always had the same family holidays after that: winters skiing in France at her friend’s chalet, and summers in the Algarve. My grandparents stayed in their hotel, the Dona Filipa, and rented a villa nearby for 13 grandchildren; I was the eldest. We had a rigid schedule: breakfast at 8am, lunch at 1pm and right on time for dinner in the hotel. My grandfather played golf all day with my uncle while we swam, and he let me drive the golf buggy if I didn’t chat too much. Once, aged ten, I drove it into a bunker and they had to tow it out. In later years my sister and I would sneak out of our bedroom window to a local nightclub with a gang of teenagers that went every year.

    Poolside cabana with fruit and drinks.

    Bangkok’s Mandarin Oriental was a highlight in Thailand

    My first trip as a grown-up was backpacking from Thailand to Malaysia with my friend Felicia when I was 18. Felicia had her passport stolen and we had no phones, but at that age you feel invulnerable. We stayed in hostels with no showers and were incredibly grubby, so it was a real highlight when Mum paid for us to have two nights at Bangkok’s Mandarin Oriental. They looked us up and down when we arrived. We didn’t leave for a day, and we had room service and shower after shower. Reality returned in Malaysia when we arrived at our hostel and an enormous live rat fell through the ceiling.

    I’m a much more anxious person now than I was then and my children don’t enjoy being with me so much. I loved holidays when they were little and wanted to play with me on the beach, in places like Turks and Caicos in the Caribbean. I recently visited New York with my daughter and had to find a hotel where I could afford two rooms. Only my son is young enough not to mind sharing a room with me!
    The Hotel Inspector airs on Thursdays at 8pm on Channel 5

    In our weekly My Hols interview, famous faces from the worlds of film, sport, politics, and more share their travel stories from childhood to the present day. Read more My Hols interviews here

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  • Risk in Context Podcast: Building nimble supply chains to mitigate current and future risks

    Risk in Context Podcast: Building nimble supply chains to mitigate current and future risks

    Today’s interconnected global supply chains are vulnerable to a multitude of risks stemming from geopolitical and geoeconomic conflicts, including the introduction of tariffs and counter-tariffs, natural catastrophes, and climate change. This web of risks can cause disruptions that lead to delays, shortages, and increased costs.

    The complexity and fragility of supply chains is often compounded by limited visibility into upstream suppliers, making it difficult to assess potential vulnerabilities and respond proactively.

    The potential implications of this lack of visibility underscore the importance of robust risk mitigation strategies and business continuity plans. By gaining a clearer understanding of their entire upstream supply chain, using tools like Marsh McLennan’s AI-powered Sentrisk, organizations can identify challenges early, evaluate their possible impacts, and implement effective mitigation plans. With a better understanding of supplier sites, organizations can utilize other tools to overlay risks to identify potential disruptions, including through real time alerts.

    In this episode of Risk in Context, Karl Bryant, Senior Engagement Lead within Marsh’s Strategic Risk Consulting Practice, speaks with Amy Barnes, Marsh’s Global Head of Energy and Power, who also heads Marsh’s Climate Change and Sustainability Strategy, Jason Brewer, Lead Meteorologist within Marsh McLennan Agency, and John Davies, Commercial Director for Marsh McLennan’s Sentrisk product. They discuss the wide range of challenges that could disrupt supply chains and some of the actions that senior leaders should consider to mitigate evolving and emerging supply chain risks.

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  • Australia's internet network signs Amazon satellite service – Reuters

    1. Australia’s internet network signs Amazon satellite service  Reuters
    2. Amazon’s Kuiper broadband service to launch in mid-2026  theregister.com
    3. Amazon takes on Musk’s Starlink in internet speed race  The Australian
    4. Albanese Government delivering high speed broadband for regional Australia  The National Tribune
    5. Project Kuiper partners with NBN Co to bring low Earth orbit satellite broadband to rural Australia  About Amazon Australia

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  • LptM protein revealed as essential to outer membrane stability in bacteria

    LptM protein revealed as essential to outer membrane stability in bacteria

    Gram-negative bacteria pose a significant threat to global health due to their high resistance to antibiotics compared to that of Gram-positive bacteria. Their formidable defensive capabilities stem from their outer membrane (OM), which acts as a selective barrier against harmful compounds. The OM is not merely a static shield but a dynamic structure crucial for the bacteria’s survival and virulence. Thus, understanding how the OM is built and maintained is critical in our battle against drug-resistant infections.

    To construct such an effective protective layer, bacteria rely on specialized molecular machinery. The lipopolysaccharide transport (Lpt) system is a key player in this process, as it integrates functional lipopolysaccharide complexes into the OM. Although some components of this transport pathway, such as the LptDE complex, are known to be essential for bacterial survival, the precise mechanisms governing their assembly and maturation remain unclear. 

    In a recent study, a research team led by Assistant Professor Ryoji Miyazaki from the Nara Institute of Science and Technology (NAIST), Japan, made an important discovery toward a better understanding of these processes. Their study, made available online on July 16, 2025, and scheduled for publication on August 26, 2025, in Volume 44, Issue 8 of the journal Cell Reports, reveals the critical role of a small protein called LptM in maturing and stabilizing LptD, which, together with LptE, forms the LptDE complex. The study was co-authored by Mai Kimoto, Dr. Hidetaka Kohga, and Professor Tomoya Tsukazaki from NAIST.

    The team employed a combination of advanced techniques to shed light on the function of LptM. They investigated the precise timing of various events during LptD maturation, demonstrating that LptM acts at a later stage, influencing already-folded LptD intermediates. Through comprehensive mutational analyses, they identified a short region of LptM, comprising fewer than ten amino acid residues, as essential for its purpose. The researchers then used cryo-electron microscopy to acquire a high-resolution structure of the Escherichia coli LptDEM complex. This analysis, combined with biochemical experiments, provided an unprecedented molecular view of how LptM directly interacts with and stabilizes the LptDE complex.

    Their results revealed that LptM positions itself at a critical interface within LptD, suggesting its role in fine-tuning the structure of this protein for Lpt. This enhanced understanding of the LptDE assembly process has significant implications for future therapeutic advances. “Our study highlights the essential role of LptM, providing fundamental insights that may support antibiotic design, as the LptDE complex has been identified as a potential target for novel antibiotics,” states Dr. Miyazaki. “Thus, our findings contribute to the advancement of research that could guide future drug discovery.”

    Beyond potential drug targets, this research also sheds important light on a broader principle in biology. “Our findings suggest that small proteins, many of which have been previously overlooked, may play critical roles in the assembly and regulation of larger membrane protein complexes. This opens up a new perspective in basic biology, underscoring the functional relevance of small proteins,” remarks Dr. Miyazaki.

    Indeed, such results could open doors to new avenues for exploring the previously unrecognized functions of these “microproteins” in various cellular processes.

    Source:

    Nara Institute of Science and Technology

    Journal reference:

    Miyazaki, R., et al. (2025). Structural basis of lipopolysaccharide translocon assembly mediated by the small lipoprotein LptM. Cell Reports. doi.org/10.1016/j.celrep.2025.116013.

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  • Pakistan calls on international community to urge India to halt ‘human rights crimes’ in Kashmir

    Pakistan calls on international community to urge India to halt ‘human rights crimes’ in Kashmir

    PM announces Rs4 billion for mapping, rebuilding flood-hit infrastructure in Gilgit-Baltistan


    ISLAMABAD: Prime Minister Shehbaz Sharif on Monday announced Rs4 billion ($14 million) funds for mapping and rebuilding flood-hit infrastructure in the northern Gilgit-Baltistan (GB) region.


    At least 10 people have died and five others have sustained injuries in the region in rain- and flood-related incidents in GB, according to the National Disaster Management Authority (NDMA). Several people, including tourists, remain missing after deadly flash floods.


    The region, home to thousands of glaciers and five out of 14 world peaks above the height of 8,000 meters, has suffered the highest infrastructure losses, with 347 houses destroyed and 196 partially damaged, and several roads and bridges damaged and blocked by raging floodwaters over the last few weeks.


    Sharif arrived in Gilgit city on Monday to review the flood situation in the region and presided over a meeting, attended by senior officials and ministers of the regional and central governments, to take stock of the damages during the monsoon season.


    “Today, I stand before you, alongside members of my cabinet, to express our heartfelt solidarity with the people of Gilgit-Baltistan. I assure you, God willing, that I will remain present with you until you are fully settled in your homes once again,” he told affected people at a ceremony to distribute compensation cheques, urging regional and federal authorities to work relentlessly to prepare against climate disasters.


    “I will return at the end of August, God willing, during which [NDMA chief] Inam Haider is tasked to conduct full mapping of the losses, estimate damages, and report back. I expect contributions from both federal and Gilgit-Baltistan governments. Today, I announce a fund of 4 billion rupees for this purpose.”


    Pakistan ranks among the most climate-vulnerable countries despite contributing less than one percent of global greenhouse gas emissions. The country has witnessed increasingly erratic weather events in recent years, including record-breaking rains, floods, heatwaves, droughts and severe storms.


    Sharif said his government was responsible for installing advanced warning systems across the region, acknowledging that though development programs had been ongoing in the region on paper for seven years, “little real work has been done, whether by the federal or provincial governments.”


    “Over these seven years, negligible progress occurred,” he said. “I emphasize that the timeline set must be adhered to strictly — not even an hour of delay is acceptable.”


    The prime minister announced Rs1 million for the deceased individuals, Rs400,000 for severely injured persons, Rs300,000 for the injured, Rs600,000 for those whose houses were destroyed and Rs400,000 for the one with partial damages to their homes.


    “Those with business losses, shops, or small enterprises will receive tiered compensation accordingly,” he announced, tasking members of his cabinet with overseeing road repairs, water and power projects.


    “I previously announced a 100 MW solar power project through the national solar energy program. I expect that by next summer, especially in the harsh winter months when you face acute power shortages, this project will significantly alleviate them,” Sharif told the attendees.


    The PM’s visit came hours after the Pakistan Meteorological Department warned of more rains in the country, saying monsoon currents penetrating Pakistan were expected to intensify from Aug. 4.


    It said heavy rains may generate flash floods in local nullahs/streams of Chitral, Dir, Swat, Shangla, Mansehra, Kohistan, Abbottabad, Buner, Charsadda, Nowshera, Swabi, Mardan, Murree, Galliyat, Islamabad, Rawalpindi, northeast Punjab and Azad Kashmir from Aug. 5 to Aug. 7.


    “Landslides/mudslides may cause roads’ closure in the vulnerable hilly areas of Khyber Pakhtunkhwa, Gilgit-Baltistan, Murree, Galliyat and Kashmir during the forecast period,” the PMD said.


    In May, at least 32 people were killed in severe storms, while a third of Pakistan was submerged by devastating floods in 2022 that killed more than 1,700 people, affected over 30 million and caused an estimated $35 billion in damages.

     

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  • From Pollutant to Valuable Chemical Product

    From Pollutant to Valuable Chemical Product

    In two studies that have just been published in the renowned journal Nature Catalysis, the research teams show how the two nickel-containing enzymes carbon monoxide dehydrogenase (CODH) and acetyl-CoA synthase (ACS) transform CO2 into activated acetic acid. These detailed insights into the mechanism provide new approaches for developing synthetic catalysts that could use CO2 as a raw material.

    Two Enzymes – How Structural Changes Control the Reaction

    The investigations focus on two enzymes in which nickel and iron ions are uniquely linked in the active sites: CODH and ACS. These enzymes work hand in hand to first convert CO2 into carbon monoxide (CO) and then into acetyl-CoA, an activated form of acetic acid. This reaction chain is an essential part of the so-called Wood–Ljungdahl pathway, one of the oldest biological processes for carbon fixation.

    In one study, scientists from Humboldt Universität, in collaboration with researchers from TU Berlin, demonstrated that the nickel ion in the active site of CODH not only binds CO2 but also supplies the electrons required for the reaction. This flexibility makes the nickel ion the key player in CO2 activation and conversion. Using a combination of X-ray diffraction and spectroscopy on CODH crystals, they succeeded for the first time in visualizing all catalytically relevant states with bound reaction partners in the enzyme at atomic resolution.

    “Since our first structure of Ni-containing carbon monoxide dehydrogenases in 2001, I have wondered why these enzymes need Ni ions. Our new work provides an answer, which lies in the unusual coordination of nickel,” says Prof. Holger Dobbek, head of the Structural Biology and Biochemistry research group at Humboldt Universität. Yudhajeet Basak, the study’s first author, adds: “By understanding the ancient mechanisms of CO₂ fixation, we can transfer them to the development of novel catalysts that could accelerate the transition to a carbon-neutral industry.”

    In a complementary study led by Prof. Petra Wendler from the University of Potsdam, the researchers investigated how the binding of small molecules to the nickel center of ACS trigger large-scale structural changes in the enzyme. Using high-resolution cryo-electron microscopy, the team was able to visualize six previously unknown intermediate states of the enzyme. The results show that the enzymes do not operate as rigid structures; rather, ligand binding induces dynamic movements that control the reaction process.

    Relevance for Climate Protection and Sustainable Chemistry

    The findings are significant not only for basic research. They may also indicate how to transfer biological principles of catalysis to technical processes. In the future, synthetic catalysts modeled after these enzymes could efficiently convert CO2 into valuable chemical products – an important contribution to a more sustainable circular economy.

    Original publication

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  • IHC orders talks with BYC to clear capital streets – Pakistan

    IHC orders talks with BYC to clear capital streets – Pakistan

    ISLAMABAD: The Islamabad High Court (IHC) on Monday ordered the deputy commissioner of Islamabad to negotiate with the Baloch Yakjehti Committee protesters and clear roads that have been blocked for weeks, crippling a local business.

    Chief Justice Sardar Mohammad Sarfraz Dogar issued the directive while hearing a petition from a petrol station operator whose business has been severely disrupted by the prolonged demonstration near the National Press Club.

    During the hearing, key officials including Advocate General Islamabad Ayaz Shaukat, Deputy Commissioner Irfan Nawaz Memon, SSP Operations Shoaib Khan, and DSP Legal Sajid Cheema were present.

    The chief justice questioned the administration for allowing the lengthy disruption.

    Instructs city administration to protect rights and property of others as well

    “Under what law is someone’s property being blocked?” he asked city officials in the courtroom. “The steps you’ve taken are insufficient. You must protect the rights and property of others.”

    The petition was filed by M/S Awan Associates, which operates a PSO fuel station.

    It challenged indefinite road closures that have paralysed business and, according to the petition, violated multiple constitutional rights.

    Islamabad Advocate General Ayaz Shaukat told the court that no official permission had been granted for the protest, which is being led by members of the Baloch Yakjehti Committee.

    “We disperse them, but they return,” he said.

    Deputy Commissioner Memon said the administration could offer an alternate location for the protest.

    The chief justice instructed him to negotiate with the demonstrators and inform them they could not continue occupying the current site.

    He ordered the submission of a compliance report at the next hearing.

    “The direction has been given. It’s not the court’s job to spoon-feed the administration,” the chief justice remarked before adjourning the case.

    The petition filed through advocate Kashif Ali Malik cited respondents in the case include the Federation of Pakistan, Capital Development Authority (CDA), chief commissioner, deputy commissioner, and inspector general of Islamabad.

    During the hearing, the petitioner’s lawyer told the court that key routes — Nazim-ud-Din Road, Shaheed-i-Millat Road, and Polyclinic underpass — have remained closed for weeks, causing a “drastic decline” in customers.

    He said the blockade also hampers access for emergency vehicles and suppliers, rendering operations “unsustainable”.

    Mr Malik argued the closures violate fundamental rights to life, movement, trade, property, and education as guaranteed in Constitution.

    Citing Supreme Court precedents, he contended that protests cannot override the public’s right to healthcare, education, or livelihood.

    While acknowledging protests are a protected right, the petition stressed that such demonstrations cannot “paralyse the entire locality” or indefinitely restrict public movement.

    The court has been asked to declare the road closures “illegal, unconstitutional, and without lawful authority” and to order the immediate restoration of traffic.

    Published in Dawn, August 5th, 2025

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  • ‘Two-in-one’ RNA molecule can simultaneously turn off two difficult-to-target cancer-related genes

    ‘Two-in-one’ RNA molecule can simultaneously turn off two difficult-to-target cancer-related genes

    University of North Carolina Lineberger Comprehensive Cancer Center researchers have developed a “two-in-one” molecule that can simultaneously turn off two notoriously difficult-to-target cancer-related genes, KRAS and MYC, as well as directly deliver drugs to tumors that express these genes. This advance holds special promise for treating cancers that have been historically challenging to treat.

    The new technology incorporates novel compositions of inverted RNAi molecules that have shown a marked ability to co-silence mutated KRAS and over-expressed MYC. RNA interference (RNAi) is a cellular process that uses small interfering RNAs (siRNAs) to selectively turn off, or silence, mutated genes. The co-silencing resulted in an up to a 40-fold improvement in inhibition of cancer cell viability compared to the use of individual siRNAs.

    The laboratory findings were published in the Journal of Clinical Investigation on July 31.

    “Targeting two cancer-causing genes at the same time is akin to slicing both Achilles heels of cancer, which has tremendous potential,” said Chad V. Pecot, MD, corresponding author of the article, professor of medicine at UNC School of Medicine. “Our inverted molecule establishes proof-of-concept for dual-silencing of KRAS and MYC in cancer and constitutes an innovative molecular strategy for co-targeting not just those two genes, but any two genes of interest, which has broad implications.”

    Mutated KRAS and MYC can work together to promote and maintain aggressive tumor development through several mechanisms, including stimulation of inflammation, activation of cancer cell survival pathways and suppression of cancer cell death.

    KRAS mutations are present in nearly 25% of all human cancers, and they frequently occur in some of the most prevalent tumor types. MYC is also regarded as a critical cancer-related gene and is dysfunctional in approximately 50-70% of cancers. Several studies have shown that inactivation of MYC can substantially inhibit tumor development, making it a very attractive therapeutic co-target.

    MYC seems to be nearly as important a target as KRAS, however there are still no successful drugs capable of targeting MYC,” said Pecot, co-leader of the UNC Lineberger Cancer Therapeutics Program and director of the UNC RNA Discovery Center. “Our study is one of the first to deeply characterize the therapeutic implications of targeting both genes at the same time. We have also made the first ‘two-in-one’ molecule capable of silencing both the KRAS and MYC proteins.”

    Because most cancers depend on multiple genetic mutations, or drivers, for survival, this technology is especially valuable for targeting two key drivers at once. It holds particular promise when both targets, like MYC and KRAS, are critical to the cancer cell’s ability to stay alive but have historically been difficult to treat with drugs. Pecot noted that the unique features of their design make it possible to begin exploring the ability to silence three targets at one time. “The opportunities are vast,” he says.

    This discovery builds on a related finding from Pecot’s lab published in Cancer Cell in June, which described a targeted drug delivery mechanism for a specific KRAS variant known as KRAS G12V. Now, Pecot and his colleagues have developed an RNA silencing molecule capable of shutting down all KRAS mutations found in cancer.

    While this broader approach is less specific than the earlier KRAS G12V-targeted method, it has the potential to treat a much larger group of patients, including those with the most common KRAS mutations found in lung, colorectal, and pancreatic cancers. Together, these cancers are expected to account for nearly half a million new cases in the U.S. this year, according to the American Cancer Society.

    “Overall, this is another nice example of RNA therapeutics being made at UNC as part of the RNA Discovery Center,” Pecot said. “These advances could bring real hope to patients with KRAS-related cancers.”

    Source:

    University of North Carolina Health Care

    Journal reference:

    Chareddy, Y. S., et al. (2025) Inverted chimeric RNAi molecules synergistically co-target MYC and KRAS in KRAS-driven cancers. Journal of Clinical Investigation. https://doi.org/10.1172/JCI187204

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  • Alzheimer’s risk may start at the brain’s border, not inside it

    Alzheimer’s risk may start at the brain’s border, not inside it

    The brain’s health depends on more than just its neurons. A complex network of blood vessels and immune cells acts as the brain’s dedicated guardians — controlling what enters, cleaning up waste, and protecting it from threats by forming the blood-brain barrier.

    A new study from Gladstone Institutes and UC San Francisco (UCSF) reveals that many genetic risk factors for neurological diseases like Alzheimer’s and stroke exert their effects within these very guardian cells.

    “When studying diseases affecting the brain, most research has focused on its resident neurons,” says Gladstone Investigator Andrew C. Yang, PhD, senior author of the new study. “I hope our findings lead to more interest in the cells forming the brain’s borders, which might actually take center stage in diseases like Alzheimer’s.”

    The findings, published in Neuron, address a long-standing question about where genetic risk begins and suggest that vulnerabilities in the brain’s defense system may be a key trigger for disease.

    Mapping the Brain’s Guardians

    For years, large-scale genetic studies have linked dozens of DNA variants to a higher risk of neurological diseases like Alzheimer’s, Parkinson’s, or multiple sclerosis.

    Yet, a major mystery has persisted: over 90% of these variants lie not in the genes themselves, but in the surrounding DNA that does not contain the code for making proteins, once dismissed as “junk DNA.” These regions act as complex dimmer switches, turning genes on or off.

    Until now, scientists haven’t had a full map of which switches control which genes or in which specific brain cells they operate, hindering the path from genetic discovery to new treatments.

    A New Technology Finds Answers

    The blood-brain barrier is the brain’s frontline defense — a cellular border made up of blood vessel cells, immune cells, and other supporting cells that meticulously controls access to the brain.

    Yet, these important cells have been difficult to study, even using the field’s most powerful genetic techniques. To overcome this, the Gladstone team developed MultiVINE-seq, a technology that gently isolates the vascular and immune cells from postmortem human brain tissue.

    This technology allowed the team, for the first time, to simultaneously map two layers of information: the gene activity and the “dimmer switch” settings — known as chromatin accessibility — within each cell. The scientists studied 30 brain samples from individuals with and without neurological disease, giving them a detailed look at how genetic risk variants function across all major brain cell types.

    Working closely with Gladstone Investigators Ryan Corces, PhD, and Katie Pollard, PhD, lead authors Madigan Reid, PhD, and Shreya Menon integrated their single-cell atlas with large-scale genetic data from studies of Alzheimer’s, stroke, and other brain diseases. This revealed where disease-associated variants are active — and many were found to be active in vascular and immune cells rather than neurons.

    “Before this, we knew these genetic variants increased disease risk, but we didn’t know where or how they acted in the context of brain barrier cell types,” Reid says. “Our study shows that many of the variants are actually functioning in blood vessels and immune cells in the brain.”

    Different Diseases, Different Disruptions

    One of the study’s most striking findings is that genetic risk variants affect the brain’s barrier system in fundamentally different ways, depending on the disease.

    “We were surprised to see that the genetic drivers for stroke and Alzheimer’s had such distinct effects, even though they both involve the brain’s blood vessels,” Reid says. “That tells us they involve really distinct mechanisms: structural weakening in stroke, and dysfunctional immune signaling in Alzheimer’s.”

    In stroke, genetic variants primarily affected genes responsible for the structural integrity of blood vessels, potentially weakening the vessels’ physical structure. Whereas in Alzheimer’s, the variants amplified genes that regulate immune activity, suggesting that overactive inflammation — not structural weakness — is the key issue.

    Among the Alzheimer’s-associated variants, one stood out. A common variant near the PTK2B gene, which is found in more than a third of the population, was most active in T cells, a type of immune cell. The variant enhances expression of the gene, which may promote T cell activation and entry into the brain, putting immune cells into overdrive. The team found these super-charged immune cells near amyloid plaques, the sticky protein buildups that mark Alzheimer’s.

    “Scientists are debating the role of T cells and related components of the immune system in Alzheimer’s,” Yang says. “Here, we provide genetic evidence in humans that a common Alzheimer’s risk factor may work through T cells.”

    Excitingly, PTK2B is a known “druggable” target, and therapies that inhibit its function are already in clinical trials for cancer. The new study opens a fresh avenue to investigate whether such drugs could be repurposed for Alzheimer’s disease.

    Location, Location, Location

    The study’s findings on the brain’s “guardian” cells point to two new opportunities for protecting the brain.

    Located at the critical interface between the brain and the body, the cells are continually influenced by lifestyle and environmental exposures, which could synergize with genetic predispositions to drive disease. Their location also makes them a promising target for future therapies, potentially allowing for drugs that can bolster the brain’s defenses from the “outside” without needing to cross the formidable blood-brain barrier.

    “This work brings the brain’s vascular and immune cells into the spotlight,” Yang says. “Given their unique location and role in establishing the brain’s relationship with the body and outside world, our work could inform new, more accessible drug targets and lifestyle interventions to protect the brain from the outside in.”

    About the Study

    The study, “Human brain vascular multi-omics elucidates disease risk associations,” was published in the journal Neuron on July 28, 2025.

    In addition to Yang, Reid, Corces, and Pollard, the study’s other authors are Shreya Menon, Hao Liu, Haoyue Zhou, Zhirui Hu, Bella Ding, Zimo Zhang, Sophia Nelson, and Amanda Apolonio of Gladstone; Simon Frerich of UC San Francisco; Shahram Oveisgharan and David A. Bennett of Rush University Medical Center; and Martin Dichgans of LMU Munich.

    The work was supported by the National Institute of Neurological Disorders and Stroke (1R01NS128909-01), Alzheimer’s Association (ADSF-24-1345199-C, AARF-22-923641), BrightFocus Foundation (A2022027F), Cure Alzheimer’s Fund, the Ludwig Family Foundation, the Dolby Family Fund, the Bakar Aging Research Institute, National Institute of Mental Health (R01- 503 MH123178), National Institute of Aging (P01-AG073082, U01-AG072573), The Leducq Foundation (22CVD01, BRENDA), the Joachim Herz Foundation, and the National Human Genome Research Institute (UM1-HG012076).

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