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A study has identified a protein complex that is activated by defects in the spliceosome, the molecular scissors that process genetic information. Future research could lead to new therapeutic approaches to treat diseases caused by faulty splicing.
The genetic material, in the form of DNA, contains the information that is crucial for the correct functioning of every human and animal cell. From this information repository, RNA, an intermediate between DNA and protein, the functional unit of the cell, is generated. During this process, the genetic information must be tailored for specific cell functions. Information that is not needed (introns) is cut out of the RNA and the important components for proteins (exons) are preserved. A team of researchers led by Professor Dr Mirka Uhlirova at the University of Cologne’s CECAD Cluster of Excellence in Aging Research has now discovered that if the processing of this information no longer works properly, a protein complex (C/EBP heterodimer) is activated and directs the cell towards a dormant state, known as cellular senescence. The results have appeared under the title ‘Xrp1 governs the stress response program to spliceosome dysfunction’ in Nucleic Acids Research.
All eukaryotes (i.e. organisms in which DNA is enclosed within the cell nucleus) have a spliceosome. This is a machine that performs ‘splicing’, the removal of introns and linking exons to form messenger RNA (mRNA). Malfunctions in the spliceosome lead to diseases known as spliceosomopathies, which may affect many different tissues, and manifest as retinal degeneration or myelodysplastic syndrome, a group of bone marrow diseases affecting the blood.
In the study, the Uhlirova lab used the model organism Drosophila melanogaster, a fruit fly, to investigate how cells within a developing organism respond to spliceosome malfunction. The scientists used a combination of genomics and functional genetics to determine the role of individual genes and interactions among them. The study showed that cells suffering from a defective spliceosomal U5 snRNP (U5 small nuclear ribonucleoprotein particle) activate a stress signalling response and cellular behaviours that are characteristic of cellular senescence. The senescence programme changes crucial functions of the cells. It prevents cells from dividing while stimulating their secretion. Senescence is triggered to preserve cells that are damaged, as their immediate elimination would cause more harm than good. However, senescent cell accumulation can have a negative impact on a tissue as well as the whole organism. Therefore, these cells are ultimately eliminated.
Uhlirova’s team identified the C/EBP-heterodimer protein complex, Xrp1/Irbp18, as the critical driver of the stress response programme caused by faulty splicing. Upregulation of Xrp1/Irbp18 in damaged cells led to increased protein production and induced a senescence-like state. “Senescence is a double-edged sword,” said Uhlirova. One advantage of senescent cells is that they are not all eliminated by cell death at the same time, thus maintaining the integrity of the tissue. After all, partially intact tissue is better than none at all. However, these cells create problems in the long term, as their accumulation promotes disease and ageing.
“A functioning spliceosome is a basic prerequisite for healthy cells, tissue and the entire organism,” she concluded. “Additional investigation of the stress signalling programme we have identified will be important to further unpack the complex responses triggered by defects in the essential machines controlling gene expression — and how we can influence them.” In future, the results could contribute to the development of therapeutic approaches to treat diseases that are caused by malfunctions of the spliceosome.

A group of patients with a hereditary disorder have had their lives transformed by a single treatment of a breakthrough gene-editing therapy, according to the lead researcher.
The patients from New Zealand, the Netherlands and the UK have hereditary angioedema, a genetic disorder characterised by severe, painful and unpredictable swelling attacks. These interfere with daily life and can affect airways and prove fatal.
Now researchers from the University of Auckland, Amsterdam University Medical Center and Cambridge University Hospitals have successfully treated more than ten patients with the CRISPR/Cas9 therapy, with interim results just published in a leading journal.
“It looks as if the single-dose treatment will provide a permanent cure for my hereditary angioedema patients’ very disabling symptoms,” says principal investigator Dr Hilary Longhurst, who is both a clinical immunologist at Auckland Hospital Te Toku Tumai and an honorary associate professor at the University of Auckland.
“Plus, of course, there is huge potential for development of similar CRISPR/Cas9 treatments for other genetic disorders.”
Globally, it is estimated one in 50,000 people have hereditary angioedema, however, because it is rare, it is often not correctly diagnosed.
In the phase one study, there were no serious or lasting side-effects from the single infusion, which took place over two to four hours under clinical supervision from late 2021 and onwards.

The investigational therapy, called NTLA-2002, utilises in vivo CRISPR/Cas9 technology to target the KLKB1 gene, which is responsible for producing plasma prekallikrein.
By editing this gene, the therapy reduces the levels of total plasma kallikrein, effectively preventing angioedema (swelling) attacks.
The trial, published in the New England Journal of Medicine, demonstrated dose-dependent reduction in total plasma kallikrein protein with reductions of up to 95 percent achieved.
A mean reduction of 95 percent in angioedema attacks was observed across all patients through to the latest follow-up.
The patients from the initial study will be followed up for a further 15 years to continue to assess long-term safety and efficacy.
A larger and more robust, double-blinded, placebo-controlled phase two trial is under way and a Phase 3 trial is planned to start in the second half of 2024.

Dr Danny Cohn, from the Department of Vascular Medicine at the Amsterdam University Medical Center says these promising results are a step forward for this group of patients.
“We’ve never been closer to the ultimate treatment goal of normalising hereditary angioedema patients’ lives and offering total control of the disease,” says Dr Cohn.
Dr Padmalal Gurugama, consultant in clinical immunology and allergy at Cambridge University Hospitals, UK says the gene editing therapy has the potential to significantly improve patients’ lives.
“Hereditary angioedema can cause patients severe swellings and intense pain which can be life-threatening as well as restricting normal activities, such as going to work or school.
“Because it is often misdiagnosed, many patients undergo unnecessary treatments and invasive procedures.”
The therapy affects only the patient and is not passed onto their children, who still have an even chance of inheriting the disorder.
The studies have been funded by US company Intellia Therapeutics, which chose New Zealand to lead the research as, at that time — late 2021, it had relatively fewer Covid-19 cases than other countries.
So far, the only approved CRISPR therapy, CASGEVY, is for sickle cell disease and beta thalassemia. However, CASGEVY is an ex vivo CRISPR therapy, where the cells are taken from the patient and edited outside of the body and then reinfused, whereas NTLA-2002 is an in vivo CRISPR therapy, where the targeted gene editing occurs directly within the body.
CRISPR technologies are being used to develop treatment for a wide range of diseases, such as genetic disease, cardiovascular disease, cancer and autoimmune diseases.

Scientists led by a team at Duke-NUS Medical School have made a breakthrough in understanding the mechanisms that influence cancer cell growth and development. Publishing in the Journal of Clinical Investigation, the researchers illuminate the previously hidden role of a novel enzyme, called fatty acid hydroxylase domain containing 2 (FAXDC2), revealing its pivotal role in cholesterol synthesis and cancer progression.
The study details the cascade of molecular events beginning from the suppression of FAXDC2 to the disruption of normal cholesterol synthesis to altered cancer fates, highlighting a potential vulnerability in cancer cells that could be targeted for therapeutic intervention.
“Our journey into the cellular drivers of cancer started with an exploration of the Wnt signalling pathway, a crucial player in cell growth and development,” explained Assistant Professor Babita Madan, first author of the study from Duke-NUS’ Cancer & Stem Cell Biology (CSCB) Programme. “It was during these studies that we stumbled upon the enzyme FAXDC2, which emerged as a central figure in controlling cancer and stem cells. Our discovery suggests that FAXDC2’s activity, or its suppression, has profound implications for cellular growth and differentiation, painting a complex picture of the relationship between cancer biology and cholesterol synthesis.”
The research began with a deep dive into the Wnt signalling pathway, known for its critical role in the regulation of both normal and cancer cell growth. Wnt signalling is a key signalling pathway that regulates growth and development and maintaining brain, skin, hair and intestinal cells. However, hyperactive Wnt signalling — present in the cancer models employed in the study — impairs cell differentiation and keeps the cancers in a stem cell-like state. These undifferentiated cancer stem cells proliferate rapidly and uncontrollably, promoting faster tumour progression, and are resistant to anti-cancer therapies.
Employing cutting-edge genomic technologies to unravel this complex biological process, the scientists’ attention was drawn to the enzyme FAXDC2 when they found it increased dramatically after pancreatic cancer models were treated with a made-in-Singapore Wnt inhibitor, ETC-159. In-depth analyses of colorectal cancer tissue samples corroborated this finding, showing a consistent pattern of FAXDC2 suppression and subsequent buildup of cholesterol precursors, including a building block of cholesterol called lophenol. The lower the FAXDC2 expression, the higher the level of lophenol.
“FAXDC2 is a previously unknown enzyme that helps make cholesterol from the precursor lophenol. Importantly, how much FAXDC2 you have in your cells changes the amount of lophenol you have,” explained Professor David Virshup, Director of the CSCB Programme and the senior author of the study. “Lophenol appears to modulate the activity of the differentiation pathway and, therefore, we think it helps to keep cancer cells in a more stem cell-like state.”
Prof Virshup emphasised the broader implications of these insights, saying, “This study provides a fascinating glimpse into the molecular machinery of cancer cells. The role of FAXDC2 in regulating cholesterol synthesis opens new pathways for future therapies. Understanding these complex mechanisms paves the way for innovative approaches to combat cancer, emphasising the importance of cholesterol biosynthesis intermediates as important signalling molecules and potential drugs.”
The discovery of FAXDC2’s role in cancer biology marks just the beginning of a longer scientific journey. Further research is necessary to fully understand how the suppression of FAXDC2 and the resulting changes in cholesterol metabolism can be leveraged to develop new cancer therapies. The research team is keen on exploring the therapeutic potential of targeting FAXDC2 in cancer treatment, considering it as a possible avenue for the development of drugs that could inhibit cancer growth by modulating cholesterol synthesis pathways.
Additionally, the findings spur interest in preventative strategies that could mitigate the risk of cancer development by maintaining the balance of cholesterol precursors in the body. Understanding the triggers that lead to the suppression of FAXDC2 in cancer cells could pave the way for novel prevention methodologies, potentially offering new hope in the fight against cancer.
“These findings resonate with our unwavering commitment to improving patient care through pivotal discoveries,” commented Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS. “The road ahead involves rigorous research and collaboration across various disciplines, all aimed at translating these fundamental insights into tangible medical breakthroughs that could one day transform cancer treatment and prevention strategies.”

Scientists from the German Cancer Research Center (DKFZ) and Heidelberg University investigated in mice how spreading tumor cells behave at the site of metastasis: Some tumor cells immediately start to form metastases. Others leave the blood vessel and may then enter a long period of dormancy. What determines which path the cancer cells take is their epigenetic status. This was also confirmed in experiments with human tumor cells. The results of the study could pave the way for novel diagnostic and therapeutic applications.
What makes cancer so dangerous? Cancer cells that leave the primary tumor to reach distant sites of the body where they may grow into daughter tumors, called metastases. While most primary tumors can be effectively treated, metastases are the real danger. Oncologists estimate that more than 90 percent of all cancer deaths in solid tumors are due to metastases.
Researchers have been working for decades to understand and prevent the spread of tumor cells. However, the mechanisms that enable a cancer cell to survive in a distant organ and ultimately grow into a metastasis are still largely unknown.
To spread throughout the body, cancer cells travel through blood and lymphatic system. Scientists at the DKFZ and at Heidelberg University have now developed a method to observe the behavior of migrating cancer cells in mice immediately upon arrival in the metastatic organ — in this case the lung.
The team led by the two first authors Moritz Jakab and Ki Hong Lee discovered that some tumor cells, once they have arrived in the metastatic organ, leave the blood vessel and enter a resting state. Other cancer cells start to divide directly within the blood vessel and grow into metastases.
This delicate fate decision of the metastasizing tumor cells is controlled by the endothelial cells that line the inside of all blood vessels. They release factors from the Wnt signaling pathway that promote the exit of tumor cells from the blood vessel and thereby initiate latency. When the researchers switched off the Wnt factors, latency no longer occurred.
What distinguishes latent from growing metastasizing cancer cells?
“At this point, we asked ourselves the question: Why do some cancer cells immediately form a metastasis, while others fall into a kind of sleep?” says Moritz Jakab. The dormant and metastasizing cancer cells did not differ genetically, nor in many other molecular aspects. But the researchers were able to detect a subtle difference: The methylation of the DNA differed between the two cell types. Tumor cells, whose DNA was less methylated, responded sensitively to the Wnt factors, which resulted in extravasation from the blood vessel and subsequent latency. On the other hand, the more methylated cancer cells did not respond to the Wnt factors, remained in the blood vessel and immediately started metastatic growth.
To test this hypothesis, the team examined the DNA methylation status of various tumor cell lines. Indeed, they found that this directly correlated with their metastatic potential.
“These results are surprising and could have far-reaching consequences for tumor diagnosis and therapy. The results of the study could, for example, help to use certain methylation patterns as biomarkers to predict for patients how high the load of dormant cancer cells is and, thus, how likely the patient is to relapse after successful treatment of the primary tumor,” says senior author Hellmut Augustin. “But first we need to study whether natural human tumors behave in the same way as the employed cell lines or experimental tumors.”

The NewsIn California, days that experienced both extreme heat and wildfire smoke at the same time have seen disproportionate numbers of hospitalizations for heart and lung ailments, a new study found. The research highlights the public health dangers of distinct climate threats that can have a compound effect when they occur simultaneously.The research, published on Friday in the journal Science Advances, also found that this compounding effect was greater in communities with lower levels of income, education, health insurance coverage and tree cover.Smoke from wildfires turned the skies orange in the Bay Area in September 2020.Jim Wilson/The New York TimesBackground: Global warming is intensifying both threats.As humans warm the planet, both heat waves and wildfires are becoming more severe and longer-lasting in the American West. That also means they are more likely to overlap. Researchers have estimated that two-thirds of California’s land area experienced broiling heat and heavy wildfire smoke concurrently at some point during the state’s record fire year of 2020.Both hazards are harmful to health on their own: Heat stress increases cardiac strain, and inhaling wildfire smoke can aggravate lung conditions. The new study, led by researchers at the Scripps Institution of Oceanography at the University of California, San Diego, looked at the health effects when the two threats appeared in tandem.On exceptionally hot and smoky days, staying indoors doesn’t always help, and certainly not for people who don’t have air-conditioners and air purifiers, said Tarik Benmarhnia, an environmental epidemiologist at Scripps and one of the study’s authors. “Air pollution doesn’t stay politely outside,” he said. “It gets inside, interacts with a lot of indoor air pollutants and can lead to a lot of issues.”The Findings: Compounding harms, and unequal ones, too.The researchers took state data on unscheduled hospitalizations between 2006 and 2019 and combined it with detailed readings of temperatures and wildfire smoke.We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

An array of obstacles make it difficult for patients to obtain Wegovy or Zepbound. Finding Wegovy is “like winning the lottery,” one nurse practitioner said.Talk to people who have tried to get one of the wildly popular weight-loss drugs, like Wegovy, and they’ll probably have a story about the hoops they had to jump through to get their medication — if they could get it at all.Emily Weaver, a nurse practitioner in Cary, N.C., said she told her patients that finding Wegovy was “like winning the lottery.”Here are six reasons why.1. Demand is very high.Fueled in part by TikTok videos and celebrity testimonials, people are increasingly seeking prescriptions for appetite-suppressing medications. The drugs in this class have long been used to treat diabetes but more recently have been recognized for their extraordinary ability to help patients lose weight. The medications are injected weekly and have sticker prices as high as $16,000 a year.About 3.8 million people in the United States — four times the number two years ago — are now taking the most popular weight-loss drugs, according to the IQVIA Institute for Human Data Science, an industry data provider. Some of these prescriptions are for diabetes. The medicines are Novo Nordisk’s Ozempic and Wegovy (the same drug sold under different brand names), and Eli Lilly’s Mounjaro and Zepbound (also the same drug).We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

Meet Sholto David, whose error-spotting has raised a question: If researchers aren’t getting the little things right, what else might be wrong?Sholto David, 32, has a Ph.D. in cellular and molecular biology from Newcastle University in England. He is also developing an expertise in spotting errors in scientific papers. Most recently, and notably, he discovered flawed or manipulated data in studies conducted by top executives at the Harvard-affiliated Dana-Farber Cancer Institute. The institute said that it was requesting retraction of six manuscripts and had found 31 other manuscripts that required corrections.From his home in Wales, Dr. David scours new research publications for images that are mislabeled and manipulated, and he regularly finds mistakes, or malfeasance, in some of the most prominent scientific journals. Accuracy is vital, as peer-reviewed papers often provide the evidence for drug trials or further lines of research. Dr. David said that the frequency of such errors suggests an underlying problem for science.His interview with The New York Times has been edited and condensed.Are you done hunting scientists for the day?I haven’t had time today. But if I spent a couple of hours reading papers, I’d probably write four or five comments about errors in scientific papers. It’s not hard to find these problems, and it’s not hard to find them at any institution. They’re all out there to find, if anyone wants to read the scientific literature.What motivates you to spend the time to do it?I’m not an anti-vaxxer, I’m not a crank conspiracist or anything like that. I’m a scientist myself, and I care about getting the science right.We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

Published3 hours agoShareclose panelShare pageCopy linkAbout sharingImage source, PA MediaBy Lorna GordonBBC News Scotland correspondentSenior politicians from both the Scottish and UK governments gave evidence to the UK Covid inquiry on its third and final week of hearings in Edinburgh. Here are five things we learned.1. Who was playing politics during the pandemic?Nicola Sturgeon responded robustly to charges that she politicised the pandemic to advance the cause of Scottish independence. She’d never thought about the subject less in her life, she said, than while trying to steer the country through the crisis. Ms Sturgeon insisted the suggestion she’d seen it as an “opportunity” to differentiate her leadership from the UK government’s “just wasn’t true”, one of several moments when she appeared tearful. The UK government minister responsible for relations between the two governments at the time, Michael Gove, was also challenged on constitutional matters. Image source, PA MediaThe inquiry was shown a paper Mr Gove presented to his colleagues in July 2020, called “State of the Union”. It contained notes on polling, indicating that voters in Scotland had a more positive view of the Scottish government’s handling of the pandemic than they did of the UK government’s response. “Absent Covid-19,” Mr Gove wrote, “I am firmly of the view that the risk to the Union would be the greatest challenge this government needed to confront.” He advocated highlighting how being part of the UK benefited people grappling with “hardship” brought on by the pandemic. Two days later, the then-prime minister, Boris Johnson, visited Scotland. Mr Gove, who was a journalist before entering politics, delivered an attention-grabbing line when he observed: “The political aim of the SNP is to destroy the United Kingdom, and from time to time they will make political points to that end.” But elsewhere in his evidence, he repeatedly stated his admiration for the professionalism and integrity of Scottish government ministers and his belief that their “overwhelming motivation” was to protect the people of Scotland.It seems implausible that Ms Sturgeon, Mr Gove, or the governments they were part of entirely set aside their core political philosophies overnight when the pandemic hit. The real question for Lady Hallett is whether this made any real-world difference to the decisions they made. 2. Who was making the decisions in Scotland?Image source, PA MediaWas the Scottish cabinet in the driving seat when it came to deciding how to tackle the Covid pandemic or was power concentrated in the hands of a few? Cabinet minutes dated December 2020 showed that ministers agreed to delegate to Ms Sturgeon the responsibility for finalising proposals to deal with the new Alpha variant of Covid. The cabinet also agreed to give her and her deputy, John Swinney, the responsibility for further decisions if circumstances changed. Mr Swinney said this was consistent with cabinet having set the direction. He also added said that some decisions during Covid had to be made quickly. Mr Swinney was also asked whether a message from the national clinical director Prof Jason Leitch, which stated Nicola Sturgeon wants “to keep it small”, was an indication that the former first minister in effect expected to take the decisions herself. “The idea of it being a small cast list about who was discussing these points is not one I would accept,” he said. Ms Sturgeon also rejected this suggestion, pointing out that cabinet met around 100 times during Covid and that each time detailed minutes would record both the options assessed and decisions reached. So called “Gold Command” meetings – involving Nicola Sturgeon, trusted advisers and a smaller revolving group of ministers – which met in the days ahead of cabinet were not, however, minuted, which means it’s impossible to know what role “Gold” meetings played in decision making. Ms Sturgeon denied she reached decisions based on her “instincts” and rejected suggestions she was given “carte blanche” by the Scottish cabinet.3. Deleted WhatsApps still dominate discussionsHow many times did we hear WhatsApp mentioned? The use of the app, what was said in those informal messages, and why they were or were not deleted have been recurring themes. Former Deputy First Minister John Swinney said he deleted his manually. Alister Jack, the Scottish Secretary, said he had deleted all of his to free up memory on his phone. For Nicola Sturgeon, the question of what happened to hers – after months of press speculation on the subject – eventually came down to one, six-word exchange. Senior counsel to this phase of the Inquiry, Jamie Dawson KC, asked the former first minister: “But did you delete them?” She replied: “Yes”. She used WhatsApp with no more than a handful of people, she said, adding that the exchanges were only ever about “routine” matters or for “passing on information”. Image source, PA MediaBut the inquiry was also shown messages between her and her senior adviser Liz Lloyd, discussing what Ms Sturgeon should do about what she described as “a bit of a crisis of decision-making” on policies affecting the hospitality sector.The Scottish Covid Bereaved Group said they believed there was a culture of secrecy that continued to this day. Ms Sturgeon’s critics accuse her of a cover up. The former first minister insisted anything relevant to the business of government was recorded officially. The inquiry has to take her word for that.4. The regrets about pandemic decisionsAnother theme running through Nicola Sturgeon’s five hours of testimony to the inquiry was regret.Regret, inevitably, over the loss of life during the pandemic – particularly in care homes. And regret, too, over what she called the “loss of opportunity” when it came to education.But the former first minister said her “chief” regret was not imposing the first lockdown – introduced on 23 March 2020 – one or two weeks earlier.That will come as little surprise to those who observed Ms Sturgeon and her largely safety-first approach at close quarters throughout the pandemic: Mask-wearing was mandatory for longer in Scotland than anywhere else in the UK. And at the start of the second wave there were harsher restrictions on entering each other’s homes. But when it came to locking down at the very start of Covid Ms Sturgeon acted at exactly the same time as the then Prime Minister Boris Johnson.5. Did the right governments have the right powers?Policy about health falls under the remit of the Scottish government. But there has always been a keen debate about how much economic policy is devolved. The issue of furlough during the pandemic brought it into sharper focus. When the third wave of Covid hit, Kate Forbes, who was the Scottish government’s finance secretary, repeatedly requested that furlough, which was decided by the UK Treasury, be extended or reintroduced. One of her officials told her there was no appetite for this in the Treasury; that the reaction to this suggestion had been allergic. Image source, PA MediaMs Forbes said she believed Treasury officials were speaking “honestly and truthfully” at the times when they said no further funding would be forthcoming but the position changed shortly afterwards. She said “it was largely because they didn’t know rather than that they were being deceptive”. When asked, she agreed that it was a failure of the UK government to communicate the change to its own officials. The former finance secretary also said she thought the UK mechanism for allocating money back to the Scotland government, known as the Barnett formula wasn’t flexible enough to deal with an emergency. In his evidence, Michael Gove stated that he believed there was a case for “greater clarity overall about reserved and devolved responsibilities”. The inquiry also heard evidence that Matt Hancock, the then UK secretary of state for health, thought public health matters such as “fat fighting” were devolved while public health emergencies were for the Westminster government to decide. Mr Gove rejected suggestions that Mr Hancock’s views were indicative of a wider attitude within the UK government but went on to say that some within the UK government occasionally found it “irksome” dealing with devolved governments taking a different view.Listen to Newscast: Nicola Sturgeon at the Covid Inquiry here

Published3 hours agoShareclose panelShare pageCopy linkAbout sharingImage source, Getty ImagesBy Emily Coady-StempBBC News, South EastOnline services for GPs across Surrey leave many patients feeling “helpless and lost”, a new report says.Healthwatch Surrey said some patients felt “defeated” by online systems and that issues were worse in certain groups.This included people with English as a second language and those less confident with technology.Surrey Heartlands said it had been listening to feedback to make online access “as easy as possible”.Online services include booking appointments, requesting repeat prescriptions and viewing test results.Healthwatch Surrey, which gathers the views of local people on health and social care services in the county, said: “Confusion around the appointment booking process and a perception that appointments are hard, or even impossible, to book online is the issue people tell us most about.”This leaves many people feeling helpless and ‘lost’, in or outside the system.”Online ‘defeats me’One Epsom and Ewell resident was asked by their surgery to book a blood test online.They told Healthwatch: “I tried but I couldn’t understand how to do it and so I called back. “I’m in my 80s and I try to be as independent as I can, but some of these processes defeat me.”Sam Botsford, contract manager at Healthwatch Surrey, said communication was key in ensuring patients knew how to use online services.She said: “People feel they’re being pushed online, and that spans a range of different demographics. “It’s really important for practices to identify the needs of their patients and how they can best meet those.”Nikki Mallinder, director of primary care at Surrey Heartlands Health and Care Partnership, said: “We understand that not everyone will want, or be able to, access online services.”But some people tell us they prefer to access services in this way because they find it easier and more convenient to go online.”Follow BBC South East on Facebook, on X, and on Instagram. Send your story ideas to southeasttoday@bbc.co.uk. More on this storyHealth boss warns of measles outbreak in SurreyPublished19 JanuaryMP to contact health secretary over GP redundanciesPublished11 JanuaryGP redundancies due to ‘new ways of working’Published9 JanuaryRelated Internet LinksHealthwatch SurreySurrey Heartlands Health and Care PartnerrshipThe BBC is not responsible for the content of external sites.

Disrupted function of “cleaning cells” in the body may help to explain why some people with obesity develop type 2 diabetes, while others do not. A study from the University of Gothenburg describes this newly discovered mechanism.
It is well known that obesity increases the risk of insulin resistance and type 2 diabetes. It is also well known that some people who gain weight suffer from the disease and others do not. The reasons for these differences are not clear, but they are related to the function of the adipose tissue rather than the amount of body fat.
The current study, published in the journal PNAS, is mainly based on experiments in mice, but the research indicates that the newly discovered mechanism also applies to humans.
Weight gain increases the breakdown of the structural protein collagen to make room for the growing fat cells within adipose tissue. Collagen is a natural building block in the body that provides strength to cartilage, muscles, and skin.
The breakdown of collagen is handled by macrophages, a type of white blood cell that is part of the immune system. Macrophages are involved in the destruction of invading bacteria, but they also engulf and digest damaged cells and debris such as degraded collagen in adipose tissue during weight gain.
The macrophage function is impaired in obesity
The collagen is fragmented by enzymatic degradation outside the fat cells, and the collagen fragments are then engulfed by macrophages for complete degradation. What this study shows and describes is how highly regulated this uptake of collagen fragments is.

And it is fast when it works properly. However, this function of macrophages was found to be deactivated in obesity and insulin resistance, leading to the accumulation of collagen fragments in adipose tissue.
While this has not been considered a problem until now, the study shows that collagen fragments are not just debris, but actively influence various cellular processes such as inflammation and cell division.
The process thus goes from maintaining normal adipose tissue function during weight gain, to becoming pathogenic in some cases. When samples of human macrophages were exposed to diabetes-like conditions, they also lost their ability to “clean up” collagen.
Identification and prevention
The study was carried out by a research team at the Sahlgrenska Academy, University of Gothenburg, led by Ingrid Wernstedt Asterholm, Professor in Physiology.
“When adipose tissue grows, macrophages help the remodel the tissue in a controlled way. Exactly why this mechanism is sometimes deactivated is difficult to say, but perhaps it happens when there is at a certain, genetically determined, degree of adiposity” she says.
“It is our hope that these results ultimately lead to new strategies for preventing or treating type 2 diabetes. It is also conceivable that certain collagen fragments could serve as measurable biological markers, for example to identify individuals at higher risk of developing type 2 diabetes.”