This DNA repair gene went rogue and exposed a cancer weakness

 Tumor suppressor genes are often viewed as the body's built-in defense system against cancer. They produce proteins that help maintain and repair DNA, reducing the chances that harmful mutations will accumulate. When these genes stop working properly or are present at low levels, cancer risk can rise.

But new research suggests that having too much of one DNA repair protein can also be a problem.

Researchers at Penn State College of Medicine found that excessive activity of the gene EXO1 can damage DNA rather than protect it. Instead of repairing genetic material, too much EXO1 can break down DNA and destabilize the genome, a key feature of cancer.

The findings, published in Nature Communications, show that EXO1 is overexpressed in 20% to 30% of breast and ovarian cancers, as well as in melanoma, testicular, cervical and hepatobiliary cancers, which occur in the liver, gall bladder and bile duct.

The team also discovered that cancer cells with unusually high levels of EXO1 behave much like cells carrying BRCA mutations, which are well known for increasing the risk of hereditary breast and ovarian cancers. Importantly, these BRCA-like behaviors occurred even when no BRCA mutation was present.

EXO1 May Help Identify Patients for Targeted Therapies

The researchers found that tumors with elevated EXO1 responded to treatments in ways that closely resembled BRCA-mutant cancers.

"EXO1 doesn't predict cancer risk, but it could potentially serve as a biomarker to help predict which patients are more likely to respond to certain chemotherapy treatments, leading to more personalized therapies," said George-Lucian Moldovan, professor of molecular and precision medicine and senior author on the study. "The same drugs that are reserved for treating BRCA-mutant tumors and that have fewer side effects could potentially be used to treat EXO1 overexpressing tumors, which don't have BRCA mutations. It would expand the applicability of those drugs."

To investigate the role of EXO1, the researchers analyzed tumor data from The Cancer Genome Atlas, a National Cancer Institute cancer genomics program. They found evidence of EXO1 overproduction in multiple cancer types, including tumors of the breast, skin, liver and cervix, consistent with earlier research. Elevated EXO1 levels were especially associated with basal-like breast cancer, an aggressive form of the disease.

How Excess EXO1 Damages DNA

The team then performed laboratory experiments using commercially available human cancer cells.

Researchers artificially increased EXO1 production in the cells to determine how excess amounts of the protein affected DNA. They also created a disabled version of EXO1 that produced protein but lacked its normal biochemical activity. This allowed them to confirm that any observed DNA damage was caused by the protein's activity rather than simply its presence.

Under normal conditions, EXO1 functions like a pair of molecular scissors, helping trim and repair damaged DNA. However, when too much EXO1 is present, those scissors begin cutting DNA structures that should remain intact.

The researchers found that excess EXO1 destabilizes newly formed DNA through two main mechanisms, expanding single-stranded DNA gaps and degrading reversed replication forks. Both processes erode DNA and result in localized loss of genetic material, Moldovan explained.

"Regardless of which pathway, EXO1 overexpression leads to the generation and accumulation of toxic lesions in DNA, such as double strand breaks, which we ultimately think is what makes the tumor more sensitive to chemotherapy and increases cell death," said Alexandra Nusawardhana, the lead author of the study and who earned her doctorate in biomedical sciences this year from Penn State College of Medicine.

Why EXO1 Mimics BRCA Mutations

BRCA genes normally produce proteins that help protect vulnerable DNA structures during replication. When BRCA genes are mutated, cells lose part of this protective function, which can contribute to cancer development.

In the current study, however, researchers found that excessive EXO1 activity was able to overwhelm those protective mechanisms even when BRCA genes were functioning normally and carried no mutations.

The team also discovered that EXO1 works alongside another protein called MRE11 to enlarge DNA gaps and generate dangerous DNA breaks.

"Mechanistically, this overexpression does exactly what the loss of the BRCA pathway does in BRCA-mutant tumor cells," Moldovan said.

He noted that EXO1 overexpression differs from BRCA mutations in an important way. It is not inherited, and researchers do not yet know whether it directly causes cancer.

Potential Impact on Cancer Treatment

Because EXO1-overexpressing tumors behaved so much like BRCA-mutant tumors, the researchers investigated whether they would also respond similarly to treatment.

They tested olaparib, a drug commonly used against BRCA-mutant cancers that targets cellular DNA repair pathways. Tumors with elevated EXO1 were highly sensitive to the treatment and responded in a manner similar to BRCA-mutant cancers.

The results suggest that patients whose tumors overexpress EXO1 could potentially benefit from the same repair-targeted therapies, even if they do not carry BRCA mutations.

The researchers also found that EXO1-overexpressing tumors responded to cisplatin, a widely used chemotherapy drug. Their findings raise the possibility that lower doses of cisplatin might achieve comparable tumor shrinkage while reducing side effects.

Because EXO1 overexpression appears in a wider range of tumors than BRCA mutations, Moldovan said it could become a valuable biomarker for guiding treatment decisions.

"We shouldn't treat cancers based on what tissue they come from but based on the landscape of the genetic mutations present in the tumors," Moldovan said. "That would result in high efficiency treatment. That's the future of cancer treatment."

The research team plans to continue studying EXO1 with the long-term goal of launching clinical trials involving patients whose tumors overexpress the gene.

Claudia Nicolae, assistant professor of molecular and precision medicine at Penn State College of Medicine, also contributed to the study.

Source: ScienceDaily

As lakes turn brown, trout and bass decline while pike and walleye thrive

 The lakes, streams and ponds you’ve visited for years are likely looking more brown than they used to. And people who are fishing those waters are likely catching different species and sizes of fish than in the past.

Our research has identified a link between those two developments, which means that trout, bass, perch and whitefish may become less common in unstocked lakes. But pike and walleye anglers may be in for a trophy-sized surprise.

In the past several decades, across much of northeastern North America and northern Europe, many freshwater ecosystems are getting darker, and they are changing in other ways as a result.

What is freshwater browning?

The specific phenomenon of darkening water, called “freshwater browning,” is driven by a few factors. Among the reasons are climate change, as higher temperatures and increased runoff are combining to increase the amount and types of carbon compounds that move from soil and land into bodies of water.

Similarly, as people have taken steps to reduce acidic emissions coming from smokestacks and other sources, less acid has fallen as precipitation, changing the chemistry of soils. Those chemical changes are also increasing the flow of carbon to bodies of water.

Higher levels of carbon make water look brown because it’s basically dissolved plant matter that stains the water like tea leaves would.

Underwater visibility

It’s harder to see in browner waters, which makes it harder for fish to locate prey, escape from predators and find suitable habitat to live in.

Our recent study combined a review of past research with some new analyses to examine how different kinds of fish do in darker water. Working with a large team of experts, we tallied findings from previous studies that looked at the relationship between the darkness of a body of water and fish growth rates in that same body of water.

We found that in browner waters, fish often grow more slowly. The decreased growth rate in individual fish appears to reduce the population sizes of these fish, which may, in turn, change the quantities and proportions of different kinds of fish in a lake.

But freshwater browning doesn’t affect all species of fish equally.

Unsurprisingly, we found that vision appeared to be quite important for navigating browner waters. When we studied fish communities in 303 Canadian lakes, we found that in lakes with darker water, fish species with larger eyes were more common.

When we looked at data on populations of eight economically important fish in 871 lakes across North America and Europe, we found that browning was associated with smaller populations of several species, including lake trout, lake whitefish, yellow perch, largemouth bass and smallmouth bass. Brook trout abundance was not affected by freshwater browning.

Browning was associated with larger populations of northern pike and walleye.

We believe that’s because walleye, for example, have a specialized retina that helps them see in browner waters with poorer visibility. Similarly, pike have a well-developed lateral-line sensory system that allows them to sense vibration, movement and pressure changes in the water.

A change for anglers

People fishing in browner lakes may consider appealing to the senses of the fish that are likely to be in the water. For example, rather than using colorful or shiny lures to attract their visual attention, when fishing in darker water, consider using vibrating lures that a fish’s lateral line system can detect, or scented lures that trigger an olfactory response.

By examining what’s happening to the water and in it, both scientists and people who enjoy fishing can understand the changes we’re seeing and what they mean in practical terms. 

Source: ScienceDaily

Chinese sodium battery surprised scientists by matching key Tesla benchmarks

 A widely used sodium-ion battery developed by Chinese manufacturer Hina has achieved performance and manufacturing quality levels comparable to Tesla's lithium-ion batteries, according to research published in the Cell Press journal Cell Reports Physical Science.

The findings suggest sodium-ion technology could become a lower-cost alternative for future electric vehicles and large-scale energy storage systems. To reach that goal, however, the battery will need further improvements in low-temperature charging and energy density. Unlike lithium, sodium is abundant and readily available, making it an attractive material for reducing battery costs and supply chain concerns.

"The combination of good uniformity, high power capability, and strong low-temperature performance makes these cells attractive for stationary storage, grid services, and shorter-range or commercial vehicles where potential lower cost and resource availability matter more than maximum driving range," says Moritz Schütte, a battery researcher at RWTH Aachen University in Germany.

Comparing Sodium-Ion Batteries With Tesla Technology

To evaluate the Hina battery, Schütte and colleagues examined 120 sodium-ion cells using impedance spectroscopy, a non-destructive method that measures battery uniformity.

The researchers then tested the cells under a variety of real-world operating conditions. Performance was measured across different current levels and temperatures ranging from −20 °C to 45 °C. The team also used X-rays to examine the batteries internally before disassembling them to analyze electrode dimensions, material composition, and microscopic structural features.

One notable discovery was the battery's tabless, double-aluminum current collector design. This configuration helps reduce electrical resistance and promotes more even temperature distribution throughout the cell. The researchers noted that this design closely resembles the architecture currently used in Tesla batteries.

"We were positively surprised by how uniform the cells are," says Schütte.

Strengths and Remaining Challenges

Despite the encouraging results, the researchers identified several areas where the sodium-ion battery still trails leading lithium-ion technologies.

"The high-power performance was better than one might expect from an early commercial sodium-ion product," says Schütte. "However, for applications that require frequent charging at low ambient temperatures, appropriate thermal management or operating strategies will be important because low-temperature charging remains a clear weakness."

The team also detected unexpectedly high concentrations of copper in certain regions of the battery's cathode. In addition, the copper was unevenly distributed throughout those areas.

According to Schütte, this finding "raises interesting questions about its role in performance and aging.""It will be exciting to see future sodium-ion technologies that are free of nickel and copper, as well, while achieving competitive energy density," he said.

Why Sodium Could Matter for Future Batteries

Because sodium is far more abundant and widely available than lithium, manufacturers could potentially lower raw material costs while reducing long-term supply chain risks.Sodium-ion batteries also maintain strong performance under load in cold conditions, making them attractive for stationary energy storage systems and mobile applications operating in colder climates."However, today's commercial sodium-ion cells generally have lower energy density than the best lithium-ion cells, and the technology is less mature overall," said Schütte.

Next Steps for Sodium-Ion Research

The researchers plan to focus on improving charging performance at low temperatures, with the goal of enabling safer and more efficient charging below 0°C.

Additional work will also explore ways to optimize the materials used in sodium-ion batteries "Advances in hard-carbon anodes and electrolyte formulations may be especially promising," he said.The study was supported by the Federal Ministry of Research, Technology, and Space and the Federal Ministry for Economic Affairs and Energy.

Source: ScienceDaily

One common fat may fuel type 2 diabetes while another helps fight it

 Researchers are taking a closer look at how different types of dietary fat may influence the risk of type 2 diabetes, a disease that affects millions of people worldwide and is linked to serious health complications and premature death. A new review published in Trends in Endocrinology & Metabolism (Cell Press) explores the contrasting effects of two major fatty acids found in the diet: palmitic acid and oleic acid.

The work was led by teams from the CIBER Area for Diabetes and Associated Metabolic Diseases (CIBERDEM) at the University of Barcelona.

"Palmitic acid, a saturated fatty acid widely found in foods, is associated with impaired insulin sensitivity, whereas oleic acid, abundant in olive oil, may have a protective effect against these metabolic disorders," says Professor Manuel Vázquez-Carrera, from the UB's Faculty of Pharmacy and Food Sciences, the UB Institute of Biomedicine (IBUB), the Sant Joan de Déu Research Institute (IRSJD) and CIBERDEM.

Other contributors include Ricardo Rodríguez-Calvo of CIBERDEM at the Pere Virgili Institute for Health Research (IISPV), Marta Tajes of the CIBER Area for Cardiovascular Diseases (CIBERCV) at the Bellvitge Biomedical Research Institute (IDIBELL), and Walter Wahli of the University of Lausanne (Switzerland).

According to Vázquez-Carrera, the findings suggest that the type of fat people consume may be more important than the overall amount.

"This review highlights the significant role of the quality of dietary fat, rather than the total amount consumed," notes Professor Manuel Vázquez-Carrera, who is a group leader at CIBERDEM at the UB.

How Palmitic Acid May Promote Diabetes

The researchers examined evidence showing that palmitic acid can trigger several biological processes linked to metabolic disease.

As Xavier Palomer (UB-IBUB-CIBER-IRSJD), the article's first author, says, "at the molecular level, palmitic acid promotes the accumulation of potentially toxic bioactive lipids, fosters low-grade chronic inflammation, and contributes to the dysfunction of cellular organelles, such as the endoplasmic reticulum and the mitochondria."

The team notes that these cellular changes "are closely linked to impaired insulin action and the progression of metabolic disease."

Oleic Acid Shows Protective Effects

The picture looks quite different for oleic acid, a monounsaturated fat found in high amounts in olive oil.

According to the review, oleic acid encourages the body to store fats in forms that are metabolically less disruptive and have little effect on normal cellular function. It also helps maintain healthy insulin signaling in important metabolic tissues, including the liver, muscles, and adipose tissue.

Researchers say oleic acid may also offset many of the harmful effects associated with palmitic acid. This could help explain why eating patterns rich in monounsaturated fats, including the Mediterranean diet, are consistently linked to a lower risk of type 2 diabetes and other metabolic disorders.

Improving Nutrition Strategies for Diabetes Prevention

The authors emphasize that more targeted research is needed to better understand differences seen across population studies.

"It is important to consider variables such as the source of fatty acids, their dietary context, interactions with other nutrients, and different food processing methods," says Manuel Vázquez-Carrera.

The researchers believe that gaining a clearer understanding of these factors will improve scientists' ability to evaluate how different fats affect metabolic health. In turn, that knowledge could support the development of more effective dietary approaches for preventing and managing type 2 diabetes.

Source: ScienceDaily

Long-lived families reveal a rare genetic clue to healthy aging

 People age differently. Some remain free of major diseases well into old age, while others develop serious health problems much earlier. Understanding why this happens is becoming increasingly important as populations grow older around the world.

Although life expectancy has risen dramatically over the past 200 years, the number of years people spend in good health has not increased at the same pace. Researchers have long known that exceptional longevity (longevity) often runs in families and is linked to a later onset of chronic illnesses. However, the genetic factors that help protect these families remain poorly understood.

Most previous studies have focused on the genetics of individual people who live long lives. New research being presented at the annual conference of the European Society of Human Genetics in Gothenburg suggests that studying entire long-lived families may provide a clearer picture of the biological mechanisms that support a longer healthspan. (A person's healthspan is the number of years they live free from chronic disease and cognitive decline).

Why Family Studies Matter

Studying families offers an important advantage because longevity is influenced by many factors beyond genetics. Socioeconomic status, lifestyle, behavior, and environmental influences all play major roles in determining both lifespan and healthspan. As a result, some people from families with average life expectancy may still live exceptionally long lives, while others from long-lived families may not.

Presenting findings from the intergenerational aging study, Mr. Pasquale Putter, a final-year PhD student in Prof. Eline Slagboom's group at Leiden University Medical Center in Leiden, The Netherlands, explained that previous research from the team had already revealed a striking pattern.

Middle-aged individuals with long-lived parents developed cardiometabolic diseases an average of 13 years later than their partners whose parents had shorter lifespans.

"This made it clear that their longer healthspan was passed down to subsequent generations," he says.

Searching for Longevity Genes

To investigate further, researchers analyzed the genomes of 212 groups of long-lived sibships (offspring with the same two parents) participating in the Leiden Longevity Study.

The team identified four regions of the genome that appeared likely to contain genes linked to longevity.

"This meant that we could restrict our focus to 350 genes rather than around 20,000," says Mr. Putter.

Additional analysis narrowed the search even further, revealing 12 rare protein-altering genetic variants that may contribute to longer and healthier lives.

A Promising Role for the CGAS Gene

One of those variants was found in the CGAS (cyclic GMP-AMP synthase) gene, which has previously been linked to aging. The variant appeared in two long-lived families included in the study.

CGAS helps trigger inflammation when DNA is detected where it does not belong inside a cell. This can happen during viral infections or when cells are damaged.

"It is likely that members of these families had only one active copy of the CGAS gene, rather than two, and that this will have reduced the inflammatory response in their bodies, while still being sufficient to clear infections and repair damage, thereby contributing to the protective mechanisms that enable extended healthspan and survival," Mr. Putter says.

The researchers believe this reduced inflammatory response may help protect against some of the damaging effects associated with aging while preserving the body's ability to defend itself.

"We hope that taking this family approach will help us to untangle some of the environmental factors from those that are truly genetic, particularly those where rare mutations are involved. We have been surprised by the magnitude of the effect of the CGAS mutation in the in vitro experiments we have carried out to date."

Next Step: Testing the Mutation in Killifish

The scientists caution that much more work is needed before any implications for human health can be determined. The effects of CGAS depend heavily on context.

Completely shutting down the CGAS pathway could make people more vulnerable to infections and cancer. On the other hand, excessive activation of the pathway can lead to chronic inflammation and long-term tissue damage.

To better understand how the mutation functions in a living organism, the researchers are moving from in vitro experiments to in vivo studies. They plan to introduce the CGAS mutation into killifish at the Max Planck Institute for the Biology of Ageing in Cologne, Germany.

"Killifish are the shortest-lived vertebrates, with a natural lifespan of between three to nine months. Using them as a model will enable us to determine whether the mutation contributes to increased lifespan when compared with control groups, and also to investigate its health effects in tissues," says Mr. Putter.

Source: ScienceDaily

New study explores potential cross-species spread of chronic wasting disease

 Chronic wasting disease (CWD) is best known as a disease affecting wildlife such as deer and elk. However, a new study from researchers at the University of Calgary and their international collaborators examined whether the disease could potentially move beyond cervid (hooved, plant-eating) animals and infect other species.

There has never been a confirmed case of CWD in people. Even so, scientists say the new findings highlight the importance of continued monitoring and research as the disease continues to spread into new areas.

CWD is a fatal neurological disease caused by infectious proteins called prions. It is becoming increasingly widespread across North America, including expanding regions of Alberta.

Study Examines Cross-Species Transmission Potential

In research published in Science Advances, investigators used controlled laboratory experiments to study the zoonotic potential of CWD. Most of the animals involved did not develop symptoms. However, researchers detected small amounts of infectious prions in their tissues. When samples from those animals were transferred to other species, the recipients developed signs of CWD.

"These findings show that even without obvious (clinical signs), infectious prions can still be present and transmissible," says Dr. Samia Hannaoui, PhD, researcher and assistant professor at the University of Calgary Faculty of Veterinary Medicine (UCVM), and first author on the study.

Why Prion Diseases Are Difficult To Predict

Prions differ from many other infectious agents because they can change as they move between hosts. Over time, this process may produce new strains with different characteristics.

"We're not dealing with a single, fixed agent," says Dr. Hermann Schaetzl, MD, Dr. med, UCVM professor and last author on the study. "Prion strains can evolve, and that evolution can influence how the disease behaves."

According to the researchers, this ability to change makes prion diseases especially challenging to forecast and manage.

CWD presents another problem. Animals infected with the disease can release infectious prions into the environment long before symptoms become visible. Prions can be shed through urine and feces for months or even years, contaminating vegetation and soil.

"By the time you see clinical signs, the animal has often been infectious for a long time," says Schaetzl. "That's what makes this disease particularly challenging to control."

What the Findings Mean for Human Risk

The researchers emphasize that their results do not point to an immediate threat to humans.

"Our findings don't indicate an immediate risk to humans, but they do suggest the situation is more nuanced than previously understood," says Schaetzl. "As CWD becomes more widespread, understanding these dynamics becomes increasingly important."

Scientists also note that prion diseases have crossed species barriers in the past. One well-known example is bovine spongiform encephalopathy (BSE), commonly called "mad cow disease," which was transmitted from cattle to humans.

Current evidence indicates that a strong barrier exists between CWD and humans. Nevertheless, studies such as this are designed to investigate whether prions could gradually adapt in ways that change how they spread or how disease develops.

Growing Prevalence Raises Concerns

Although researchers consider the current risk to people low, they say the continued expansion of CWD in wildlife makes surveillance and disease control efforts increasingly important.

"The more the disease spreads in animals, the more opportunities there are for exposure," says Schaetzl. "Risk is linked to prevalence."

Researchers at UCalgary are also working on potential ways to reduce transmission among cervid populations. Early vaccine studies using mouse models that mimic infection in deer and elk have produced encouraging results. Vaccinated animals shed fewer infectious prions during both the early and later stages of disease and survived longer following exposure.

"If we can reduce shedding, we may be able to reduce transmission," says Hannaoui. "That could have important implications at the cervid population level."

As chronic wasting disease continues to expand, researchers say it remains essential to better understand how prion diseases spread and evolve, including the possibility of silent or unusual infections. That knowledge could play an important role in protecting wildlife and supporting public health efforts in the future.

Source: ScienceDaily

10 surprising ways diabetes and dementia are connected

 The link between diabetes and dementia is becoming increasingly clear. New research shows how blood sugar problems affect brain health and vice versa. Here are ten evidence-based insights into how the two conditions are related.

1. Diabetes raises the risk of dementia

People with diabetes are about 60% more likely to develop dementia than those without, and frequent episodes of low blood sugar are linked to a 50% higher chance of cognitive decline.

2. Insulin resistance affects the brain too

Insulin resistance – the major cause of type 2 diabetes – happens when cells stop responding properly to insulin. This means that too much sugar, in the form of glucose, is left in the blood, leading to complications.

It usually affects the liver and muscles, but it also affects the brain. In Alzheimer’s, this resistance may make it harder for brain cells to use glucose for energy, contributing to cognitive decline.

3. A brain sugar shortage in dementia

The brain is only 2% of our body weight, but uses about 20% of the body’s energy. In dementia, brain cells appear to lose the ability to use glucose properly.

This mix of poor use of glucose and insulin resistance is sometimes unofficially called type 3 diabetes.

4. Alzheimer’s can raise diabetes risk

People with Alzheimer’s often have higher fasting blood glucose, even if they don’t have diabetes. This is a form of pre-diabetes. Animal studies also show that Alzheimer’s-like changes in the brain raise blood glucose levels.

Also, the highest genetic risk factor for Alzheimer’s, the APOE4 genetic variant, reduces insulin sensitivity by trapping the insulin receptor inside the cell, where it cannot be switched on properly.

5. Blood vessel damage links both conditions

Diabetes damages blood vessels, causing complications in the eyes, kidneys and heart. The brain is also at risk. High or varying blood glucose levels can injure vessels in the brain, reducing blood flow and oxygen delivery.

Diabetes can also weaken the brain’s protective barrier, letting harmful substances in. This leads to inflammation. Reduced blood flow and brain inflammation are strongly linked to dementia.

6. Memantine: a dementia drug born from diabetes research

Memantine, used to treat moderate to severe Alzheimer’s symptoms, was originally developed as a diabetes medication. It didn’t succeed in controlling blood glucose, but researchers later discovered its benefits for brain function. This story shows how diabetes research may hold clues for treating brain disorders.

7. Metformin might protect the brain

Metformin, the most widely used diabetes drug, does more than just lower blood glucose. It gets in to the brain and may lower brain inflammation.

Some studies suggest that people with diabetes who take metformin are less likely to develop dementia, and those who stop taking it may see their risk increase again.

Trials are testing its effects in people without diabetes.

Source: ScienceDaily