Dresden University of Technology

PHILADELPHIA, June 11, 2024 /PRNewswire/ -- As humans age, hematopoietic stem cells—the immature precursor cells that give rise to all blood and immune cells—accumulate mutations. Some of the mutations allow these stem cells to self-renew and expand more effectively than their non-mutated counterparts. This relatively poorly understood condition, known as clonal hematopoiesis of indeterminate potential (CHIP), is detectable in more than 10% of people older than 65 and is linked to increased risks of various inflammation-related diseases. "These mutations change the character of the progeny cells, making them more inflammatory," says Dr. George Hajishengallis of Penn Dental Medicine. "When a large fraction of your immune cells are derived from these mutant stem cells, it spells bad news for chronic inflammatory diseases." Now, a team led by Hajishengallis, together with collaborators at the Dresden University of Technology and the University of North Carolina at Chapel Hill (UNC), have uncovered mechanistic insights into CHIP. They also found that an FDA-approved drug for preventing organ transplant rejection, rapamycin, has the potential to block these mutant stem cells and treat CHIP-driven inflammatory bone loss diseases, such as periodontitis and arthritis. Their research is published in the journal Cell. "We found a compelling observational association between DNMT3A, a gene most commonly affected in CHIP, and the prevalence and severity of periodontitis in a cohort of 4,946 people aged 52 to 74," Hajishengallis says. "What's more, we corroborated these findings with our mouse model, demonstrating a strong causal relationship between DNMT3A mutations and increased susceptibility to inflammatory bone loss disorders. And most excitingly, we were able to show the efficacy of rapamycin in protecting mice from CHIP-exacerbated inflammatory bone loss, which paves the way for eventually treating such diseases in humans." Considering potential therapeutic strategies Hajishengallis says, "Screening for CHIP among the elderly population may identify individuals with increased risk for inflammatory comorbidities." These individuals may benefit from therapeutic interventions aiming to block the aberrant expansion of the CHIP-mutant hematopoietic stem cell clones and their adverse impact on chronic inflammatory comorbidities. Read more on the study >> CONTACT: Beth Adams, [email protected] SOURCE PENN DENTAL MEDICINE

New study suggests that temperature can influence the microbial competition in rivers. Antimicrobial resistant genes (ARGs) from wastewater can end up in natural biofilms in rivers, but they may not stick around very long. This week in mSphere, researchers report that after ARGs are introduced to a river they invade and initially join natural biofilms. But as the temperature of the river increases, the abundance of those invasive ARGs drops off significantly, suggesting that the already-present community of microbes edge out the resistant newcomers. For river water at 30 degrees Celsius (86 degrees Fahrenheit), the level of ARGs returned to its initial state after only 2 weeks. The finding suggests that rivers may offer a kind of defense against the spread of ARGs in wastewater. It was also contrary to what the researchers expected. Most ARGs in wastewater originate in human feces and thrive at the temperature of the human body, which is higher than most waterways. The microbiologists anticipated that warm rivers would be a welcome environment. "We thought they should be rather well-adapted to higher temperatures," said microbiologist Uli Klümper, Ph.D., at Technische Universität Dresden's Institute of Hydrobiology. "So if river temperatures are rising with climate change, we wanted to know if these bacteria from wastewater would have an easier time integrating with the natural biofilms." Klümper co-led the study with his Ph.D. student Kenyum Bagra, who joined TU Dresden on a DAAD exchange fellowship from the Indian Institute of Technology Roorkee, led the study. The work was funded through the ANTIVERSA project by BiodivERsA, a European biodiversity organization. Klümper, Bagra and their colleagues first immersed 27 glass slides in the Lockwitzbach River, in eastern Germany, for a month. "It's relatively pristine," Klümper said. They collected the slides, which had amassed a natural biofilm from the river, and immersed them in artificial river systems at 1 of 3 temperatures. After a week, they observed that the abundance of naturally occurring ARGs increased in the warmest water, at 30 degrees Celsius. Then, they exposed all the test slides to wastewater for 1 day and monitored the abundance of ARGs, both those that occurred naturally and those from wastewater, over the next 2 weeks. The ARGs from the wastewater readily invaded the biofilm in all 3 cases, with no difference in abundance by temperature. "The introduction seems to be temperature independent," Klümper said. But that's where the similarities ended. In the warmest water, the abundance of the invasive ARGs dropped significantly over 2 weeks. By the end of the experiment, the overall level of ARGs had returned to its initial, natural abundance, and the invasive ARGs had all but vanished. In the other 2 groups, the invasive ARGs fared better. In some cooler samples they were able to establish in the biofilm community, even at abundances far higher than the naturally occurring ARGs. Those results suggested that the competition between invasive and indigenous microbes was mediated by temperature, Klümper said. "We were really surprised." Researchers often assume that a warming world will promote pathogenic ARGs, he said, but it's likely not so straightforward. A river is a complex system, Klümper said, and responds to warming in ways that are difficult to model. "It's not only one effect that's at play," he said. In addition, he noted that in their experiment, the initial sample came from a pristine river and a single exposure to wastewater, but in many cases wastewater is constantly released. "So in those biofilms there might be members that originated from wastewater but adapted well to that ecosystem," he said. Klümper hopes the study will not only inform future work into understanding how rivers may act as barriers against the spread of antimicrobial resistance, but also play a role in improving environmental surveillance of emerging risks.

A precursor of cholesterol, previously categorized as harmful, can protect cancer cells from cell death. In a groundbreaking study, a team led by Würzburg Professor José Pedro Friedmann Angeli has shown that the cholesterol precursor 7-dehydrocholesterol (7-DHC) plays a crucial role as an antioxidant: it integrates into the cell membranes and protects the cells by preventing a certain type of cell death, known as ferroptosis. "Until now, the accumulation of 7-DHC was only associated to neurodevelopmental defects, now we show that it actually increases cellular fitness and could promote a more aggressive behaviour in cancers such as Burkitt's lymphoma and neuroblastoma," says Friedmann Angeli. The newly discovered protective function of 7-DHC opens up exciting prospects for further improving the treatment of cancer and other diseases associated with ferroptosis: "It gives us new opportunities to test potential inhibitors that target cholesterol biosynthesis and are already established in medical practice." The researchers report this in the journal Nature. In addition to the Würzburg team from the Rudolf Virchow Zentrum -- Center for Integrative and Translational Bioimaging, the following scientists contributed to the study: Dr Maria Fedorova (Dresden University of Technology), Marcus Conrad (Helmholtz Munich), Derek Pratt (University of Ottawa), and Andreas Trumpp and Hamed Alborzinia (German Cancer Research Center, DKFZ Heidelberg). Observing Changes in 7-DHC Levels High cholesterol levels are associated with health problems such as heart disease and diabetes. Most studies focus on how cholesterol contributes directly to these diseases. In this area, the discovery of the cholesterol precursor 7-DHC as an antioxidant opens up new possibilities: Studies on changes in 7-DHC levels could provide crucial new insights into the diseases. In addition, drugs that specifically block 7-DHC production should be researched in combination with other drugs -- this could have a positive effect in the treatment of some cancers. Possible Effects on Tumour Development "Our next research goal is to investigate the effects of 7-DHC accumulation during tumour development," says Würzburg ferroptosis expert José Pedro Friedmann Angeli. The team responsible for the publication in Nature also calls for further epidemiological studies. Background: There are drugs authorised by the US Food and Drug Administration (FDA) that can inhibit the DHCR7 enzyme. These include trazodone, which is prescribed around 20 million times a year in the USA, sometimes even for off-label use to treat insomnia. "Studies have shown that people taking this drug have elevated plasma levels of 7-DHC. Epidemiological studies are crucial to better understand possible effects here," says Friedmann Angeli. These studies would help to find out whether there is a connection between patient groups who regularly take ferroptose-modulating drugs such as trazodone and cancer incidence, the occurrence of metastases or other critical aspects of public health.