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

在一项新的研究中，来自德国埃尔朗根-纽伦堡大学、德国神经退行性疾病中心、德国糖尿病研究中心、德累斯顿工业大学、美国索尔克生物研究所和奥地利科学技术研究所的研究人员证实大脑神经细胞中的某些 RNA 分子终生不会更新。相关研究结果发表在2024年4月5日的Science期刊上，论文标题为“Lifelong persistence of nuclear RNAs in the mouse brain”。RNA 通常是寿命很短的分子，会根据环境条件不断重建。这些作者希望通过这项新研究的成果，破译大脑复杂的衰老过程，并更好地了解相关的退行性疾病。人体内的大多数细胞都会定期更新，从而保持活力。但也有例外：心脏、胰腺和大脑中的细胞在整个生命周期中都不会更新，但仍要保持完全正常的工作状态。论文共同通讯作者、埃尔朗根-纽伦堡大学神经表观基因组学教授Tomohisa Toda 博士说，“衰老的神经元是阿尔茨海默病等神经退行性病变的重要风险因素。深入了解细胞衰老过程以及那些维护细胞基本功能的关键组件，对于开发有效的治疗方法至关重要。”在这项新颖的研究工作中，研究团队揭示了大脑衰老过程中的一个核心要素：首次证明了一部分负责保护遗传物质的核糖核酸分子具有与神经元同等的长寿属性。Toda博士对此感到惊讶：“与相对稳定的DNA不同，大多数RNA分子的寿命十分短暂且处于不断替换的状态，而此次发现的某些RNA分子却能伴随神经元终身存在。”为了确定 RNA 分子的寿命，Toda及其团队与奥地利科技研究所细胞生物学家Martin Hetzer教授的团队进行了合作。凭借在表观遗传学和神经生物学方面的深厚造诣，Toda博士阐述：“我们巧妙地运用荧光标记技术追踪了RNA分子在小鼠脑细胞中的存续状况，令人惊奇的是，我们甚至能在相当于人类七旬老人的两岁小鼠体内，识别出带有荧光标记的长寿命RNA（long-lived RNA, LL-RNA）。不仅在成熟的神经元中，还在大脑的成体神经干细胞中发现了此类LL-RNA。”图片来自Science, 2024, doi:10.1126/science.adf3481此外，他们还发现LL-RNA往往位于细胞核中，与染色质紧密相连，其中染色质是由DNA和蛋白组成的复合物，经浓缩后会形成染色体。这表明LL-RNA 在调节染色质方面发挥着关键作用。为了证实这一假设，这些研究人员在成年神经干细胞模型的体外实验中降低了LL-RNA的浓度，结果发现染色质的完整性受到了严重损害。Toda博士进一步阐释：“我们现在有足够的证据相信，LL-RNA在基因组稳定性长期维护以及神经细胞生存全程中均发挥了核心作用。未来的科研项目将深入探究LL-RNA长期稳定的生物物理机制。我们期待能更多地揭示LL-RNA在染色质调控中的生物功能细节，同时探索衰老过程对这些精细调控机制的影响。”参考资料：Sara Zocher et al. Lifelong persistence of nuclear RNAs in the mouse brain. Science, 2024, doi:10.1126/science.adf3481.Neuroscientists at FAU discover building blocks in nerve cells that last a life timehttps://www.fau.eu/2024/04/05/news/research/rna-that-doesnt-age/本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

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.