Christine Chesley, Rob Evans, Jessica M. Warren, Andrew C. Gase, Jacob Perez, Christopher Armerding, Hannah Brewer, Paige Koenig, Eric Attias, Bailey L. Fluegel, Jae-Deok Kim, Natalie Hummel, Katherine Enright, Emilia Topp-Johnson, Margaret S. Boettcher
Although oceanic transform faults (OTFs) are ubiquitous plate boundaries, the geological processes occurring along these systems remain underexplored. The Gofar OTF of the East Pacific Rise has gained attention due to its predictable, yet enigmatic, earthquake cycle. Here, we present results from the first ever controlled-source electromagnetic survey of an OTF, which sampled Gofar. We find that the fault is characterized by a subvertical conductor, which extends into the lower crust and thus implies deep fluid penetration. We also image subhorizontal crustal conductors distributed asymmetrically about the fault. We interpret these subhorizontal anomalies as crustal brines, and we suggest that the high permeability of the fault combined with the influence of melt in the transform domain can promote hydrothermal circulation and brine condensation at OTFs.
{"title":"Evidence for crustal brines and deep fluid infiltration in an oceanic transform fault","authors":"Christine Chesley, Rob Evans, Jessica M. Warren, Andrew C. Gase, Jacob Perez, Christopher Armerding, Hannah Brewer, Paige Koenig, Eric Attias, Bailey L. Fluegel, Jae-Deok Kim, Natalie Hummel, Katherine Enright, Emilia Topp-Johnson, Margaret S. Boettcher","doi":"10.1126/sciadv.adu3661","DOIUrl":"10.1126/sciadv.adu3661","url":null,"abstract":"<div >Although oceanic transform faults (OTFs) are ubiquitous plate boundaries, the geological processes occurring along these systems remain underexplored. The Gofar OTF of the East Pacific Rise has gained attention due to its predictable, yet enigmatic, earthquake cycle. Here, we present results from the first ever controlled-source electromagnetic survey of an OTF, which sampled Gofar. We find that the fault is characterized by a subvertical conductor, which extends into the lower crust and thus implies deep fluid penetration. We also image subhorizontal crustal conductors distributed asymmetrically about the fault. We interpret these subhorizontal anomalies as crustal brines, and we suggest that the high permeability of the fault combined with the influence of melt in the transform domain can promote hydrothermal circulation and brine condensation at OTFs.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 15","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adu3661","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sophia N. Fricke, Mia Salgado, Shira Haber, Jeremy Demarteau, Mutian Hua, Ah-Young Song, Brett A. Helms, Jeffrey A. Reimer
Chemical recycling of commodity and specialty polymers presents a multifaceted challenge for industrial societies. On one hand, macromolecular architectures must be engineered to yield durable products that, on the other hand, rapidly deconstruct to recyclable monomers under pre-determined conditions. Polymer deconstruction is a chemical process that requires deep understanding of molecular reactivity in heterogeneous media, where porous material architectures evolve in both space and time. To build this understanding, we develop herein experimental and analytical methods describing sets of diffusive eigenmodes that exist within time-varying, non-Euclidean boundary conditions, a situation commonly encountered in the reactive deconstruction of polymers where chain fragments splay, alter their local dynamics, and evolve in their confinement of reacting media. Diffusion power spectra, discerned experimentally by NMR, yield polymer and solvent frequency-domain velocity autocorrelation functions that are analyzed in the context of physical models for chemical reactions parameterized with fractal mathematics. The results connect local motion in polymers to chemical reactivity during acidolysis of circular elastomers.
{"title":"Diffusion power spectra as a window into dynamic materials architecture","authors":"Sophia N. Fricke, Mia Salgado, Shira Haber, Jeremy Demarteau, Mutian Hua, Ah-Young Song, Brett A. Helms, Jeffrey A. Reimer","doi":"10.1126/sciadv.adt6144","DOIUrl":"10.1126/sciadv.adt6144","url":null,"abstract":"<div >Chemical recycling of commodity and specialty polymers presents a multifaceted challenge for industrial societies. On one hand, macromolecular architectures must be engineered to yield durable products that, on the other hand, rapidly deconstruct to recyclable monomers under pre-determined conditions. Polymer deconstruction is a chemical process that requires deep understanding of molecular reactivity in heterogeneous media, where porous material architectures evolve in both space and time. To build this understanding, we develop herein experimental and analytical methods describing sets of diffusive eigenmodes that exist within time-varying, non-Euclidean boundary conditions, a situation commonly encountered in the reactive deconstruction of polymers where chain fragments splay, alter their local dynamics, and evolve in their confinement of reacting media. Diffusion power spectra, discerned experimentally by NMR, yield polymer and solvent frequency-domain velocity autocorrelation functions that are analyzed in the context of physical models for chemical reactions parameterized with fractal mathematics. The results connect local motion in polymers to chemical reactivity during acidolysis of circular elastomers.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 15","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adt6144","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Varun Tej Raviprolu, Aaron Gregory, Isaac Banda, Scott G. McArthur, Sarah E. McArthur, William A. Goddard III, Charles B. Musgrave III, Vincent Lavallo
In 1958, Breslow proposed that the coenzyme thiamine, also known as vitamin B1, acted as a source of transient carbenes that facilitated the catalytic activity of various important enzymes. This was a controversial hypothesis, as, then and still now, carbenes are believed to be incompatible with water. Although evidence such as deuterium labeling experiments and the trapping of the so-called Breslow intermediate support Breslow’s hypothesis, no spectroscopic evidence has ever been presented to prove that carbenes can exist or be generated in water. In this study, we disclose the synthesis and complete spectroscopic characterization by nuclear magnetic resonance and a single-crystal structure of a carbene that can be generated in water and isolated as a stable species, thus unambiguously validating Breslow’s visionary hypothesis.
{"title":"Confirmation of Breslow’s hypothesis: A carbene stable in liquid water","authors":"Varun Tej Raviprolu, Aaron Gregory, Isaac Banda, Scott G. McArthur, Sarah E. McArthur, William A. Goddard III, Charles B. Musgrave III, Vincent Lavallo","doi":"10.1126/sciadv.adr9681","DOIUrl":"10.1126/sciadv.adr9681","url":null,"abstract":"<div >In 1958, Breslow proposed that the coenzyme thiamine, also known as vitamin B<sub>1</sub>, acted as a source of transient carbenes that facilitated the catalytic activity of various important enzymes. This was a controversial hypothesis, as, then and still now, carbenes are believed to be incompatible with water. Although evidence such as deuterium labeling experiments and the trapping of the so-called Breslow intermediate support Breslow’s hypothesis, no spectroscopic evidence has ever been presented to prove that carbenes can exist or be generated in water. In this study, we disclose the synthesis and complete spectroscopic characterization by nuclear magnetic resonance and a single-crystal structure of a carbene that can be generated in water and isolated as a stable species, thus unambiguously validating Breslow’s visionary hypothesis.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 15","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adr9681","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sanghun Lee, Rachel S. Kelly, Kevin M. Mendez, Dmitry Prokopenko, Georg Hahn, Sharon M. Lutz, Juan C. Celedón, Clary B. Clish, Scott T. Weiss, Christoph Lange, Jessica A. Lasky-Su, Julian Hecker, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Metabolomic genome-wide association studies (mGWASs), or metabolomic quantitative trait locus (metQTL) analyses, are gaining growing attention. However, robust methods and analysis guidelines, vital to address the complexity of metabolomic data, remain to be established. Here, we use whole-genome sequencing and metabolomic data from two independent studies to compare different approaches. We adopted three popular data transformation methods for metabolite levels—(i) log10 transformation, (ii) rank inverse normal transformation, and (iii) a fully adjusted two-step procedure—and compared population-based versus family-based analysis approaches. For validation, we performed permutation-based testing, Huber regression, and independent replication analysis. Simulation studies were used to illustrate the observed differences between data transformations. We demonstrate the advantages and limitations of popular analytic strategies used in mGWASs where especially low-frequency variants in combination with a skewed metabolite measurement distribution can lead to potentially false-positive metQTL findings. We recommend the rank inverse normal transformation or robust test statistics such as in family-based association tests as reliable approaches for mGWASs.
{"title":"On the analysis of metabolite quantitative trait loci: Impact of different data transformations and study designs","authors":"Sanghun Lee, Rachel S. Kelly, Kevin M. Mendez, Dmitry Prokopenko, Georg Hahn, Sharon M. Lutz, Juan C. Celedón, Clary B. Clish, Scott T. Weiss, Christoph Lange, Jessica A. Lasky-Su, Julian Hecker, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium","doi":"10.1126/sciadv.adp4532","DOIUrl":"10.1126/sciadv.adp4532","url":null,"abstract":"<div >Metabolomic genome-wide association studies (mGWASs), or metabolomic quantitative trait locus (metQTL) analyses, are gaining growing attention. However, robust methods and analysis guidelines, vital to address the complexity of metabolomic data, remain to be established. Here, we use whole-genome sequencing and metabolomic data from two independent studies to compare different approaches. We adopted three popular data transformation methods for metabolite levels—(i) log<sub>10</sub> transformation, (ii) rank inverse normal transformation, and (iii) a fully adjusted two-step procedure—and compared population-based versus family-based analysis approaches. For validation, we performed permutation-based testing, Huber regression, and independent replication analysis. Simulation studies were used to illustrate the observed differences between data transformations. We demonstrate the advantages and limitations of popular analytic strategies used in mGWASs where especially low-frequency variants in combination with a skewed metabolite measurement distribution can lead to potentially false-positive metQTL findings. We recommend the rank inverse normal transformation or robust test statistics such as in family-based association tests as reliable approaches for mGWASs.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 15","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adp4532","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chromosome cohesion mediated by cohesin complex and its associated proteins is required for accurate chromosome segregation and genomic stability in mitosis. However, because of the distinct operation mechanisms, many proteins might exert different functions during meiosis in germ cells. Here, we document that cohesin-associated protein precocious dissociation of sisters 5A (Pds5A) plays a noncanonical role in the meiotic spindle assembly during oocyte maturation independent of its cohesion function. Pds5A distributes on the spindle fibers in oocytes at both metaphase I and metaphase II stages. Morpholino-based depletion or genetic ablation of Pds5A all lead to defects in spindle organization, chromosome euploidy and meiotic progression in oocytes and thus compromising the female fertility. Mechanistically, Pds5A recruits deubiquitinase ubiquitin-specific protease 14 to the spindle apparatus for stabilization of kinesin family member 5B, regulating the spindle elongation. Collectively, our findings unveil that cohesin-associated protein Pds5A can be used as a spindle regulator during oocyte meiosis.
在有丝分裂过程中，染色体的准确分离和基因组的稳定需要由凝聚素复合体及其相关蛋白介导的染色体内聚力。然而，由于运行机制不同，许多蛋白在生殖细胞减数分裂过程中可能发挥不同的功能。在这里，我们记录了凝聚素相关蛋白姐妹早熟解离5A（Pds5A）在卵母细胞成熟过程中的减数分裂纺锤体组装过程中发挥的非规范作用，而与其凝聚功能无关。Pds5A 在卵母细胞的移行期 I 和移行期 II 阶段都分布在纺锤体纤维上。基于phospholino的Pds5A耗竭或基因消减都会导致卵母细胞中纺锤体组织、染色体整倍体和减数分裂进程的缺陷，从而影响女性的生育能力。从机理上讲，Pds5A 将去泛素化酶泛素特异性蛋白酶 14 招募到纺锤体上，以稳定驱动蛋白家族成员 5B，从而调节纺锤体的伸长。总之，我们的研究结果揭示了凝聚素相关蛋白Pds5A在卵母细胞减数分裂过程中可作为纺锤体调节器。
{"title":"The cohesin-associated protein Pds5A governs the meiotic spindle assembly via deubiquitination of Kif5B in oocytes","authors":"Yu Zhang, Jie Bai, Bo Xiong","doi":"10.1126/sciadv.adt6159","DOIUrl":"10.1126/sciadv.adt6159","url":null,"abstract":"<div >Chromosome cohesion mediated by cohesin complex and its associated proteins is required for accurate chromosome segregation and genomic stability in mitosis. However, because of the distinct operation mechanisms, many proteins might exert different functions during meiosis in germ cells. Here, we document that cohesin-associated protein precocious dissociation of sisters 5A (Pds5A) plays a noncanonical role in the meiotic spindle assembly during oocyte maturation independent of its cohesion function. Pds5A distributes on the spindle fibers in oocytes at both metaphase I and metaphase II stages. Morpholino-based depletion or genetic ablation of Pds5A all lead to defects in spindle organization, chromosome euploidy and meiotic progression in oocytes and thus compromising the female fertility. Mechanistically, Pds5A recruits deubiquitinase ubiquitin-specific protease 14 to the spindle apparatus for stabilization of kinesin family member 5B, regulating the spindle elongation. Collectively, our findings unveil that cohesin-associated protein Pds5A can be used as a spindle regulator during oocyte meiosis.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 15","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adt6159","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Guobin Qi, Xianglong Liu, Hao Li, Yunyun Qian, Can Liu, Jiahao Zhuang, Leilei Shi, Bin Liu
Because of the rapid emergence of antibiotic-resistant bacteria, there is a growing need to discover antibacterial agents. Here, we design and synthesize a compound of TPA2PyBu that kills both Gram-negative and Gram-positive bacteria with an undetectably low drug resistance. Comprehensive analyses reveal that the antimicrobial activity of TPA2PyBu proceeds via a unique dual mechanism by damaging bacterial membrane integrity and inducing DNA aggregation. TPA2PyBu could provide imaging specificity that differentiates bacterial infection from inflammation and cancer. High in vivo treatment efficacy of TPA2PyBu was achieved in methicillin-resistant Staphylococcus aureus infection mouse models. This promising antimicrobial agent suggests that combining multiple mechanisms of action into a single molecule can be an effective approach to address challenging bacterial infections.
由于抗生素耐药细菌的迅速出现，人们越来越需要发现抗菌剂。在这里，我们设计并合成了一种 TPA2PyBu 化合物，它既能杀死革兰氏阴性菌，也能杀死革兰氏阳性菌，而且耐药性极低。综合分析表明，TPA2PyBu 的抗菌活性是通过独特的双重机制进行的，即破坏细菌膜完整性和诱导 DNA 聚合。TPA2PyBu 可提供成像特异性，将细菌感染与炎症和癌症区分开来。在耐甲氧西林金黄色葡萄球菌感染小鼠模型中，TPA2PyBu 取得了很高的体内治疗效果。这种前景广阔的抗菌剂表明，将多种作用机制结合到单一分子中是解决具有挑战性的细菌感染的有效方法。
{"title":"A dual-mechanism luminescent antibiotic for bacterial infection identification and eradication","authors":"Guobin Qi, Xianglong Liu, Hao Li, Yunyun Qian, Can Liu, Jiahao Zhuang, Leilei Shi, Bin Liu","doi":"10.1126/sciadv.adp9448","DOIUrl":"10.1126/sciadv.adp9448","url":null,"abstract":"<div >Because of the rapid emergence of antibiotic-resistant bacteria, there is a growing need to discover antibacterial agents. Here, we design and synthesize a compound of TPA2PyBu that kills both Gram-negative and Gram-positive bacteria with an undetectably low drug resistance. Comprehensive analyses reveal that the antimicrobial activity of TPA2PyBu proceeds via a unique dual mechanism by damaging bacterial membrane integrity and inducing DNA aggregation. TPA2PyBu could provide imaging specificity that differentiates bacterial infection from inflammation and cancer. High in vivo treatment efficacy of TPA2PyBu was achieved in methicillin-resistant <i>Staphylococcus aureus</i> infection mouse models. This promising antimicrobial agent suggests that combining multiple mechanisms of action into a single molecule can be an effective approach to address challenging bacterial infections.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 15","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adp9448","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Relativistic plasmas in strong electromagnetic fields exhibit distinct properties compared to classical plasmas. In astrophysical environments, such as neutron stars, white dwarfs, active galactic nuclei, and shocks, relativistic plasmas are pervasive and are expected to play a crucial role in the dynamics of these systems. Despite their significance, experimental and theoretical studies of these plasmas have been limited. Here, we present the first ab initio high-resolution kinetic simulations of relativistic plasmas undergoing synchrotron cooling in a highly magnetized medium. Our results demonstrate that these plasmas spontaneously generate coherent linearly polarized radiation in a wide range of parameters via the electron cyclotron maser instability, with radiative losses altering the saturation mechanism. Thus, the plasma continuously amplify coherent radiation for substantially longer durations of time. These findings highlight fundamental differences in the behavior of relativistic plasmas in strongly magnetized environments and align with astronomical phenomena, such as pulsar emission and fast radio bursts.
{"title":"Radiative cooling induced coherent maser emission in relativistic plasmas","authors":"Pablo J. Bilbao, Thales Silva, Luís O. Silva","doi":"10.1126/sciadv.adt8912","DOIUrl":"10.1126/sciadv.adt8912","url":null,"abstract":"<div >Relativistic plasmas in strong electromagnetic fields exhibit distinct properties compared to classical plasmas. In astrophysical environments, such as neutron stars, white dwarfs, active galactic nuclei, and shocks, relativistic plasmas are pervasive and are expected to play a crucial role in the dynamics of these systems. Despite their significance, experimental and theoretical studies of these plasmas have been limited. Here, we present the first ab initio high-resolution kinetic simulations of relativistic plasmas undergoing synchrotron cooling in a highly magnetized medium. Our results demonstrate that these plasmas spontaneously generate coherent linearly polarized radiation in a wide range of parameters via the electron cyclotron maser instability, with radiative losses altering the saturation mechanism. Thus, the plasma continuously amplify coherent radiation for substantially longer durations of time. These findings highlight fundamental differences in the behavior of relativistic plasmas in strongly magnetized environments and align with astronomical phenomena, such as pulsar emission and fast radio bursts.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 15","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adt8912","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abdelhakim Boudrioua, Joe D. Joiner, Iwan Grin, Thales Kronenberger, Vadim S. Korotkov, Wieland Steinchen, Alexander Kohler, Sophie Schminke, Julia-Christina Schulte, Michael Pietsch, Arun Naini, Simon Kalverkamp, Sven-Kevin Hotop, Travis Coyle, Claudio Piselli, Murray Coles, Katharina Rox, Matthias Marschal, Gert Bange, Antje Flieger, Antti Poso, Mark Brönstrup, Marcus D. Hartmann, Samuel Wagner
The enteric pathogen Salmonella enterica serovar Typhimurium relies on the activity of effector proteins to invade, replicate, and disseminate into host epithelial cells and other tissues, thereby causing disease. Secretion and injection of effector proteins into host cells is mediated by dedicated secretion systems, which hence represent major virulence determinants. Here, we report the identification of a synthetic small molecule with drug-like properties, C26, which suppresses the secretion of effector proteins and consequently hinders bacterial invasion of eukaryotic cells. C26 binds to and inhibits HilD, the transcriptional regulator of the major secretion systems. Although sharing the same binding pocket as the previously described long-chain fatty acid ligands, C26 inhibits HilD with a unique binding mode and a distinct mechanism. We provide evidence of intramacrophage activity and present analogs with improved potency and suitability as scaffolds to develop antivirulence agents against Salmonella infections in humans and animals.
{"title":"Discovery of synthetic small molecules targeting the central regulator of Salmonella pathogenicity","authors":"Abdelhakim Boudrioua, Joe D. Joiner, Iwan Grin, Thales Kronenberger, Vadim S. Korotkov, Wieland Steinchen, Alexander Kohler, Sophie Schminke, Julia-Christina Schulte, Michael Pietsch, Arun Naini, Simon Kalverkamp, Sven-Kevin Hotop, Travis Coyle, Claudio Piselli, Murray Coles, Katharina Rox, Matthias Marschal, Gert Bange, Antje Flieger, Antti Poso, Mark Brönstrup, Marcus D. Hartmann, Samuel Wagner","doi":"10.1126/sciadv.adr5235","DOIUrl":"10.1126/sciadv.adr5235","url":null,"abstract":"<div >The enteric pathogen <i>Salmonella enterica</i> serovar Typhimurium relies on the activity of effector proteins to invade, replicate, and disseminate into host epithelial cells and other tissues, thereby causing disease. Secretion and injection of effector proteins into host cells is mediated by dedicated secretion systems, which hence represent major virulence determinants. Here, we report the identification of a synthetic small molecule with drug-like properties, C26, which suppresses the secretion of effector proteins and consequently hinders bacterial invasion of eukaryotic cells. C26 binds to and inhibits HilD, the transcriptional regulator of the major secretion systems. Although sharing the same binding pocket as the previously described long-chain fatty acid ligands, C26 inhibits HilD with a unique binding mode and a distinct mechanism. We provide evidence of intramacrophage activity and present analogs with improved potency and suitability as scaffolds to develop antivirulence agents against <i>Salmonella</i> infections in humans and animals.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 15","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adr5235","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Karishma D''Sa, Minee L. Choi, Aaron Z. Wagen, Núria Setó-Salvia, Olga Kopach, James R. Evans, Margarida Rodrigues, Patricia Lopez-Garcia, Joanne Lachica, Benjamin E. Clarke, Jaijeet Singh, Ali Ghareeb, James Bayne, Melissa Grant-Peters, Sonia Garcia-Ruiz, Zhongbo Chen, Samuel Rodriques, Dilan Athauda, Emil K. Gustavsson, Sarah A. Gagliano Taliun, Christina Toomey, Regina H. Reynolds, George Young, Stephanie Strohbuecker, Thomas Warner, Dmitri A. Rusakov, Rickie Patani, Clare Bryant, David A. Klenerman, Sonia Gandhi, Mina Ryten
RNA editing is a posttranscriptional mechanism that targets changes in RNA transcripts to modulate innate immune responses. We report the role of astrocyte-specific, ADAR1-mediated RNA editing in neuroinflammation in Parkinson’s disease (PD). We generated human induced pluripotent stem cell–derived astrocytes, neurons and cocultures and exposed them to small soluble alpha-synuclein aggregates. Oligomeric alpha-synuclein triggered an inflammatory glial state associated with Toll-like receptor activation, viral responses, and cytokine secretion. This reactive state resulted in loss of neurosupportive functions and the induction of neuronal toxicity. Notably, interferon response pathways were activated leading to up-regulation and isoform switching of the RNA deaminase enzyme, ADAR1. ADAR1 mediates A-to-I RNA editing, and increases in RNA editing were observed in inflammatory pathways in cells, as well as in postmortem human PD brain. Aberrant, or dysregulated, ADAR1 responses and RNA editing may lead to sustained inflammatory reactive states in astrocytes triggered by alpha-synuclein aggregation, and this may drive the neuroinflammatory cascade in Parkinson’s.
{"title":"Astrocytic RNA editing regulates the host immune response to alpha-synuclein","authors":"Karishma D''Sa, Minee L. Choi, Aaron Z. Wagen, Núria Setó-Salvia, Olga Kopach, James R. Evans, Margarida Rodrigues, Patricia Lopez-Garcia, Joanne Lachica, Benjamin E. Clarke, Jaijeet Singh, Ali Ghareeb, James Bayne, Melissa Grant-Peters, Sonia Garcia-Ruiz, Zhongbo Chen, Samuel Rodriques, Dilan Athauda, Emil K. Gustavsson, Sarah A. Gagliano Taliun, Christina Toomey, Regina H. Reynolds, George Young, Stephanie Strohbuecker, Thomas Warner, Dmitri A. Rusakov, Rickie Patani, Clare Bryant, David A. Klenerman, Sonia Gandhi, Mina Ryten","doi":"10.1126/sciadv.adp8504","DOIUrl":"10.1126/sciadv.adp8504","url":null,"abstract":"<div >RNA editing is a posttranscriptional mechanism that targets changes in RNA transcripts to modulate innate immune responses. We report the role of astrocyte-specific, ADAR1-mediated RNA editing in neuroinflammation in Parkinson’s disease (PD). We generated human induced pluripotent stem cell–derived astrocytes, neurons and cocultures and exposed them to small soluble alpha-synuclein aggregates. Oligomeric alpha-synuclein triggered an inflammatory glial state associated with Toll-like receptor activation, viral responses, and cytokine secretion. This reactive state resulted in loss of neurosupportive functions and the induction of neuronal toxicity. Notably, interferon response pathways were activated leading to up-regulation and isoform switching of the RNA deaminase enzyme, ADAR1. ADAR1 mediates A-to-I RNA editing, and increases in RNA editing were observed in inflammatory pathways in cells, as well as in postmortem human PD brain. Aberrant, or dysregulated, ADAR1 responses and RNA editing may lead to sustained inflammatory reactive states in astrocytes triggered by alpha-synuclein aggregation, and this may drive the neuroinflammatory cascade in Parkinson’s.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 15","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adp8504","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
High-capacity stretchable batteries are crucial for next-generation wearables to enable long-term operation and mechanical conformability with the human user. In existing stretchable battery designs, increasing the active material to yield higher capacity often leads to thicker and stiffer solid electrodes with poor mechanical properties. Here, we present a concept that transfers the physical property of a battery electrode from a conventional solid into a fluid state. The mechanical and electrochemical properties of the electrode rely on the viscosity of fluids rather than Young’s modulus of solids. Fluids conform easily into any shape with minimal force, making them intrinsically deformable. This decouples the electrochemical and mechanical property of the redox-active electrofluid, leading to higher capacities with more active material loading without stiffening the cell. The cell showed excellent capacity retention over 500 charge-discharge cycles and mechanical robustness up to 100% strain. Our work provides a technological solution for stretchable batteries that balances capacity and mechanical performance.
{"title":"Make it flow from solid to liquid: Redox-active electrofluids for intrinsically stretchable batteries","authors":"Mohsen Mohammadi, Saeed Mardi, Jaywant Phopase, Filippa Wentz, Jibin J. Samuel, Ujwala Ail, Magnus Berggren, Reverant Crispin, Klas Tybrandt, Aiman Rahmanudin","doi":"10.1126/sciadv.adr9010","DOIUrl":"10.1126/sciadv.adr9010","url":null,"abstract":"<div >High-capacity stretchable batteries are crucial for next-generation wearables to enable long-term operation and mechanical conformability with the human user. In existing stretchable battery designs, increasing the active material to yield higher capacity often leads to thicker and stiffer solid electrodes with poor mechanical properties. Here, we present a concept that transfers the physical property of a battery electrode from a conventional solid into a fluid state. The mechanical and electrochemical properties of the electrode rely on the viscosity of fluids rather than Young’s modulus of solids. Fluids conform easily into any shape with minimal force, making them intrinsically deformable. This decouples the electrochemical and mechanical property of the redox-active electrofluid, leading to higher capacities with more active material loading without stiffening the cell. The cell showed excellent capacity retention over 500 charge-discharge cycles and mechanical robustness up to 100% strain. Our work provides a technological solution for stretchable batteries that balances capacity and mechanical performance.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 15","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adr9010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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