eLife最新文献

{"title":"A bacterial regulatory uORF senses multiple classes of ribosome-targeting antibiotics.","authors":"Gabriele Baniulyte, Joseph T Wade","doi":"10.7554/eLife.101217","DOIUrl":"https://doi.org/10.7554/eLife.101217","url":null,"abstract":"<p><p>Expression of many bacterial genes is regulated by <i>cis</i>- and <i>trans</i>-acting elements in their 5' upstream regions (URs). <i>Cis</i>-acting regulatory elements in URs include upstream ORFs (uORFs), short ORFs that sense translation stress that manifests as ribosomes stalling at specific codons within the uORF. Here, we show that the transcript encoding the <i>Escherichia coli</i> TopAI-YjhQ toxin-antitoxin system is regulated by a uORF that we name '<i>toiL'</i>. We propose that in the absence of translation stress, a secondary structure in the UR represses translation of the <i>topAI</i> transcript by occluding the ribosome-binding site. Translation repression of <i>topAI</i> leads to premature Rho-dependent transcription termination within the <i>topAI</i> ORF. At least five different classes of ribosome-targeting antibiotics relieve repression of <i>topAI</i>. Our data suggest that these antibiotics function by stalling ribosomes at different positions within <i>toiL</i>, thereby altering the RNA secondary structure around the <i>topAI</i> ribosome-binding site. Thus, <i>toiL</i> is a multipurpose uORF that can respond to a wide variety of translation stresses.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Menopausal hormone therapy and the female brain: Leveraging neuroimaging and prescription registry data from the UK Biobank cohort.","authors":"Claudia Barth, Liisa A M Galea, Emily G Jacobs, Bonnie H Lee, Lars T Westlye, Ann-Marie G de Lange","doi":"10.7554/eLife.99538","DOIUrl":"https://doi.org/10.7554/eLife.99538","url":null,"abstract":"<p><strong>Background: </strong>Menopausal hormone therapy (MHT) is generally thought to be neuroprotective, yet results have been inconsistent. Here, we present a comprehensive study of MHT use and brain characteristics in females from the UK Biobank.</p><p><strong>Methods: </strong>19,846 females with magnetic resonance imaging data were included. Detailed MHT prescription data from primary care records was available for 538. We tested for associations between the brain measures (i.e. gray/white matter brain age, hippocampal volumes, white matter hyperintensity volumes) and MHT user status, age at first and last use, duration of use, formulation, route of administration, dosage, type, and active ingredient. We further tested for the effects of a history of hysterectomy ± bilateral oophorectomy among MHT users and examined associations by APOE ε4 status.</p><p><strong>Results: </strong>Current MHT users, not past users, showed older gray and white matter brain age, with a difference of up to 9 mo, and smaller hippocampal volumes compared to never-users. Longer duration of use and older age at last use post-menopause was associated with older gray and white matter brain age, larger white matter hyperintensity volume, and smaller hippocampal volumes. MHT users with a history of hysterectomy ± bilateral oophorectomy showed <i>younger</i> gray matter brain age relative to MHT users without such history. We found no associations by APOE ε4 status and with other MHT variables.</p><p><strong>Conclusions: </strong>Our results indicate that population-level associations between MHT use and female brain health might vary depending on duration of use and past surgical history.</p><p><strong>Funding: </strong>The authors received funding from the Research Council of Norway (LTW: 223273, 249795, 273345, 298646, 300768), the South-Eastern Norway Regional Health Authority (CB: 2023037, 2022103; LTW: 2018076, 2019101), the European Research Council under the European Union's Horizon 2020 research and innovation program (LTW: 802998), the Swiss National Science Foundation (AMGdL: PZ00P3_193658), the Canadian Institutes for Health Research (LAMG: PJT-173554), the Treliving Family Chair in Women's Mental Health at the Centre for Addiction and Mental Health (LAMG), womenmind at the Centre for Addiction and Mental Health (LAMG, BHL), the Ann S. Bowers Women's Brain Health Initiative (EGJ), and the National Institutes of Health (EGJ: AG063843).</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transdiagnostic compulsivity is associated with reduced reminder setting, only partially attributable to overconfidence.","authors":"Annika Boldt, Celine Ann Fox, Claire M Gillan, Sam Gilbert","doi":"10.7554/eLife.98114","DOIUrl":"https://doi.org/10.7554/eLife.98114","url":null,"abstract":"<p><p>In the current study, we explored the behavioural and cognitive correlates of the transdiagnostic trait 'compulsive behaviour and intrusive thought' (CIT) in humans. CIT is associated with impaired metacognition, which in turn has been associated with cognitive offloading behaviours such as external reminder setting that play a key role in fulfilling cognitive goals. In an online study (<i>N</i>=600), we investigated individual differences in compulsivity, metacognition, and external reminder usage. Compulsive individuals had reduced preference for external reminders. This was partially, but not fully, attributable to their relative overconfidence. In contrast to previous studies, we found no evidence for an impaired confidence-action link: compulsive individuals used their metacognition to guide offloading just as much as their non-compulsive counterparts. Given the compensatory nature of cognitive offloading, our findings imply that compulsive individuals are at increased risk of inadequate external memory support. Along with transdiagnostic variation in the general population, this finding could also have implications for clinical conditions, such as obsessive-compulsive disorder (OCD).</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Force transmission through the inner kinetochore is enhanced by centromeric DNA sequences.","authors":"Elise Miedlar, Grace E Hamilton, Samuel R Witus, Sara J Gonske, Michael Riffle, Alex Zelter, Rachel E Klevit, Charles L Asbury, Yoana N Dimitrova, Trisha N Davis","doi":"10.7554/eLife.105150","DOIUrl":"https://doi.org/10.7554/eLife.105150","url":null,"abstract":"<p><p>Previously, we reconstituted a minimal functional kinetochore from recombinant <i>Saccharomyces cerevisiae</i> proteins that was capable of transmitting force from dynamic microtubules to nucleosomes containing the centromere-specific histone variant Cse4 (Hamilton et al., 2020). This work revealed two paths of force transmission through the inner kinetochore: through Mif2 and through the Okp1/Ame1 complex (OA). Here, using a chimeric DNA sequence that contains crucial centromere-determining elements of the budding yeast point centromere, we demonstrate that the presence of centromeric DNA sequences in Cse4-containing nucleosomes significantly strengthens OA-mediated linkages. Our findings indicate that centromeric sequences are important for the transmission of microtubule-based forces to the chromosome.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of p38-MK2 pathway enhances the efficacy of microtubule inhibitors in breast cancer cells.","authors":"Yu-Chia Chen, Mamoru Takada, Aerica Nagornyuk, Muhan Yu, Hideyuki Yamada, Takeshi Nagashima, Masayuki Ohtsuka, Jennifer G DeLuca, Steven M Markus, Motoki Takaku, Aussie Suzuki","doi":"10.7554/eLife.104859","DOIUrl":"https://doi.org/10.7554/eLife.104859","url":null,"abstract":"<p><p>Microtubule-targeting agents (MTAs) are widely used as first- and second-line chemotherapies for various cancers. However, current MTAs exhibit positive responses only in subsets of patients and are often accompanied by side effects due to their impact on normal cells. This underscores an urgent need to develop novel therapeutic strategies that enhance MTA efficacy while minimizing toxicity to normal tissues. Here, we demonstrate that inhibition of the p38 MAPK-MK2 signaling pathway sensitizes cancer cells to MTA treatment. We utilize CMPD1, a dual-target inhibitor, to concurrently suppress the p38-MK2 pathway and microtubule dynamicity. In addition to its established role as an MK2 inhibitor, we find that CMPD1 rapidly induces microtubule depolymerization, preferentially at the microtubule plus end, leading to the inhibition of tumor growth and cancer cell invasion in both <i>in vitro</i> and <i>in vivo</i> models. Notably, 10 nM CMPD1 is sufficient to induce irreversible mitotic defects in cancer cells, but not in non-transformed normal cells, highlighting its high specificity to cancer cells. We further validate that a specific p38-MK2 inhibitor significantly potentiates the efficacy of subclinical concentrations of MTA. In summary, our findings suggest that the p38-MK2 pathway presents a promising therapeutic target in combination with MTAs in cancer treatment.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A back-up mechanism for replication.","authors":"Godefroid Charbon, Anders Løbner-Olesen","doi":"10.7554/eLife.107379","DOIUrl":"https://doi.org/10.7554/eLife.107379","url":null,"abstract":"<p><p>A protein called PriC allows DNA replication to proceed in <i>Escherichia coli</i> when the complex that usually initiates this process is compromised.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AgRP1 modulates breeding season-dependent feeding behavior in female medaka.","authors":"Yurika Tagui, Shingo Takeda, Hiroyo Waida, Shoichi Kitahara, Tomoki Kimura, Shinji Kanda, Yoshitaka Oka, Yu Hayashi, Chie Umatani","doi":"10.7554/eLife.100996","DOIUrl":"https://doi.org/10.7554/eLife.100996","url":null,"abstract":"<p><p>Feeding and reproduction are known to be closely correlated with each other, and the seasonal breeders show breeding season-dependent feeding behavior. However, most model animals do not have definite breeding seasonality, and the mechanisms for such feeding behavior remain unclear. Here, we focused on female medaka (<i>Oryzias latipes</i>); they show breeding season-dependent feeding behavior, and their condition of breeding season can be experimentally controlled by day-length. We first demonstrated that, among previously reported feeding-related peptides (neuropeptides involved in feeding), agouti-related peptide 1 (<i>agrp1</i>) and neuropeptide y b (<i>npyb</i>) show higher brain expression under the breeding condition than under the non-breeding one. Combined with analysis of <i>agrp1</i> knockout medaka, we obtained results to suggest that long day-induced sexually mature condition, especially ovarian estrogenic signals, increase the expressions of <i>agrp1</i> in the brain, which results in increased food intake to promote reproduction. Our findings advance the understanding of neural mechanisms of feeding behavior for reproductive success.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Primosomal protein PriC rescues replication initiation stress by bypassing the DnaA-DnaB interaction step for DnaB helicase loading at <i>oriC</i>.","authors":"Ryusei Yoshida, Kazuma Korogi, Qinfei Wu, Shogo Ozaki, Tsutomu Katayama","doi":"10.7554/eLife.103340","DOIUrl":"https://doi.org/10.7554/eLife.103340","url":null,"abstract":"<p><p>In <i>Escherichia coli</i>, replisome and replication fork assembly is initiated by DnaB helicase loading at the chromosomal origin <i>oriC</i> via its interactions with the DnaA initiator and the DnaC helicase loader. Upon replication fork arrest, the replisome including DnaB dissociates from the stalled fork. Replication fork progression is rescued by primosomal protein PriA- or PriC-dependent pathway in which PriA and PriC promote reloading of DnaB in different mechanisms. However, the mechanism responsible for rescue of blocked replication initiation at <i>oriC</i> remains unclear. Here, we found that PriC rescued blocked replication initiation in cells expressing an initiation-specific DnaC mutant, in mutant cells defective in DnaA-DnaB interactions, and in cells containing truncated <i>oriC</i> sequence variants. PriC rescued DnaB loading at <i>oriC</i> even in the absence of Rep helicase, a stimulator of the PriC-dependent replication fork restart pathway. These results of in vitro reconstituted assays concordantly suggest that this initiation-specific rescue mechanism provides a bypass of the DnaA-DnaB interaction for DnaB loading by PriC-promoted loading of DnaB to the unwound <i>oriC</i> region. These findings expand understanding of mechanisms sustaining the robustness of replication initiation and specific roles for PriC in the genome maintenance.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutations that prevent phosphorylation of the BMP4 prodomain impair proteolytic maturation of homodimers leading to lethality in mice.","authors":"Hyung-Seok Kim, Mary L Sanchez, Joshua Silva, Heidi L Schubert, Rebecca Dennis, Christopher P Hill, Jan L Christian","doi":"10.7554/eLife.105018","DOIUrl":"https://doi.org/10.7554/eLife.105018","url":null,"abstract":"<p><p>Bone morphogenetic protein4 (BMP4) plays numerous roles during embryogenesis and can signal either alone as a homodimer, or together with BMP7 as a more active heterodimer. BMPs are generated as inactive precursor proteins that dimerize and are cleaved to generate the bioactive ligand and inactive prodomain fragments. In humans, heterozygous mutations within the prodomain of BMP4 are associated with birth defects. We studied the effect of two of these mutations (p.S91C and p.E93G), which disrupt a conserved FAM20C phosphorylation motif, on ligand activity. We compared the activity of ligands generated from BMP4, BMP4^S91C, or BMP4^E93G in <i>Xenopus</i> embryos and found that these mutations reduce the activity of BMP4 homodimers but not BMP4/7 heterodimers. We generated <i>Bmp4^S91C</i> and <i>Bmp4^E93G</i> knock-in mice and found that <i>Bmp4^S91C/S91C</i> mice die by E11.5 and display reduced BMP activity in multiple tissues including the heart. Most <i>Bmp4^E93G/E93G</i> mice die before weaning and <i>Bmp4^-/E93G</i> mutants die prenatally with reduced or absent eyes, heart, and ventral body wall closure defects. Mouse embryonic fibroblasts (MEFs) isolated from <i>Bmp4^S91C</i> and <i>Bmp4^E93G</i> embryos show accumulation of BMP4 precursor protein, reduced levels of cleaved BMP ligand and reduced BMP activity relative to MEFs from wild type littermates. Because <i>Bmp7</i> is not expressed in MEFs, the accumulation of unprocessed BMP4 precursor protein in mice carrying these mutations most likely reflects an inability to cleave BMP4 homodimers, leading to reduced levels of ligand and BMP activity in vivo. Our results suggest that phosphorylation of the BMP4 prodomain is required for proteolytic activation of BMP4 homodimers, but not heterodimers.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144173012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brochosomes as an antireflective camouflage coating for leafhoppers.","authors":"Wei Wu, Qianzhuo Mao, Zhuang-Xin Ye, Zhenfeng Liao, Hong-Wei Shan, Jun-Min Li, Chuan-Xi Zhang, Jian-Ping Chen","doi":"10.7554/eLife.99639","DOIUrl":"10.7554/eLife.99639","url":null,"abstract":"<p><p>In nature, insects face immense predation pressure, where visual cues play a vital role in predators locating them. To counter this threat, insects employ a variety of nano- and microstructures on their cuticular layer to manipulate and interact with light, enhancing antireflective properties and providing camouflage or reducing detectability by predators. Leafhoppers have a unique extracuticular coating called brochosome, yet its antireflective functions and protein composition remain unclear. Our study demonstrates strong antireflective properties of brochosomes, effectively reducing reflectance on the cuticle surface, especially in the ultraviolet spectrum, to improve evasion from visual predators. Furthermore, we identify four novel structural proteins of the brochosome (BSM) for the first time. Inhibiting their synthesis by RNAi alters brochosome morphology, impacting the optical properties of the cuticle surface. Evolutionary origin analysis of BSM suggests that brochosomes likely originated from a process involving duplication-divergence. Our study reveals that leafhoppers employ a unique camouflage strategy by secreting brochosomes as antireflection nanocoatings, enabling them to evade natural predators and contributing to their evolutionary success.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}